Initial treatment of limited stage (I/II) follicular 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
- Peter M Mauch, MD
Peter M Mauch, MD
- Professor of Radiation Oncology
- Harvard Medical School
Follicular lymphoma (FL, previously called follicle center lymphoma) is the second most common type of non-Hodgkin lymphoma (NHL). It is the most common of the indolent NHLs defined as those lymphomas in which survival of the untreated patient is measured in years. (See "Classification of the hematopoietic neoplasms".)
Treatment of FL depends upon the stage of disease at presentation (table 1). Patients with localized (stage I) disease are candidates for radiation therapy, which is curative in approximately half of patients. In contrast, the treatment of advanced (stage III/IV) disease is not curative and focuses largely on symptom control with chemoimmunotherapy with or without radiation therapy. The management of patients with stage II FL is more variable, with some clinicians offering treatment similar to that used for stage I disease, and others offering treatment similar to that used for advanced stage disease. There is some evidence that stage II follicular lymphoma limited to two contiguous regions has a similar prognosis to stage I. (See 'Bulky stage II FL' below.)
The initial treatment of limited stage FL is discussed here. The initial treatment of advanced stage FL and the management of relapsed or refractory FL are presented separately, as are the epidemiology, clinical presentation, pathologic features, diagnosis, and pathobiology of FL. Of importance, the recommendations presented here pertain to patients with histologic grade 1, 2, or 3a FL; patients with grade 3b FL are treated as aggressive lymphomas (eg, diffuse large B cell lymphoma). (See "Initial treatment of advanced stage (III/IV) follicular lymphoma" and "Treatment of relapsed or refractory follicular lymphoma" and "Clinical manifestations, pathologic features, diagnosis, and prognosis of follicular lymphoma" and "Pathobiology of follicular lymphoma", section on 'Introduction' and "Pathobiology of follicular lymphoma".)
The initial evaluation of a patient with non-Hodgkin lymphoma (NHL) must establish the precise histologic subtype, the extent and sites of disease, and the performance status of the patient. These investigations are important for determining the treatment strategy and for predicting outcome with the Follicular Lymphoma International Prognostic Index (FLIPI) or one of its variants. General approaches to the diagnostic work-up and staging of NHL are presented separately (table 1). (See "Clinical presentation and diagnosis of non-Hodgkin lymphoma" and "Evaluation and staging of non-Hodgkin lymphoma".)
Once a diagnosis and pathologic grade of follicular lymphoma (FL) is confirmed, the pre-treatment evaluation both determines the extent of the disease and provides information about the individual's comorbidities that are likely to have an impact on treatment options. Of particular importance, information gathered from this evaluation is used to determine the patient's Follicular Lymphoma International Prognostic Index (FLIPI) (table 2) score, which determines whether the patient is at low, intermediate, or high risk for progression. (See "Clinical manifestations, pathologic features, diagnosis, and prognosis of follicular lymphoma", section on 'Follicular lymphoma IPI (FLIPI)'.)
- Luminari S, Biasoli I, Arcaini L, et al. The use of FDG-PET in the initial staging of 142 patients with follicular lymphoma: a retrospective study from the FOLL05 randomized trial of the Fondazione Italiana Linfomi. Ann Oncol 2013; 24:2108.
- Anderson T, Chabner BA, Young RC, et al. Malignant lymphoma. 1. The histology and staging of 473 patients at the National Cancer Institute. Cancer 1982; 50:2699.
- Friedberg JW, Taylor MD, Cerhan JR, et al. Follicular lymphoma in the United States: first report of the national LymphoCare study. J Clin Oncol 2009; 27:1202.
- Krikorian JG, Portlock CS, Cooney P, Rosenberg SA. Spontaneous regression of non-Hodgkin's lymphoma: a report of nine cases. Cancer 1980; 46:2093.
- Friedberg JW, Byrtek M, Link BK, et al. Effectiveness of first-line management strategies for stage I follicular lymphoma: analysis of the National LymphoCare Study. J Clin Oncol 2012; 30:3368.
- Guadagnolo BA, Li S, Neuberg D, et al. Long-term outcome and mortality trends in early-stage, Grade 1-2 follicular lymphoma treated with radiation therapy. Int J Radiat Oncol Biol Phys 2006; 64:928.
