Editorial Comment Acta Haematol 2015;134:109–110 DOI: 10.1159/000371868
Received: January 5, 2015 Accepted after revision: January 6, 2015 Published online: April 22, 2015
Additional Support for Consolidative Radiotherapy for Diffuse Large B Cell Lymphoma in the Modern Rituximab Era Mohammad K. Khan Natia Esiashvili Christopher Flowers
In this issue of Acta Haematologica, Hu et al. [1] present a systematic review and meta-analysis of recently published series comparing the role of 6–8 cycles of R-CHOP chemotherapy with or without the addition of consolidative radiotherapy for patients with diffuse large B cell lymphoma, stages I–IV. The authors queried MEDLINE, EMBASE and the Cochrane Library databases. In addition, they also searched abstracts from ASCO, ASTRO, ASH, ECCO and ESMO from 2000 to 2013 and had a relatively stringent and appropriately defined selection and inclusion criteria. This methodology and statistical approach was appropriate and the authors also utilized internal controls with three different investigators reviewing each relevant study, with a 4th reviewer set aside to resolve any disagreements. These techniques helped to reduce bias in the identification and interpretation of studies included in the narrative review and meta-analysis. The authors initially identified 722 papers, of which only 4 studies met the prespecified stringent selection criteria. In their meta-analysis of 633 patients from these studies, the authors concluded that the addition of radiotherapy after complete response to R-CHOP statistically significantly improved overall survival (OS; hazard ratio = 0.33) and progression-free survival/event-free survival (hazard ratio = 0.24). Furthermore, in the subset of stage III/IV patients, the addition of radiotherapy statistically significantly improved local control and progression-free survival/eventfree survival, and yielded a trend toward improved OS. The role of consolidative radiotherapy after complete response to R-CHOP remains a clinically relevant ques© 2015 S. Karger AG, Basel 0001–5792/15/1342–0109$39.50/0 E-Mail [email protected] www.karger.com/aha
tion. As appropriately discussed by the authors, the National Comprehensive Cancer Center Network (NCCN) guidelines accepts 6 cycles of R-CHOP alone as being adequate treatment for many stage I–II patients, with designation that radiotherapy could be included or excluded and should be considered for bulky patients. Radiotherapy is listed as one of several options for bulky stage III/IV patients along with observation and transplant for high-risk patients after a complete response to 6 cycles of R-CHOP. As such, the use of radiotherapy varies highly from institution to institution, and the work of Hu et al. [1] adds to the limited data regarding this issue [2], especially for stage III/ IV patients where OS benefit may [3] or may not be evident. Much of the existing confusion results from the prerituximab era when the role of consolidative radiotherapy after CHOP remained incompletely defined. SWOG 8736 initially demonstrated improved OS with the addition of radiotherapy to abbreviated chemotherapy, but this improvement was lost with further follow-up due to increased systemic failures [4], despite having good local control within the radiated sites. ECOG 1484 [5], GELA LNH 93-1 [6] and GELA 93-4 [7] raised further questions about the utility of consolidative radiotherapy. However, these three trials were also fraught with controversy, particularly regarding the quality of radiotherapy delivery and, thus, they were never really able to fully answer the question [8]. Since these trials were published, additional trials demonstrating the increased efficacy of adding rituximab to CHOP [9–11] have led many to believe that the marginal Mohammad K. Khan, MD, PhD 1365 Clifton Road NE. Winship Cancer Institute, Office A1312 Atlanta, GA 30322 (USA) E-Mail drkhurram2000 @ gmail.com
Downloaded by: University Toronto Libr. 198.143.60.33 - 7/21/2015 11:43:50 PM
Emory University, Atlanta, Ga., USA
benefits of radiotherapy, if any, would be overcome with the addition of rituximab. Some of the more recent work addressing the role of radiotherapy – not included in the current paper [1] – includes the UNFOLDER, RICOVER-RT and the recently published NCCN networks meta-analysis. The RICOVER60-RT [12] prospectively (but in a nonrandomized fashion) compared those receiving radiotherapy [for bulky disease (≥7.5 cm) and extralymphatic involvement] with those not receiving radiotherapy (RICOVER60-noRTh). When analyzed on a per protocol basis, statistically significant improvement in all endpoints, including OS, was seen. Although not published, the preliminary results from the UNFOLDER trial for bulky patients (≥7.5 cm) and extranodal presentation between the ages of 18 and 60 years also suggests improvements with the addition of radiotherapy after either 6 cycles of R-CHOP-14 or R-CHOP-21. As a result, the investigators prematurely closed the chemotherapy-alone arms, while the radiotherapy arm continues to enroll [2]. Results from the UNFOLDER are much awaited and will shed further light on this topic. Additional support for consolidative radiotherapy includes the recently published observational study of 841
patients treated at NCCN institutions [13]. This analysis compared those patients who received consolidative radiotherapy after 6–8 cycles of R-CHOP with those not receiving radiotherapy, and demonstrated a statistically significant improvement in OS (91% if radiotherapy was given and 83% if not given) and failure-free survival (83 vs. 76%) [13]. When corrected for the International Prognostic Index score, B symptoms, disease bulk and response to chemotherapy, a trend towards benefit was also seen even for stage III/IV patients. In summary, future NCCN guidelines should clarify the use of consolidative radiotherapy in light of the recently published series. Additional prospective clinical trials are needed to confirm the findings and address additional radiation-related questions [radiation field (ISRT vs. INRT) design, optimal radiation dose after consolidation or partial response to chemotherapy, the role of PET/CT and interim PET response, the role of radiotherapy in the salvage/refractory setting, and pre- or posttransplant radiotherapy]. Lastly, biological surrogates, such as double-hit lymphomas, additional serum and tissue biomarkers, and improved imaging methods should be included in future clinical trials.
