Initial treatment of stage I follicular lymphoma

INTRODUCTION — Follicular lymphoma (FL) is the second most common type of non-Hodgkin lymphoma (NHL). It is the most common of the clinically indolent NHLs defined as those lymphomas in which survival of the untreated patient is measured in years. (See "Classification of hematopoietic neoplasms".)

Treatment of FL depends on the stage of disease at presentation (table 1). Patients with stage I disease are candidates for radiation therapy (RT), which is curative in a percentage of patients.

In contrast, patients with stage III or IV FL (sometimes called "advanced stage") are not cured with conventional therapies. Treatment of this group is more akin to the long-term management of a chronic disease with a focus on symptom control. Most patients with stage III or IV FL will receive a number of different treatment modalities (eg, immunotherapy, chemoimmunotherapy, RT) in various combinations, often separated by several years without active therapy.

The management of patients with stage II FL is more variable. We typically offer treatment similar to that used for stage III or IV FL, while other clinicians offer treatment similar to that used for stage I FL. (See "Initial treatment of stage II to IV follicular lymphoma", section on 'Stage II FL'.)

Treatment also depends on the histologic grade of the tumor as determined by the number of centroblasts per high power field. The recommendations presented here pertain to patients with histologic grade 1, 2, or 3a FL; patients with grade 3b FL are treated with regimens used for other clinically aggressive lymphomas (eg, diffuse large B cell lymphoma). (See 'Grade 3 FL' below.)

The initial treatment of stage I FL is discussed here. The initial treatment of stage II to IV 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.

●(See "Initial treatment of stage II to IV follicular lymphoma".)

●(See "Treatment of relapsed or refractory follicular lymphoma".)

●(See "Clinical manifestations, pathologic features, diagnosis, and prognosis of follicular lymphoma".)

●(See "Pathobiology of follicular lymphoma".)

PRETREATMENT EVALUATION — The pretreatment evaluation both determines the extent and aggressiveness of disease and provides information about the individual's performance status and comorbidities that are likely to have an impact on treatment options.

In addition to a history and physical examination, the following are part of our pretreatment evaluation of patients with FL:

●Review of the pathologic evaluation to confirm the adequacy of the histologic sample, confidence in the diagnosis, and assigned histologic grade.

●Laboratory studies include a complete blood count with differential, chemistries with liver and renal function and electrolytes, lactate dehydrogenase, and serologic testing for hepatitis B virus and human immunodeficiency virus (HIV). Some contributors routinely test for hepatitis C virus prior to starting systemic therapy for advanced stage disease.

●Baseline imaging can be performed using contrast-enhanced computed tomography (CT) of diagnostic quality or whole body combined fluorodeoxyglucose positron emission tomography with computed tomography (FDG PET/CT). FDG PET/CT is strongly preferred for patients with suspected stage I disease being evaluated for radiation therapy (RT) [1-3]. Since FL is a typically FDG-avid tumor, involved areas should show activity on PET scan allowing for the identification of those unlikely to be cured by RT due to more widespread disease. CT of the chest, abdomen, and pelvis is a less expensive alternative for patients who will be treated with systemic therapy. CT of the neck is added if lymph nodes in the neck are palpable on physical examination.

●For patients with suspected stage I disease, unilateral bone marrow biopsy is performed to rule out bone marrow involvement. We generally do not perform a bone marrow biopsy in patients with more advanced disease as it very rarely impacts the staging and response assessment of most patients with more advanced stage disease on imaging [4-7].

●Documentation of the stage of disease (table 1), Follicular Lymphoma International Prognostic Index (FLIPI) score (table 2), and performance status (table 3A-B).

●A study of cardiac ejection fraction (eg, echocardiogram, MUGA, cardiac MRI) should be performed if the planned chemotherapy regimen includes anthracyclines or anthracenediones.

●Individuals with childbearing potential should receive counseling about the potential effect of treatment on their fertility and options for fertility-preserving measures (eg, sperm banking). (See "Fertility and reproductive hormone preservation: Overview of care prior to gonadotoxic therapy or surgery".)