- Seymour JF, Pro B, Fuller LM, et al. Long-term follow-up of a prospective study of combined modality therapy for stage I-II indolent non-Hodgkin's lymphoma. J Clin Oncol 2003; 21:2115.
- http://www.nccn.org/professionals/physician_gls/f_guidelines.asp (Accessed on June 06, 2012).
- 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.
- McLaughlin P, Fuller LM, Velasquez WS, et al. Stage I-II follicular lymphoma. Treatment results for 76 patients. Cancer 1986; 58:1596.
- Fung CY, Tarbell NJ, Lucarelli MJ, et al. Ocular adnexal lymphoma: clinical behavior of distinct World Health Organization classification subtypes. Int J Radiat Oncol Biol Phys 2003; 57:1382.
- Zhou P, Ng AK, Silver B, et al. Radiation therapy for orbital lymphoma. Int J Radiat Oncol Biol Phys 2005; 63:866.
- Mac Manus MP, Hoppe RT. Is radiotherapy curative for stage I and II low-grade follicular lymphoma? Results of a long-term follow-up study of patients treated at Stanford University. J Clin Oncol 1996; 14:1282.
- Wilder RB, Jones D, Tucker SL, et al. Long-term results with radiotherapy for Stage I-II follicular lymphomas. Int J Radiat Oncol Biol Phys 2001; 51:1219.
- Pugh TJ, Ballonoff A, Newman F, Rabinovitch R. Improved survival in patients with early stage low-grade follicular lymphoma treated with radiation: a Surveillance, Epidemiology, and End Results database analysis. Cancer 2010; 116:3843.
- Monfardini S, Banfi A, Bonadonna G, et al. Improved five year survival after combined radiotherapy-chemotherapy for stage I-II non-Hodgkin's lymphoma. Int J Radiat Oncol Biol Phys 1980; 6:125.
- Toonkel LM, Fuller LM, Gamble JF, et al. Laparotomy staged I and II non-Hodgkin's lymphomas: preliminary results of radiotherapy and adjunctive chemotherapy. Cancer 1980; 45:249.
- Kelsey SM, Newland AC, Hudson GV, Jelliffe AM. A British National Lymphoma Investigation randomised trial of single agent chlorambucil plus radiotherapy versus radiotherapy alone in low grade, localised non-Hodgkins lymphoma. Med Oncol 1994; 11:19.
- Murtha AD, Rupnow BA, Hansosn J, et al. Long-term follow-up of patients with Stage III follicular lymphoma treated with primary radiotherapy at Stanford University. Int J Radiat Oncol Biol Phys 2001; 49:3.
- Lybeert ML, Meerwaldt JH, Deneve W. Long-term results of low dose total body irradiation for advanced non-Hodgkin lymphoma. Int J Radiat Oncol Biol Phys 1987; 13:1167.
- Campbell BA, Voss N, Woods R, et al. Long-term outcomes for patients with limited stage follicular lymphoma: involved regional radiotherapy versus involved node radiotherapy. Cancer 2010; 116:3797.
- 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.
- Hoskin PJ, Kirkwood AA, Popova B, et al. 4 Gy versus 24 Gy radiotherapy for patients with indolent lymphoma (FORT): a randomised phase 3 non-inferiority trial. Lancet Oncol 2014; 15:457.
- Advani R, Rosenberg SA, Horning SJ. Stage I and II follicular non-Hodgkin's lymphoma: long-term follow-up of no initial therapy. J Clin Oncol 2004; 22:1454.
- Soubeyran P, Eghbali H, Trojani M, et al. Is there any place for a wait-and-see policy in stage I0 follicular lymphoma? A study of 43 consecutive patients in a single center. Ann Oncol 1996; 7:713.
- Bosga-Bouwer AG, van Imhoff GW, Boonstra R, et al. Follicular lymphoma grade 3B includes 3 cytogenetically defined subgroups with primary t(14;18), 3q27, or other translocations: t(14;18) and 3q27 are mutually exclusive. Blood 2003; 101:1149.
- Hans CP, Weisenburger DD, Vose JM, et al. A significant diffuse component predicts for inferior survival in grade 3 follicular lymphoma, but cytologic subtypes do not predict survival. Blood 2003; 101:2363.