1 Hu C, Deng C, Zou W, Zhang G, Wang J: The role of consolidative radiotherapy after a complete response to chemotherapy in the treatment of diffuse large B-cell lymphoma in the rituximab era: results from a systematic review with a metaanalysis. Acta Hematol 2015; 134: 111–118. 2 Shi Z, Esiashvili N, Flowers C, Das S, Khan MK: Renewed interest in the role of consolidative radiotherapy in advanced stage diffuse large B-cell lymphoma. Leuk Lymphoma 2013;54:2122–2130. 3 Shi Z, Das S, Okwan-Duodu D, Esiashvili N, Flowers C, Chen Z, Wang X, Jiang K, Nastoupil LJ, Khan MK: Patterns of failure in advanced stage diffuse large B-cell lymphoma patients after complete response to R-CHOP immunochemotherapy and the emerging role of consolidative radiation therapy. Int J Radiat Oncol Biol Phys 2013;86:569–577. 4 Miller TP, Dahlberg S, Cassady JR, Adelstein DJ, Spier CM, Grogan TM, LeBlanc M, Carlin S, Chase E, Fisher RI: Chemotherapy alone compared with chemotherapy plus radiotherapy for localized intermediate- and high-grade nonHodgkin’s lymphoma. N Engl J Med 1998;339: 21–26. 5 Horning SJ, Weller E, Kim K, Earle JD, O’Connell MJ, Habermann TM, Glick JH: Chemotherapy with or without radiotherapy in limited-stage diffuse aggressive non-Hodgkin’s lymphoma: Eastern Cooperative Oncology Group study 1484. J Clin Oncol 2004;22:3032–3038. 6 Reyes F, Lepage E, Ganem G, Molina TJ, Brice P, Coiffier B, Morel P, Ferme C, Bosly A, Lederlin
110
7
8
9
10
P, Laurent G, Tilly H: ACVBP versus CHOP plus radiotherapy for localized aggressive lymphoma. N Engl J Med 2005;352:1197–1205. Feugier P, van Hoof A, Sebban C, Solal-Celigny P, Bouabdallah R, Ferme C, Christian B, Lepage E, Tilly H, Morschhauser F, Gaulard P, Salles G, Bosly A, Gisselbrecht C, Reyes F, Coiffier B: Long-term results of the R-CHOP study in the treatment of elderly patients with diffuse large B-cell lymphoma: a study by the Groupe d’Etude des Lymphomes de l’Adulte. J Clin Oncol 2005; 23:4117–4126. Bindra RS, Yahalom J: The important role of radiation therapy in early-stage diffuse large B-cell lymphoma: time to review the evidence once again. Expert Rev Anticancer Ther 2011; 11: 1367–1378. Pfreundschuh M, Trumper L, Osterborg A, Pettengell R, Trneny M, Imrie K, Ma D, Gill D, Walewski J, Zinzani PL, Stahel R, Kvaloy S, Shpilberg O, Jaeger U, Hansen M, Lehtinen T, LopezGuillermo A, Corrado C, Scheliga A, Milpied N, Mendila M, Rashford M, Kuhnt E, Loeffler M: CHOP-like chemotherapy plus rituximab versus CHOP-like chemotherapy alone in young patients with good-prognosis diffuse large-B-cell lymphoma: a randomised controlled trial by the MabThera International Trial (MInT) group. Lancet Oncol 2006;7:379–391. Coiffier B, Thieblemont C, van den Neste E, Lepeu G, Plantier I, Castaigne S, Lefort S, Marit G, Macro M, Sebban C, Belhadj K, Bordessoule D, Ferme C, Tilly H: Long-term outcome of patients
Acta Haematol 2015;134:109–110 DOI: 10.1159/000371868
in the lnh-98.5 trial, the first randomized study comparing rituximab-CHOP to standard CHOP chemotherapy in DLBCL patients: a study by the Groupe d’Etudes des Lymphomes de l’Adulte. Blood 2010;116:2040–2045. 11 Pfreundschuh M, Kuhnt E, Trumper L, Osterborg A, Trneny M, Shepherd L, Gill DS, Walewski J, Pettengell R, Jaeger U, Zinzani PL, Shpilberg O, Kvaloy S, de Nully Brown P, Stahel R, Milpied N, López-Guillermo A, Poeschel V, Grass S, Loeffler M, Murawski N; MabThera International Trial (MInT) Group: CHOP-like chemotherapy with or without rituximab in young patients with good-prognosis diffuse large-B-cell lymphoma: 6-year results of an open-label randomised study of the MabThera International Trial (MInT) group. Lancet Oncol 2011;12:1013–1022. 