The speed with which treatment should begin varies with the individual patient's condition and treatment options. In general, it is far more important to attain accurate staging information and correct or control comorbidities than it is to immediately start therapy. Although oncologic emergencies and severe disease-related complications are more common in the clinically aggressive and highly aggressive non-Hodgkin lymphoma subtypes, the physician must always be alert to their potential presence and be prepared to deal with them urgently and effectively. (See "Clinical presentation and initial evaluation of non-Hodgkin lymphoma", section on 'Oncologic emergencies'.)

INITIAL MANAGEMENT

Our approach — Our approach to patients with stage I FL depends on the histologic grade and location of disease (algorithm 1). This approach is generally consistent with that of major guidelines, including those from the National Comprehensive Cancer Network (NCCN), the European Society of Medical Oncology (ESMO), and the British Society for Haematology [8-11].

●Stage I FL; grades 1, 2, or 3a – We prefer treatment with radiation therapy (RT) administered with curative intent as long as all involved sites can be contained within a radiation field with minimal toxicity. If RT is not feasible, we prefer initial observation. (See 'Radiation therapy (RT)' below.)

Given the relatively low dose of radiation needed for cure, there are few areas that are associated with significant radiation toxicity.

●Stage I FL; grade 3b – We prefer treatment with regimens used for other clinically aggressive lymphomas such as diffuse large B cell lymphoma. (See 'Grade 3 FL' below.)

In contrast, for patients with stage II FL of grade 1, 2, or 3a, we prefer treatment similar to that used for stage III or IV FL. Other clinicians offer radiation to a subset of these patients. (See "Initial treatment of stage II to IV follicular lymphoma", section on 'Stage II FL'.)

While the recommendations presented here apply to most patients with FL, modifications to this approach are necessary when FL arises in children, in certain extranodal locations (eg, primary intestinal FL, primary cutaneous FL), and when FL-type cells are found incidentally without true lymph node involvement (ie, "in-situ" FL). (See 'Special situations' below.)

Only approximately 15 to 30 percent of patients with FL will present with stage I or II disease [12,13]. As such, there have been few prospective trials of therapy in this population and most of the data on this subgroup of patients come from retrospective analyses. Interpretation of these studies is complicated by the rare occurrence of spontaneous complete remissions. Spontaneous partial remissions occur in approximately 20 percent of patients [14].

The following bullet points summarize the outcomes and toxicities with the main management approaches. More detailed information is provided in the sections that follow.

●Radiation therapy – RT results in 10-year overall survival (OS) rates of 60 to 80 percent; median survival is approximately 19 years [15]. Some patients may have a prolonged progression-free survival (PFS) with RT alone. Short- and long-term toxicities associated with RT are dependent on the site of disease, radiation field, and dose. Limited studies suggest adjuvant therapy that incorporates rituximab may prolong PFS but does not appear to improve survival after local RT. (See 'Radiation therapy (RT)' below.)

A retrospective analysis reported a longer PFS among patients treated with RT and rituximab when compared with those treated with RT alone; however, the follow-up was shorter in patients treated with rituximab and RT, and there were no differences in OS [16]. A randomized trial comparing RT alone versus RT plus chemotherapy reported superior PFS in the combined modality arm, although there was no apparent survival advantage [17]. (See 'Systemic therapy' below.)

●Observation – Observation is a reasonable alternative to RT if significant morbidity is expected from RT based on the location of the tumor or if the patient chooses against RT. Patients who choose this approach are expected to progress sooner than those who select immediate therapy. By postponing treatment, the patient avoids potential toxicity; however, the increased size of the tumor at the time of progression may also limit treatment options at the time of progression. This approach may be most appropriate for the many stage II patients who are not ideal candidates for RT due to the location of their disease and expected toxicities. (See 'Observation' below and "Initial treatment of stage II to IV follicular lymphoma", section on 'Stage II FL'.)

