Follicular lymphoma (FL) is the most common indolent lymphoma subtype, accounting for about 20% of all newly diagnosed Non-Hodgkin lymphomas in the western countries (1). Patients are mostly diagnosed at advanced stage of the disease. The current standard therapy for FL is rituximab plus multi-agent chemotherapy. Rituximab, a monoclonal anti-CD20 antibody, showed single agent activity in previously untreated and also relapsed patients (2). However best “multi-agent chemotherapy” regimen is not determined yet and the research is still ongoing. Multiple retrospective series investigated the role of anthracycline containing regimens some showed an advantage of adding anthracycline to the regimen, while others did not (3, 4). An anthracycline containing regimen that consists of cyclophosphamide, doxorubicin, vincristine and prednisone (CHOP) is being most widely used so far.
In 2006, Fondazione Italiana Linfomi started a large randomized, prospective and multiinstitutional study to identify best chemotherapy regimen to combine with rituximab for first line treatment of advanced FL. They compared rituximab plus cyclophosphamide, vincristine, and prednisone (R-CVP), with R-CHOP and rituximab plus fludarabine and mitoxantrone (R-FM). Between March 2006 and September 2010, the trial included 504 patients, who were previously untreated, aged between 18 to 75 years, had an Arbor stage 2-4 disease and grade 1, 2, 3a follicular lymphoma, and had Eastern Cooperative Oncology Group performance status 0 to 2. A total of 58 centers across Italy participated in patients’ recruitment. Time to treatment failure (TTF) was primary end point of the study, described as time to date of study entry to last follow-up or to the first following events; less than partial response (PR), changing treatment for any reason, progression or relapse, or death. Secondary end points were determined as progression-free survival (PFS), overall survival (OS), response rate, and toxicity. The three study arms included eight courses of rituximab combined with eight courses of CVP or six cycles of CHOP or six cycles of FM, every three weeks.
This study demonstrated that R-CHOP and R-FM arms had similar TTF, which was statistically significantly compared to R-CVP (62% and 59% vs 46% at 3-years; p=0.003 and 0.006, respectively). There was no difference between overall response rates between three study arms (88%, 93% and 91%). Better PFS rates were obtained for R-CHOP and R-FM compared to R-CVP (68% and 63% vs 52% at 3 years). The R-FM arm had more grade 3 to 4 hematological toxicities and frequency of secondary malignancies than R-CHOP and R-CVP arm.
This study demonstrated better TTF and PFS with R-CHOP and R-FM regimens compared to R-CVP regimen in fist line treatment setting for advanced follicular lymphoma. This is the first prospective study that proved the benefit of adding an anthracycline to R-CVP regimen in the treatment of advanced FL. Maintenance rituximab treatment was recently proved to be efficient in the treatment (5) but this data was not available at the beginning of this study. Therefore the study protocol did not include rituximab maintenance.
In conclusion, R-CHOP and R-FM have similar effect in the first line treatment of advanced FL. However, R-CHOP has fewer side effects than R-FM, which makes it the treatment of choice in advanced FL.
What are the optimal chemotherapy treatment options for first line treatment of FL?
Is there any chemotherapy regimen with a new drug, which is as effective as R-CHOP, for the treatment of advanced FL?
- A clinical evaluation of the International Lymphoma Study Group classification of non-Hodgkins lymphoma. The Non Hodgkins Lymphoma Classification Project. Blood. 1997; 1;89:3909-18.
- Witzig TE, Vukov AM, Habermann TM et al. Rituximab therapy for patients with newly diagnosed, advanced-stage, follicular grade I non-Hodgkin's lymphoma: a phase II trial in the North Central Cancer Treatment Group. J Clin Oncol 2005; 23(6):1103-8. Epub 2005 Jan 18.
- Rigacci L, Federico M, Martelli M et al. The role of anthracyclines in combination chemotherapy for the treatment of follicular lymphoma: retrospective study of the Intergruppo Italiano Linfomi on 761 cases. Leuk Lymphoma 2003; 44:1911-7.
- Dana BW, Dahlberg S, Nathwani BN, et al. Long-term follow-up of patients with low-grade malignant lymphomas treated with doxorubicin-based chemotherapy or chemoimmunotherapy.. J Clin Oncol. 1993; 11:644-51.
- Salles G, Seymour JF, Offner F et al. Rituximab maintenance for 2 years in patients with high tumour burden follicular lymphoma responding to rituximab plus chemotherapy (PRIMA): a phase 3, randomised controlled trial. Lancet 2011; 377(9759):42-51. doi: 10.1016/S0140-6736(10)62175-7.
The content of this article reflects the personal opinions of the authors and is not necessarily the official position of the European Society for Medical Oncology.