Initial treatment of limited stage diffuse large B cell lymphoma
- Arnold S Freedman, MD
Arnold S Freedman, MD
- Section Editor — Lymphoproliferative Disorders
- Professor of Medicine
- Harvard Medical School
- Jonathan W Friedberg, MD
Jonathan W Friedberg, MD
- Professor of Medicine
- James P Wilmot Cancer Center, University of Rochester
Diffuse large B cell lymphoma (DLBCL) is the most common histologic subtype of non-Hodgkin lymphoma (NHL), accounting for approximately 30 percent of patients with NHL [1-4]. It is an aggressive NHL in which survival without treatment is measured in months. (See "Classification of the hematopoietic neoplasms".)
The initial treatment of DLBCL is dependent upon the extent of disease. The staging system used for NHL focuses on the number of tumor sites (nodal and extranodal) and their location (table 1). For treatment purposes, patients with DLBCL are generally classified as having either limited stage disease or advanced stage disease based upon whether or not the tumor can be contained within one irradiation field:
●Limited stage disease (usually stage I or II) – Limited stage DLBCL can be contained within one irradiation field. This population accounts for 30 to 40 percent of patients with DLBCL. Limited stage DLBCL is treated primarily with combined modality therapy consisting of abbreviated systemic chemotherapy (three cycles), the recombinant anti-CD20 antibody rituximab, and involved field radiation therapy. Alternatively, full course (six to eight cycles) systemic chemotherapy plus rituximab without radiation therapy may be used.
●Advanced stage disease (usually stage III or IV) – Advanced stage DLBCL cannot be contained within one irradiation field. This population accounts for 60 to 70 percent of patients with DLBCL. Advanced stage DLBCL is treated with systemic chemotherapy plus the recombinant anti-CD20 antibody rituximab. (See "Initial treatment of advanced stage diffuse large B cell lymphoma".)
Patients with bulky (>10 cm) stage II disease and patients with stage IIB disease have a less favorable prognosis than those with non-bulky stage II disease without systemic B symptoms. Many clinicians treat such patients in a similar fashion to those with advanced stage disease. (See 'Bulky disease' below.)
- Harris NL, Jaffe ES, Stein H, et al. A revised European-American classification of lymphoid neoplasms: a proposal from the International Lymphoma Study Group. Blood 1994; 84:1361.
- Harris NL, Jaffe ES, Diebold J, et al. World Health Organization classification of neoplastic diseases of the hematopoietic and lymphoid tissues: report of the Clinical Advisory Committee meeting-Airlie House, Virginia, November 1997. J Clin Oncol 1999; 17:3835.
- Armitage JO, Weisenburger DD. New approach to classifying non-Hodgkin's lymphomas: clinical features of the major histologic subtypes. Non-Hodgkin's Lymphoma Classification Project. J Clin Oncol 1998; 16:2780.
- World Health Organization Classification of Tumours of Haematopoietic and Lymphoid Tissues, Swerdlow SH, Campo E, Harris NL, et al. (Eds), IARC Press, Lyon 2008.
- Miller TP. The limits of limited stage lymphoma. J Clin Oncol 2004; 22:2982.
- Pfreundschuh M, Trümper L, Osterborg A, et al. 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.
- Miller TP, Dahlberg S, Cassady JR, et al. Chemotherapy alone compared with chemotherapy plus radiotherapy for localized intermediate- and high-grade non-Hodgkin's lymphoma. N Engl J Med 1998; 339:21.
- Stephens DM, Li H, LeBlanc ML, et al. Continued Risk of Relapse Independent of Treatment Modality in Limited-Stage Diffuse Large B-Cell Lymphoma: Final and Long-Term Analysis of Southwest Oncology Group Study S8736. J Clin Oncol 2016; 34:2997.
- Persky DO, Unger JM, Spier CM, et al. Phase II study of rituximab plus three cycles of CHOP and involved-field radiotherapy for patients with limited-stage aggressive B-cell lymphoma: Southwest Oncology Group study 0014. J Clin Oncol 2008; 26:2258.
- Reyes F, Lepage E, Ganem G, et al. ACVBP versus CHOP plus radiotherapy for localized aggressive lymphoma. N Engl J Med 2005; 352:1197.
- Bonnet C, Fillet G, Mounier N, et al. CHOP alone compared with CHOP plus radiotherapy for localized aggressive lymphoma in elderly patients: a study by the Groupe d'Etude des Lymphomes de l'Adulte. J Clin Oncol 2007; 25:787.