●Chemoimmunotherapy or immunotherapy – Chemoimmunotherapy or immunotherapy, with or without RT, such as that used for patients with stage III or IV FL, is best reserved for the rare patient who presents with bulky (>5 cm) stage I or II FL. With this approach, 10-year OS and PFS rates were 80 and 72 percent, in one case series [18]. Short-term toxicities depend on the regimen used but usually include immunosuppression, infections, gastrointestinal distress, and infusion-related reactions. (See 'Systemic therapy' below.)

Despite evidence demonstrating the potential for cure, observational studies suggest only a minority (27 percent) of patients with stage I disease treated in the United States receives RT as a single modality treatment [12,19,20]. Instead, patients commonly receive initial treatment with immunochemotherapy (28 percent), immunochemotherapy plus RT (13 percent), or single agent rituximab (12 percent), or are observed until progression (17 percent). These observational studies suggest differences in PFS rates with these different treatment strategies but have not demonstrated a difference in survival.

Radiation therapy (RT)

Efficacy and toxicity — Observational studies with long-term follow-up suggest that approximately half of patients presenting with stage I FL can be cured with RT. These studies reported 10-year OS rates of 60 to 80 percent, with 10-year relapse-free survival rates of 45 to 60 percent, and median survival of approximately 15 to 20 years [15,21-28].

Outcomes may be even better with modern staging and radiation protocols. The historical series described above included patients treated several decades ago, mostly before the availability of modern imaging for staging, and were primarily treated with outdated radiation fields, doses, and techniques. Patients identified as having stage I or II FL using more rigorous staging techniques have superior PFS than those identified with less rigorous staging [19]. In a multicenter retrospective study of patients staged with PET/CT and treated with definitive RT, estimated five-year freedom from progression rates were 74 percent among the 410 patients with stage I FL and 49 percent among the 102 patients with stage II FL [28,29]. The favorable results compared with historical series may in part be due to stage migration associated with more accurate staging. However, studies have had mixed results. Another retrospective study with rigorous staging did not demonstrate a difference in PFS when it compared systemic therapy versus RT in patients with stage I (HR 0.56; 95% CI 0.28-1.17) or stage II (HR 0.96; 95% CI 0.39-2.23) disease [30]. However, the wide confidence intervals illustrate the uncertainty in these estimates and the estimated 44 percent improvement in those with stage I disease would be clinically meaningful, if true. These results should be interpreted cautiously given its retrospective design and lack of treatment randomization.  

Short- and long-term toxicities associated with RT are dependent on the site of disease, radiation field, and dose. Contemporary RT strategies that use smaller radiation fields, conformal techniques with daily image guidance, and lower doses have been able to maintain local disease control rates and are expected to result in less toxicity [31,32]. Given the relative low dose of radiation needed for cure, there are few areas that are associated with significant radiation toxicity.

The following bullets describe large database analyses that have compared the outcomes of patients with stage I or II FL treated with and without RT. These studies must be interpreted with caution due to potential unobserved confounders and potential selection bias.

●An analysis of the Surveillance, Epidemiology, and End Results (SEER) database identified 6568 patients with stage I or stage II FL diagnosed from 1973 to 2004, 34 percent of whom were initially treated with RT [26]. When compared with those who did not receive RT, patients who received initial RT had superior rates of disease-specific survival at 5 (90 versus 81 percent), 10 (79 versus 66 percent), 15 (68 versus 57 percent), and 20 (63 versus 51 percent) years. OS rates were also superior among patients who received initial RT.

●In an analysis of the National Cancer Database (NCDB) that included 35,961 patients with stage I or stage II FL, 10-year survival rates were higher among patients who received RT versus those who did not (68 versus 54 percent) [33]. An association with improved survival persisted on multivariable analysis.

Radiation field — We recommend involved-site RT as per guidelines published by the International Lymphoma Radiation Oncology Group (ILROG) [34-36].