12 Held G, Murawski N, Ziepert M, Fleckenstein J, Poschel V, Zwick C, Bittenbring J, Hanel M, Wilhelm S, Schubert J, Schmitz N, Loffler M, Rube C, Pfreundschuh M: Role of radiotherapy to bulky disease in elderly patients with aggressive B-cell lymphoma. J Clin Oncol 2014; 32: 1112– 1118. 13 Dabaja BS, Vanderplas AM, Crosby-Thompson AL, Abel GA, Czuczman MS, Friedberg JW, Gordon LI, Kaminski M, Niland J, Millenson M, Nademanee AP, Zelenetz A, LaCasce AS, Rodriguez MA: Radiation for diffuse large B-cell lymphoma in the rituximab era: analysis of the National Comprehensive Cancer Network lymphoma outcomes project. Cancer 2014, Epub ahead of print.
Khan/Esiashvili/Flowers
Downloaded by: University Toronto Libr. 198.143.60.33 - 7/21/2015 11:43:50 PM
References
Received: January 5, 2015 Accepted after revision: January 6, 2015 Published online: April 22, 2015
Additional Support for Consolidative Radiotherapy for Diffuse Large B Cell Lymphoma in the Modern Rituximab Era Mohammad K. Khan Natia Esiashvili Christopher Flowers
In this issue of Acta Haematologica, Hu et al. [1] present a systematic review and meta-analysis of recently published series comparing the role of 6–8 cycles of R-CHOP chemotherapy with or without the addition of consolidative radiotherapy for patients with diffuse large B cell lymphoma, stages I–IV. The authors queried MEDLINE, EMBASE and the Cochrane Library databases. In addition, they also searched abstracts from ASCO, ASTRO, ASH, ECCO and ESMO from 2000 to 2013 and had a relatively stringent and appropriately defined selection and inclusion criteria. This methodology and statistical approach was appropriate and the authors also utilized internal controls with three different investigators reviewing each relevant study, with a 4th reviewer set aside to resolve any disagreements. These techniques helped to reduce bias in the identification and interpretation of studies included in the narrative review and meta-analysis. The authors initially identified 722 papers, of which only 4 studies met the prespecified stringent selection criteria. In their meta-analysis of 633 patients from these studies, the authors concluded that the addition of radiotherapy after complete response to R-CHOP statistically significantly improved overall survival (OS; hazard ratio = 0.33) and progression-free survival/event-free survival (hazard ratio = 0.24). Furthermore, in the subset of stage III/IV patients, the addition of radiotherapy statistically significantly improved local control and progression-free survival/eventfree survival, and yielded a trend toward improved OS. The role of consolidative radiotherapy after complete response to R-CHOP remains a clinically relevant ques© 2015 S. Karger AG, Basel 0001–5792/15/1342–0109$39.50/0 E-Mail [email protected] www.karger.com/aha
tion. As appropriately discussed by the authors, the National Comprehensive Cancer Center Network (NCCN) guidelines accepts 6 cycles of R-CHOP alone as being adequate treatment for many stage I–II patients, with designation that radiotherapy could be included or excluded and should be considered for bulky patients. Radiotherapy is listed as one of several options for bulky stage III/IV patients along with observation and transplant for high-risk patients after a complete response to 6 cycles of R-CHOP. As such, the use of radiotherapy varies highly from institution to institution, and the work of Hu et al. [1] adds to the limited data regarding this issue [2], especially for stage III/ IV patients where OS benefit may [3] or may not be