- Phan J, Mazloom A, Medeiros LJ, et al. Benefit of consolidative radiation therapy in patients with diffuse large B-cell lymphoma treated with R-CHOP chemotherapy. J Clin Oncol 2010; 28:4170.
- Hong J, Kim AJ, Park JS, et al. Additional rituximab-CHOP (R-CHOP) versus involved-field radiotherapy after a brief course of R-CHOP in limited, non-bulky diffuse large B-cell lymphoma: a retrospective analysis. Korean J Hematol 2010; 45:253.
- Dunleavy K, Mikhaeel G, Sehn LH, et al. The value of positron emission tomography in prognosis and response assessment in non-Hodgkin lymphoma. Leuk Lymphoma 2010; 51 Suppl 1:28.
- Ballonoff A, Rusthoven KE, Schwer A, et al. Outcomes and effect of radiotherapy in patients with stage I or II diffuse large B-cell lymphoma: a surveillance, epidemiology, and end results analysis. Int J Radiat Oncol Biol Phys 2008; 72:1465.
- Chen MG, Prosnitz LR, Gonzalez-Serva A, Fischer DB. Results of radiotherapy in control of stage I and II non-Hodgkin's lymphoma. Cancer 1979; 43:1245.
- Jones SE, Miller TP, Connors JM. Long-term follow-up and analysis for prognostic factors for patients with limited-stage diffuse large-cell lymphoma treated with initial chemotherapy with or without adjuvant radiotherapy. J Clin Oncol 1989; 7:1186.
- Miller TP, LeBlanc M, Spier C, et al. CHOP alone compared to CHOP plus radiotherapy for early stage aggressive non-Hodgkin's lymphomas: update of the Soutwest Oncology Group (SWOG) randomized trial (abstract). Blood 2001; 98:724.
- Horning SJ, Weller E, Kim K, et al. 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.
- Wilder RB, Tucker SL, Ha CS, et al. Dose-response analysis for radiotherapy delivered to patients with intermediate-grade and large-cell immunoblastic lymphomas that have completely responded to CHOP-based induction chemotherapy. Int J Radiat Oncol Biol Phys 2001; 49:17.
- Connors JM, Klimo P, Fairey RN, Voss N. Brief chemotherapy and involved field radiation therapy for limited-stage, histologically aggressive lymphoma. Ann Intern Med 1987; 107:25.
- Yamashita H, Izutsu K, Nakamura N, et al. Treatment results of chemoradiation therapy for localized aggressive lymphomas: A retrospective 20-year study. Ann Hematol 2006; 85:523.
- Lowry L, Smith P, Qian W, et al. Reduced dose radiotherapy for local control in non-Hodgkin lymphoma: a randomised phase III trial. Radiother Oncol 2011; 100:86.
- Yu JI, Nam H, Ahn YC, et al. Involved-lesion radiation therapy after chemotherapy in limited-stage head-and-neck diffuse large B cell lymphoma. Int J Radiat Oncol Biol Phys 2010; 78:507.
- Campbell BA, Connors JM, Gascoyne RD, et al. Limited-stage diffuse large B-cell lymphoma treated with abbreviated systemic therapy and consolidation radiotherapy: involved-field versus involved-node radiotherapy. Cancer 2012; 118:4156.
- Kaminski MS, Coleman CN, Colby TV, et al. Factors predicting survival in adults with stage I and II large-cell lymphoma treated with primary radiation therapy. Ann Intern Med 1986; 104:747.
- Sweet DL, Kinzie J, Gaeke ME, et al. Survival of patients with localized diffuse histiocytic lymphoma. Blood 1981; 58:1218.
- Spicer J, Smith P, Maclennan K, et al. Long-term follow-up of patients treated with radiotherapy alone for early-stage histologically aggressive non-Hodgkin's lymphoma. Br J Cancer 2004; 90:1151.
- Longo DL, Glatstein E, Duffey PL, et al. Treatment of localized aggressive lymphomas with combination chemotherapy followed by involved-field radiation therapy. J Clin Oncol 1989; 7:1295.
- Tondini C, Zanini M, Lombardi F, et al. Combined modality treatment with primary CHOP chemotherapy followed by locoregional irradiation in stage I or II histologically aggressive non-Hodgkin's lymphomas. J Clin Oncol 1993; 11:720.
- Armitage JO, Cheson BD. Interpretation of clinical trials in diffuse large-cell lymphoma. J Clin Oncol 1988; 6:1335.