When RT is given as a single modality with curative intent, the clinical target volume (CTV) definition is more generous than in the setting of combined modality therapy in which microscopic disease is addressed by systemic therapy. As an example, in a patient with stage I FL of the groin, the CTV should include adjacent vessels that contain lymphatic tissues, as well as adjacent nodes that may harbor microscopic disease. For extranodal FL, organ involvement may be multifocal and limitations in imaging sensitivity may mandate inclusion of the whole organ as part of the CTV.

The CTV definition should be assessed on a case-by-case basis and take into account the quality and accuracy of imaging, potential changes in volume since staging imaging, patterns of the disease spread and likelihood of microscopic involvement of neighboring structures. The expansion from CTV to planning target volume (PTV) allows for uncertainties in planning or treatment delivery and is designed to ensure that the RT dose is actually delivered to the CTV. This expansion also needs to be individualized, depending on the immobilization device, body site, and patient cooperation. In general, the CTV to PTV expansion ranges from 0.5 cm to 1 cm.

Radiation dose — We recommend a radiation dose of 24 gray (Gy) in 2 Gy fractions in most patients [34]. Low dose radiation (eg, 4 Gy in two fractions) is not appropriate for treatment with curative intent. However, some clinicians may reasonably offer a palliative low dose approach to selected patients unlikely to tolerate standard dose radiation either due to comorbidities or location of involvement.

A phase 3 study evaluating the optimal radiation dose on local control randomly assigned radiation at lower doses (24 Gy in 12 fractions) or higher doses (40 to 45 Gy in 20 to 23 fractions) for 261 sites of indolent non-Hodgkin lymphoma (60 percent FL) [37]. The overall response rate was 93 percent. At a median follow-up of 5.6 years, lower dose radiation resulted in similar rates of in-field progression (hazard ratio [HR] 1.09, 95% CI 0.76-1.56), PFS (HR 1.13, 95% CI 0.73-1.75), and OS (HR 0.96, 95% CI 0.66-1.41).

Another phase 3 randomized, noninferiority trial (FoRT) compared 4 Gy in two fractions versus 24 Gy in 12 fractions as curative (40 percent) or palliative treatment of 614 sites of indolent non-Hodgkin lymphoma (86 percent FL) [38,39]. The lower radiation dose was less toxic. However, after a median follow-up of 74 months, lower dose radiation resulted in a higher rate of local progression (29 versus 9 percent).

Early results of an adaptive approach to low-dose RT have been reported [40]. Patients received 4 Gy in two fractions followed by response assessment in 8 to 12 weeks, with planned observation if a complete response is achieved. Included in the study were 52 patients with localized, potentially curable disease. Among 42 patients with an evaluable response, the two-year cumulative incidence of local progression was 9 percent at a median follow-up of 1.7 years. Given the short follow-up, small patient number in a selected group of patients, further study is needed to confirm the efficacy of this experimental approach in patients with localized disease treated with curative intent.

Observation — Observation with treatment at the time of progression (ie, watch and wait) is an acceptable treatment option for patients with stage I or II FL. This is a particularly attractive option if significant morbidity is expected from RT based on the location of the tumor or if the patient chooses against RT.

The following are the largest studies that have evaluated this approach:

●A retrospective analysis of 43 patients with stage IA or IIA FL observed for at least three months reported a median OS of 19.1 years and estimated survival rates at 5, 10, and 20 years of 97, 85, and 22 percent, respectively [41]. After a median follow-up of 7.2 years, 27 patients (63 percent) had not yet required treatment; the median time to treatment for the other 16 patients was 22 months.

●Another retrospective analysis of 43 consecutive patients with stage I FL with no residual tumor following the initial diagnostic surgery included 26 patients who were observed initially and 17 who underwent involved-field RT with or without chemotherapy [42]. After a median follow-up of 6.3 years, 13 of the 26 patients had not relapsed after observation alone. Six had relapsed locally at a median of 4.2 years from diagnosis, all of whom achieved a second complete remission with RT. Seven relapsed in a distant location after a median of one year. Of the patients who underwent initial therapy, none relapsed locally, but seven relapsed at distant sites.