- Shustik J, Quinn M, Connors JM, et al. Follicular non-Hodgkin lymphoma grades 3A and 3B have a similar outcome and appear incurable with anthracycline-based therapy. Ann Oncol 2011; 22:1164.
- Wahlin BE, Yri OE, Kimby E, et al. Clinical significance of the WHO grades of follicular lymphoma in a population-based cohort of 505 patients with long follow-up times. Br J Haematol 2012; 156:225.
- Jegalian AG, Eberle FC, Pack SD, et al. Follicular lymphoma in situ: clinical implications and comparisons with partial involvement by follicular lymphoma. Blood 2011; 118:2976.
- Trotman J, Fournier M, Lamy T, et al. Positron emission tomography-computed tomography (PET-CT) after induction therapy is highly predictive of patient outcome in follicular lymphoma: analysis of PET-CT in a subset of PRIMA trial participants. J Clin Oncol 2011; 29:3194.
- Dupuis J, Berriolo-Riedinger A, Julian A, et al. Impact of [(18)F]fluorodeoxyglucose positron emission tomography response evaluation in patients with high-tumor burden follicular lymphoma treated with immunochemotherapy: a prospective study from the Groupe d'Etudes des Lymphomes de l'Adulte and GOELAMS. J Clin Oncol 2012; 30:4317.
- Luminari S, Biasoli I, Versari A, et al. The prognostic role of post-induction FDG-PET in patients with follicular lymphoma: a subset analysis from the FOLL05 trial of the Fondazione Italiana Linfomi (FIL). Ann Oncol 2014; 25:442.
- Tychyj-Pinel C, Ricard F, Fulham M, et al. PET/CT assessment in follicular lymphoma using standardized criteria: central review in the PRIMA study. Eur J Nucl Med Mol Imaging 2014; 41:408.
- Czuczman MS, Grillo-López AJ, McLaughlin P, et al. Clearing of cells bearing the bcl-2 [t(14;18)] translocation from blood and marrow of patients treated with rituximab alone or in combination with CHOP chemotherapy. Ann Oncol 2001; 12:109.
- Rambaldi A, Lazzari M, Manzoni C, et al. Monitoring of minimal residual disease after CHOP and rituximab in previously untreated patients with follicular lymphoma. Blood 2002; 99:856.
- López-Guillermo A, Cabanillas F, McLaughlin P, et al. The clinical significance of molecular response in indolent follicular lymphomas. Blood 1998; 91:2955.
- van Oers MH, Tönnissen E, Van Glabbeke M, et al. BCL-2/IgH polymerase chain reaction status at the end of induction treatment is not predictive for progression-free survival in relapsed/resistant follicular lymphoma: results of a prospective randomized EORTC 20981 phase III intergroup study. J Clin Oncol 2010; 28:2246.
- Goff L, Summers K, Iqbal S, et al. Quantitative PCR analysis for Bcl-2/IgH in a phase III study of Yttrium-90 Ibritumomab Tiuxetan as consolidation of first remission in patients with follicular lymphoma. J Clin Oncol 2009; 27:6094.
- Ladetto M, Lobetti-Bodoni C, Mantoan B, et al. Persistence of minimal residual disease in bone marrow predicts outcome in follicular lymphomas treated with a rituximab-intensive program. Blood 2013; 122:3759.
- Galimberti S, Luminari S, Ciabatti E, et al. Minimal Residual Disease after Conventional Treatment Significantly Impacts on Progression-Free Survival of Patients with Follicular Lymphoma: The FIL FOLL05 Trial. Clin Cancer Res 2014; 20:6398.
- PRE-TREATMENT EVALUATION
- INITIAL MANAGEMENT
- Radiation therapy
- - Radiation field
- - Radiation dose
- Chemoimmunotherapy or immunotherapy alone
- SPECIAL SITUATIONS
- Grade 3 FL
- Bulky stage II FL
- Intrafollicular neoplasia ("in-situ") FL
- Primary intestinal FL
- Primary cutaneous FL
- EVALUATION OF RESPONSE TO THERAPY
- SURVEILLANCE FOR RELAPSE
- CLINICAL TRIALS
- HISTOLOGIC TRANSFORMATION
- INFORMATION FOR PATIENTS
- SUMMARY AND RECOMMENDATIONS