evident. Much of the existing confusion results from the prerituximab era when the role of consolidative radiotherapy after CHOP remained incompletely defined. SWOG 8736 initially demonstrated improved OS with the addition of radiotherapy to abbreviated chemotherapy, but this improvement was lost with further follow-up due to increased systemic failures [4], despite having good local control within the radiated sites. ECOG 1484 [5], GELA LNH 93-1 [6] and GELA 93-4 [7] raised further questions about the utility of consolidative radiotherapy. However, these three trials were also fraught with controversy, particularly regarding the quality of radiotherapy delivery and, thus, they were never really able to fully answer the question [8]. Since these trials were published, additional trials demonstrating the increased efficacy of adding rituximab to CHOP [9–11] have led many to believe that the marginal Mohammad K. Khan, MD, PhD 1365 Clifton Road NE. Winship Cancer Institute, Office A1312 Atlanta, GA 30322 (USA) E-Mail drkhurram2000 @ gmail.com
Downloaded by: University Toronto Libr. 198.143.60.33 - 7/21/2015 11:43:50 PM
Emory University, Atlanta, Ga., USA
benefits of radiotherapy, if any, would be overcome with the addition of rituximab. Some of the more recent work addressing the role of radiotherapy – not included in the current paper [1] – includes the UNFOLDER, RICOVER-RT and the recently published NCCN networks meta-analysis. The RICOVER60-RT [12] prospectively (but in a nonrandomized fashion) compared those receiving radiotherapy [for bulky disease (≥7.5 cm) and extralymphatic involvement] with those not receiving radiotherapy (RICOVER60-noRTh). When analyzed on a per protocol basis, statistically significant improvement in all endpoints, including OS, was seen. Although not published, the preliminary results from the UNFOLDER trial for bulky patients (≥7.5 cm) and extranodal presentation between the ages of 18 and 60 years also suggests improvements with the addition of radiotherapy after either 6 cycles of R-CHOP-14 or R-CHOP-21. As a result, the investigators prematurely closed the chemotherapy-alone arms, while the radiotherapy arm continues to enroll [2]. Results from the UNFOLDER are much awaited and will shed further light on this topic. Additional support for consolidative radiotherapy includes the recently published observational study of 841
patients treated at NCCN institutions [13]. This analysis compared those patients who received consolidative radiotherapy after 6–8 cycles of R-CHOP with those not receiving radiotherapy, and demonstrated a statistically significant improvement in OS (91% if radiotherapy was given and 83% if not given) and failure-free survival (83 vs. 76%) [13]. When corrected for the International Prognostic Index score, B symptoms, disease bulk and response to chemotherapy, a trend towards benefit was also seen even for stage III/IV patients. In summary, future NCCN guidelines should clarify the use of consolidative radiotherapy in light of the recently published series. Additional prospective clinical trials are needed to confirm the findings and address additional radiation-related questions [radiation field (ISRT vs. INRT) design, optimal radiation dose after consolidation or partial response to chemotherapy, the role of PET/CT and interim PET response, the role of radiotherapy in the salvage/refractory setting, and pre- or posttransplant radiotherapy]. Lastly, biological surrogates, such as double-hit lymphomas, additional serum and tissue biomarkers, and improved imaging methods should be included in future clinical trials.