These retrospective studies suggest that a percentage of a highly selected patient population may be spared the morbidities associated with RT if observation is used as an initial approach. However, given the potential for cure with RT, we reserve observation for patients who would require RT to areas with high complication rates.

Systemic therapy — Systemic therapy with immunotherapy (eg, rituximab) or chemoimmunotherapy (eg, bendamustine plus rituximab) is generally reserved for patients with symptomatic stage II, III, or IV FL. Systemic therapy has rarely been studied in patients with stage I FL due to the extreme radioresponsiveness of these tumors. (See "Initial treatment of stage II to IV follicular lymphoma", section on 'Stage II FL'.)

In a multicenter phase III trial, 150 patients with stage I or II FL were randomly assigned to RT alone or RT followed by six cycles of chemotherapy [17,43,44]. All patients were staged with computed tomography and bone marrow biopsy; half also underwent FDG-PET. Three-quarters had stage I disease. Involved-field RT 30 to 36 Gy was administered to all known disease sites. The chemotherapy regimen consisted of cyclophosphamide, vincristine, and prednisolone (CVP); rituximab was added to the CVP after a protocol amendment. Chemotherapy increased the number of grade 3 or greater acute toxicity events (35 versus 2 events). After a median follow-up of 9.6 years, the addition of chemotherapy improved PFS (59 versus 41 percent at 10 years; HR 0.57, 95% CI 0.34-0.95). On multivariable analysis, staging with FDG-PET and use of rituximab were predictors of superior PFS. This improved PFS has not translated into superior OS. Over 85 percent of patients in both arms were alive at 10 years.

In the largest prospective observational series, 206 patients with stage I FL confirmed by imaging studies underwent initial management with radiation alone (56 patients), watchful waiting (35 patients), rituximab alone (25 patients), chemoimmunotherapy (57 patients), or chemoimmunotherapy plus RT (26 patients) [19]. The population that received chemoimmunotherapy with or without RT included a higher percentage of patients with grade 3 histology (36 percent) than the other groups (11 percent). At a median follow-up of 57 months, 9 of 57 patients (16 percent) treated with chemoimmunotherapy had progressed. Additional follow-up is needed to evaluate long-term disease control and toxicities.

SPECIAL SITUATIONS

Grade 3 FL — Our approach to the treatment of patients with histologic grade 3 FL differs between cases with grade 3a and grade 3b:

●Patients with grade 3a FL are managed similarly to patients with grade 1 or 2 FL. (See 'Our approach' above.)

●Patients with grade 3b FL are treated with regimens used for clinically aggressive lymphomas (eg, diffuse large B cell lymphoma [DLBCL]). (See "Initial treatment of limited stage diffuse large B cell lymphoma".)

FL tumors are graded on a scale from 1 to 3 according to the number of centroblasts per high powered field. Those with >15 centroblasts per high power field are categorized as grade 3. Grade 3 FL is subdivided into grade 3a, in which centrocytes are present, and grade 3b, in which there are solid sheets of centroblasts [45]. Although controversial, differences in molecular genetics as well as clinical behavior suggest that FL grade 3a is an indolent disease and 3b a more aggressive one [45-48].

FL grade 3b is often referred to as follicular large cell lymphoma. In contrast to lower grade FLs, this histologic variant has a lesser tendency to involve the bone marrow or peripheral blood and often presents with larger lymphoid masses. Although the follicular architecture is preserved, the clinical presentation, behavior, and outcome with treatment more closely approximates that of DLBCL.

Patients with grade 3b FL commonly present with a more clinically aggressive course, which may resemble histologic transformation. If histologic transformation is suspected, repeat biopsy is indicated. (See 'Histologic transformation' below.)

