Update: Follicular Lymphoma by Sarah Milgrom, MD and Rahul Parikh, MD

Originally published 9/13/2017

Brief Overview:
Follicular lymphoma (FL) is the most common indolent non-Hodgkin lymphoma.  It arises from follicle center B-cells, contains centrocytes and centroblasts, and has at least a partially follicular pattern.  The majority of cases are advanced stage at diagnosis, with frequent nodal and bone marrow involvement.  Approximately 25% of patients have localized (stage I-II) disease at the time of presentation.  FL is exquisitely radiosensitive, with high rates of disease response observed after treatment with low doses of radiation therapy (RT).  In the subset of patients with localized disease, RT may be curative; in those with advanced stage disease, RT provides effective palliation.
For patients with stage I or contiguous stage II, grade 1-2 FL, involved site RT is the treatment of choice.  Data from multiple groups have shown local control rates of >90% following definitive RT.  However, in historical series, relapse with systemic disease outside of the radiation field was common, with 10-year relapse-free and overall survival rates of approximately 50% and 70%, respectively.  A plateau in the disease-free survival curve was observed beyond 10-15 years, suggesting that a proportion of patients were cured with RT (Guadagnolo et al. 2006; MacManus et al. 1996). An important limitation of these older published series is that at least some patients were treated before metabolic imaging was used for staging.  Therefore, patients may have had undiagnosed advanced-stage disease.  Furthermore, the RT fields were more extensive and salvage options more limited, so it may be difficult to apply the data to today’s experience and prognosis discussions.  To address these concerns, ILROG recently reported the outcomes of curative RT for localized FL in patients treated in the modern era and staged with PET-CT.  They found that 5-year freedom from progression (FFP) was 70.2% and overall survival was 95.8%.  5-year FFP was 74.3% for patients with stage I disease and 48.1% for stage II (Brady et al. 2017).  Thus, outcomes after RT in these PET‐CT-staged patients were better than in some earlier series, suggesting that the curative potential of RT for truly localized FL may have been underestimated previously.
The accepted radiation doses for the management of FL were established by 2 dose de-escalation studies.  First, in the trial published by Lowry et al, patients with indolent NHL (primarily FL) were randomized to receive the historical, standard dose of 40–45 Gy or the experimental, reduced dose of 24 Gy.  No difference was observed between the arms in disease response, local progression, disease free-survival, or overall-survival rates (Lowry et al. 2011).  Thus, 24 Gy in 12 fractions became the accepted dose for definitive RT.  The reported efficacy of even lower doses of RT prompted the FORT trial, which compared outcomes after treatment to a total dose of 24 Gy in 12 fractions vs. 4 Gy in 2 fractions.  In the patients treated with just 4 Gy, the overall response rate (ORR) was 81% (48% complete response [CR] and 32% partial response [PR]).  The CR rate was higher in patients treated with 24 Gy.  However, given the high ORR, ease of administration, and minimal toxicity associated with 4 Gy, the authors concluded that this very low dose is a useful alternative to 24 Gy in instances when local control is less of a priority (Hoskin et al. 2014).
Given the potential for early-stage FL patients to experience prolonged disease-free intervals and even cure after localized RT, both the National Comprehensive Cancer Network and European Society for Medical Oncology have published guidelines recommending primary RT in this setting.  Furthermore, a modeling study presented at ASCO 2017 demonstrated that the most cost-effective treatment of early-stage, low-grade FL is frontline RT, with R-CHOP used if needed for relapsed disease (Yang et al. 2017).  Despite these recommendations and findings, only a minority of patients with stage I disease are treated with upfront RT in the United States.  The LymphoCare study was designed to collect information on treatment regimens and outcomes for patients with newly diagnosed FL in the United States.  Of the stage I patients enrolled, only 23% received RT at diagnosis and an additional 8% had RT immediately after chemotherapy, suggesting a combined modality approach (Friedberg et al. 2009).  Thus, contrary to practice guidelines, clinicians omit RT frequently in the management of stage I FL.
The role of systemic therapy, given in combination with definitive RT, is an area of ongoing study.  Recently presented phase III data suggested that treatment with CVP +/- rituximab in combination with RT resulted in superior PFS than treatment with RT alone in stage I-II, low-grade FL (MacManus et al. 2016).  Final publication of these results is eagerly anticipated to further elucidate the role of combined modality therapy in the management of early-stage, low-grade FL patients.
Selected Papers:
1) RT is effective therapy for localized, low-grade FL: 
Guadagnolo et al.  IJROBP 2006;64(3):928-34.  Long-term outcome and mortality trends in early-stage, grade 1-2 follicular lymphoma treated with radiation therapy
MacManus et al.  J Clin Oncol 1996; Apr;14(4):1282-90.  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.
Brady JL et al.  Presented at the International Conference on Malignant Lymphoma 2017.  Outcome of curative radiotherapy for localized follicular lymphoma in the era of 18F-FDG PET-CT staging: an international collaborative study on behalf of ILROG
2) Defining the optimal RT dose:
Lowry et al.  Radiother and Oncol 2011;100:86-92.  Reduced dose radiotherapy for local control in non-Hodgkin lymphoma: a randomised phase III trial
Hoskin et al. Lancet Oncol 2014;15:457-63.  4 Gy versus 24 Gy radiotherapy for patients with indolent lymphoma (FORT): a randomised phase 3 non-inferiority trial 
3) Cost-effectiveness of RT: 
Yang et al.  Presented at ASCO 2017.  Cost-effectiveness analysis of first-line treatments for early-stage low-grade follicular lymphoma
4) Patterns of care in the United States: 
Friedberg et al. J Clin Oncol. 2009 Mar 10; 27(8): 1202–1208.  Follicular Lymphoma in the United States: First Report of the National LymphoCare Study
5) Role of systemic therapy:
MacManus et al.  Presented at ASTRO 2016.  Treatment with 6 cycles of CVP or R-CVP after involved field radiation therapy (IFRT) significantly improves progression-free survival compared to IFRT alone in stage I-II low-grade follicular lymphoma: results of an international randomized trial