- Shikama N, Ikeda H, Nakamura S, et al. Localized aggressive non-Hodgkin's lymphoma of the nasal cavity: a survey by the Japan Lymphoma Radiation Therapy Group. Int J Radiat Oncol Biol Phys 2001; 51:1228.
- Armitage JO. How I treat patients with diffuse large B-cell lymphoma. Blood 2007; 110:29.
- Pfreundschuh M, Ho AD, Cavallin-Stahl E, et al. Prognostic significance of maximum tumour (bulk) diameter in young patients with good-prognosis diffuse large-B-cell lymphoma treated with CHOP-like chemotherapy with or without rituximab: an exploratory analysis of the MabThera International Trial Group (MInT) study. Lancet Oncol 2008; 9:435.
- Hasselblom S, Ridell B, Wedel H, et al. Testicular lymphoma--a retrospective, population-based, clinical and immunohistochemical study. Acta Oncol 2004; 43:758.
- Gundrum JD, Mathiason MA, Moore DB, Go RS. Primary testicular diffuse large B-cell lymphoma: a population-based study on the incidence, natural history, and survival comparison with primary nodal counterpart before and after the introduction of rituximab. J Clin Oncol 2009; 27:5227.
- Zucca E, Conconi A, Mughal TI, et al. Patterns of outcome and prognostic factors in primary large-cell lymphoma of the testis in a survey by the International Extranodal Lymphoma Study Group. J Clin Oncol 2003; 21:20.
- Takahashi H, Tomita N, Yokoyama M, et al. Prognostic impact of extranodal involvement in diffuse large B-cell lymphoma in the rituximab era. Cancer 2012; 118:4166.
- Connors JM, Klimo P, Voss N, et al. Testicular lymphoma: improved outcome with early brief chemotherapy. J Clin Oncol 1988; 6:776.
- Tondini C, Ferreri AJ, Siracusano L, et al. Diffuse large-cell lymphoma of the testis. J Clin Oncol 1999; 17:2854.
- Visco C, Medeiros LJ, Mesina OM, et al. Non-Hodgkin's lymphoma affecting the testis: is it curable with doxorubicin-based therapy? Clin Lymphoma 2001; 2:40.
- Avilés A, Neri N, Huerta-Guzmán J, et al. Testicular lymphoma: organ-specific treatment did not improve outcome. Oncology 2004; 67:211.
- Park BB, Kim JG, Sohn SK, et al. Consideration of aggressive therapeutic strategies for primary testicular lymphoma. Am J Hematol 2007; 82:840.
- Fonseca R, Habermann TM, Colgan JP, et al. Testicular lymphoma is associated with a high incidence of extranodal recurrence. Cancer 2000; 88:154.
- Zouhair A, Weber D, Belkacémi Y, et al. Outcome and patterns of failure in testicular lymphoma: a multicenter Rare Cancer Network study. Int J Radiat Oncol Biol Phys 2002; 52:652.
- Seymour JF, Solomon B, Wolf MM, et al. Primary large-cell non-Hodgkin's lymphoma of the testis: a retrospective analysis of patterns of failure and prognostic factors. Clin Lymphoma 2001; 2:109.
- Vitolo U, Chiappella A, Ferreri AJ, et al. First-line treatment for primary testicular diffuse large B-cell lymphoma with rituximab-CHOP, CNS prophylaxis, and contralateral testis irradiation: final results of an international phase II trial. J Clin Oncol 2011; 29:2766.
- Cheah CY, Wirth A, Seymour JF. Primary testicular lymphoma. Blood 2014; 123:486.
- Osborne BM, Robboy SJ. Lymphomas or leukemia presenting as ovarian tumors. An analysis of 42 cases. Cancer 1983; 52:1933.
- Zhao XY, Hong XN, Cao JN, et al. Clinical features and treatment outcomes of 14 cases of primary ovarian non-Hodgkin's lymphoma: a single-center experience. Med Oncol 2011; 28:1559.
- PRETREATMENT EVALUATION
- INITIAL TREATMENT
- Chemotherapy with or without radiation
- - Is radiation therapy necessary?
- - Radiation dose
- - Radiation field size
- Radiation alone
- Our general approach
- SPECIAL SCENARIOS
- Bulky disease
- Unusual sites of involvement
- - Mediastinum
- - CNS involvement
- - Testicular
- - Ovarian
- - Breast
- Double hit DLBCL
- PATIENT FOLLOW-UP
- INFORMATION FOR PATIENTS
- SUMMARY AND RECOMMENDATIONS