Stage II FL — For patients with stage II FL, we prefer a management approach similar to that used for stage III or IV FL. Other clinicians offer radiation therapy (RT) to a subset of these patients in which the disease can be encompassed by a reasonable radiation field (eg, stage II disease with groin and ipsilateral iliac involvement). (See "Initial treatment of stage II to IV follicular lymphoma", section on 'Stage II FL'.)

Intrafollicular neoplasia ("in-situ") FL — Intrafollicular neoplasia is a pathologic diagnosis used to describe the identification of follicles, typically several in number, that have a high content of BCL2-positive B cells within a lymph node that otherwise lacks the diagnostic features of FL. Such patients are not considered as having a diagnosis of FL. Following removal of the involved lymph node, these patients should be followed clinically for evidence of progression. (See "Clinical manifestations, pathologic features, diagnosis, and prognosis of follicular lymphoma", section on 'Intrafollicular neoplasia'.)

Little is known regarding the natural history of patients with this finding who have no evidence of FL on further evaluation. A retrospective analysis of 21 cases of in situ FL with a median follow-up of 41 months reported only one case of progression to disseminated FL [49].

Primary intestinal FL — Primary intestinal FL is a variant of FL characterized by lymphomatous disease pathologically consistent with FL confined to the intestine without lymph node involvement [50]. "Duodenal-type follicular lymphoma" is considered a unique clinicopathologic entity in the World Health Organization classification of lymphoid neoplasms [51,52].

Given the potential toxicity of RT and the indolent nature of primary intestinal FL, we suggest a watch-and-wait strategy rather than initial RT. For those who choose RT, techniques that avoid whole abdominal radiation are preferred.

Primary intestinal FL is a rare entity initially described in small case series [51,53-61]. The largest series included 63 patients with stage I FL of the small intestine diagnosed by endoscopic biopsy and followed for a median of 77 months [51]. Four general treatment strategies were used:

●Watch and wait – Of the 24 patients managed with serial endoscopies, 7 experienced a complete remission (CR), 17 had stable disease, and 2 developed nodal FL. Both patients who developed nodal FL achieved CR after treatment with combination chemotherapy. None of these patients developed symptoms directly related to gastrointestinal involvement requiring intervention.

●Radiation therapy – All 19 patients treated with local radiation with a focal dose of 30 to 45.3 Gy and abdominal bath of 24.5 to 30 Gy attained a CR.

●Rituximab monotherapy – Of the five patients who received rituximab alone, four had a CR, and one had stable disease.

●Chemotherapy with or without radiation – All eight patients who were treated with chemotherapy with or without radiation attained a CR. Three developed duodenal relapse.

In another series of 21 patients with duodenal FL treated with involved-site RT with inclusion of the entire duodenum in the target volume, treated to a median dose of 30.6 Gy, the three-year overall survival, relapse-free survival, and local control rates were 95, 79, and 100 percent, respectively [62].

Radiation of the small bowel is associated with chronic radiation enteritis manifested by malabsorption and diarrhea. This toxicity can be minimized by using a technique that avoids whole abdominal irradiation. For this technique, a radiopaque clip is placed by endoscopy at the location of the tumor and this clip is then used to identify and treat involved bowel plus a margin of normal tissue to 24 Gy. (See "Overview of gastrointestinal toxicity of radiation therapy", section on 'Late'.)

Primary cutaneous FL — Primary cutaneous follicle center lymphoma is a unique clinicopathologic entity similar to FL that presents in the skin without evidence of extracutaneous disease at the time of diagnosis and after the completion of an initial staging evaluation. The diagnosis and treatment of primary cutaneous follicle center lymphoma are discussed separately. (See "Primary cutaneous follicle center lymphoma".)

Pediatric-type FL — Pediatric-type FL is considered a distinct clinicopathologic entity that is usually seen in children and rarely presents in adults. This is discussed separately. (See "Clinical manifestations, pathologic features, diagnosis, and prognosis of follicular lymphoma", section on 'Children'.)