1 Hu C, Deng C, Zou W, Zhang G, Wang J: The role of consolidative radiotherapy after a complete response to chemotherapy in the treatment of diffuse large B-cell lymphoma in the rituximab era: results from a systematic review with a metaanalysis. Acta Hematol 2015; 134: 111–118. 2 Shi Z, Esiashvili N, Flowers C, Das S, Khan MK: Renewed interest in the role of consolidative radiotherapy in advanced stage diffuse large B-cell lymphoma. Leuk Lymphoma 2013;54:2122–2130. 3 Shi Z, Das S, Okwan-Duodu D, Esiashvili N, Flowers C, Chen Z, Wang X, Jiang K, Nastoupil LJ, Khan MK: Patterns of failure in advanced stage diffuse large B-cell lymphoma patients after complete response to R-CHOP immunochemotherapy and the emerging role of consolidative radiation therapy. Int J Radiat Oncol Biol Phys 2013;86:569–577. 4 Miller TP, Dahlberg S, Cassady JR, Adelstein DJ, Spier CM, Grogan TM, LeBlanc M, Carlin S, Chase E, Fisher RI: Chemotherapy alone compared with chemotherapy plus radiotherapy for localized intermediate- and high-grade nonHodgkin’s lymphoma. N Engl J Med 1998;339: 21–26. 5 Horning SJ, Weller E, Kim K, Earle JD, O’Connell MJ, Habermann TM, Glick JH: Chemotherapy with or without radiotherapy in limited-stage diffuse aggressive non-Hodgkin’s lymphoma: Eastern Cooperative Oncology Group study 1484. J Clin Oncol 2004;22:3032–3038. 6 Reyes F, Lepage E, Ganem G, Molina TJ, Brice P, Coiffier B, Morel P, Ferme C, Bosly A, Lederlin
110
7
8
9
10
P, Laurent G, Tilly H: ACVBP versus CHOP plus radiotherapy for localized aggressive lymphoma. N Engl J Med 2005;352:1197–1205. Feugier P, van Hoof A, Sebban C, Solal-Celigny P, Bouabdallah R, Ferme C, Christian B, Lepage E, Tilly H, Morschhauser F, Gaulard P, Salles G, Bosly A, Gisselbrecht C, Reyes F, Coiffier B: Long-term results of the R-CHOP study in the treatment of elderly patients with diffuse large B-cell lymphoma: a study by the Groupe d’Etude des Lymphomes de l’Adulte. J Clin Oncol 2005; 23:4117–4126. Bindra RS, Yahalom J: The important role of radiation therapy in early-stage diffuse large B-cell lymphoma: time to review the evidence once again. Expert Rev Anticancer Ther 2011; 11: 1367–1378. Pfreundschuh M, Trumper L, Osterborg A, Pettengell R, Trneny M, Imrie K, Ma D, Gill D, Walewski J, Zinzani PL, Stahel R, Kvaloy S, Shpilberg O, Jaeger U, Hansen M, Lehtinen T, LopezGuillermo A, Corrado C, Scheliga A, Milpied N, Mendila M, Rashford M, Kuhnt E, Loeffler M: CHOP-like chemotherapy plus rituximab versus CHOP-like chemotherapy alone in young patients with good-prognosis diffuse large-B-cell lymphoma: a randomised controlled trial by the MabThera International Trial (MInT) group. Lancet Oncol 2006;7:379–391. Coiffier B, Thieblemont C, van den Neste E, Lepeu G, Plantier I, Castaigne S, Lefort S, Marit G, Macro M, Sebban C, Belhadj K, Bordessoule D, Ferme C, Tilly H: Long-term outcome of patients
Acta Haematol 2015;134:109–110 DOI: 10.1159/000371868
in the lnh-98.5 trial, the first randomized study comparing rituximab-CHOP to standard CHOP chemotherapy in DLBCL patients: a study by the Groupe d’Etudes des Lymphomes de l’Adulte. Blood 2010;116:2040–2045. 11 Pfreundschuh M, Kuhnt E, Trumper L, Osterborg A, Trneny M, Shepherd L, Gill DS, Walewski J, Pettengell R, Jaeger U, Zinzani PL, Shpilberg O, Kvaloy S, de Nully Brown P, Stahel R, Milpied N, López-Guillermo A, Poeschel V, Grass S, Loeffler M, Murawski N; MabThera International Trial (MInT) Group: CHOP-like chemotherapy with or without rituximab in young patients with good-prognosis diffuse large-B-cell lymphoma: 6-year results of an open-label randomised study of the MabThera International Trial (MInT) group. Lancet Oncol 2011;12:1013–1022. 12 Held G, Murawski N, Ziepert M, Fleckenstein J, Poschel V, Zwick C, Bittenbring J, Hanel M, Wilhelm S, Schubert J, Schmitz N, Loffler M, Rube C, Pfreundschuh M: Role of radiotherapy to bulky disease in elderly patients with aggressive B-cell lymphoma. J Clin Oncol 2014; 32: 1112– 1118. 13 Dabaja BS, Vanderplas AM, Crosby-Thompson AL, Abel GA, Czuczman MS, Friedberg JW, Gordon LI, Kaminski M, Niland J, Millenson M, Nademanee AP, Zelenetz A, LaCasce AS, Rodriguez MA: Radiation for diffuse large B-cell lymphoma in the rituximab era: analysis of the National Comprehensive Cancer Network lymphoma outcomes project. Cancer 2014, Epub ahead of print.
Khan/Esiashvili/Flowers
Downloaded by: University Toronto Libr. 198.143.60.33 - 7/21/2015 11:43:50 PM
References