EVALUATION OF RESPONSE TO THERAPY — An initial response assessment is performed approximately one month following the completion of planned therapy (or sooner if the outcome is unfavorable). This evaluation includes a history, physical examination, and laboratory studies (complete blood count with differential, chemistries with liver and renal function and electrolytes, and lactate dehydrogenase). In addition, a whole body combined fluorodeoxyglucose positron emission tomography with computed tomography (FDG PET/CT) is performed six to eight weeks after the completion of chemotherapy or chemoimmunotherapy and 8 to 12 weeks after radiation [1,2].

FDG PET/CT is the preferred modality as it provides a more precise estimation of disease burden than CT alone and may provide prognostic information [1,2,63]. FDG PET/CT is interpreted using the Deauville score (table 4), which visually compares the FDG avidity of suspected disease in relation to FDG uptake in the mediastinal blood pool and liver as an internal control [64].

Disease response incorporates information gathered from the history, physical, and imaging (table 5) [1]. While the goal of treatment is a complete remission, many patients with advanced disease only obtain a partial remission. Patients who fail to obtain a partial remission have refractory disease. Treatment of refractory disease is presented separately. (See "Treatment of relapsed or refractory follicular lymphoma".)

The accuracy of imaging tests in the follow-up of patients with lymphoma is discussed separately. (See "Pretreatment evaluation and staging of non-Hodgkin lymphomas".)

SURVEILLANCE FOR RELAPSE — Following the completion of therapy, restaging, and documentation of complete or partial remission, patients are seen at periodic intervals to monitor for treatment complications and assess for progression. The frequency and extent of these visits depends on the comfort of both the patient and physician. There have been no prospective, randomized trials comparing various schedules of follow-up.

Our approach to patient surveillance is to schedule patient visits every three months during the first year and then every three to six months thereafter. At these visits we perform a history and physical examination, complete blood count, chemistries, and lactate dehydrogenase. The role of routine imaging in the longitudinal follow-up of asymptomatic patients after response assessment is uncertain, and routine imaging in this population is discouraged [1,65,66]. There is no role for PET imaging in disease surveillance.

Relapsed disease can be suggested by findings on the physical examination and changes on imaging studies but can only be confirmed by biopsy. Biopsy also evaluates for histologic transformation to more aggressive disease. As such, a biopsy should always be obtained to document relapsed disease before proceeding to further therapy. The treatment of relapsed FL is presented separately. (See "Treatment of relapsed or refractory follicular lymphoma".)

Patients treated for FL require surveillance for potential long-term toxicities. The long-term care of the non-Hodgkin lymphoma survivor is presented separately, focusing on issues that require attention at approximately five years from the completion of therapy onwards. (See "Overview of care for adult survivors of non-Hodgkin lymphoma".)

CLINICAL TRIALS — Often there is no better strategy to offer a patient than enrollment onto a well-designed, scientifically valid, peer-reviewed clinical trial. Additional information and instructions for referring a patient to an appropriate research center can be obtained from the United States National Institutes of Health (www.clinicaltrials.gov).

PROGNOSIS — Patients with stage I FL generally have an excellent prognosis and a percentage may be cured with radiation therapy; however, there are groups of patients who have more as well as less favorable survival. The Follicular Lymphoma International Prognostic Index (FLIPI) (table 2) is the main prognostic tool used for patients with FL. This and other prognostic tools are described in more detail separately. (See "Clinical manifestations, pathologic features, diagnosis, and prognosis of follicular lymphoma", section on 'Follicular lymphoma IPI (FLIPI)'.)

HISTOLOGIC TRANSFORMATION — An integral part of the natural history of FL is progression to a higher-grade histologic subtype, such as diffuse large B cell lymphoma. As detailed separately, a subgroup of patients with FL who transform to a more aggressive histology may attain complete remission following treatment with chemoimmunotherapy, and some may be cured by high dose chemotherapy followed by autologous hematopoietic cell transplantation. (See "Autologous hematopoietic cell transplantation in follicular lymphoma", section on 'Following histologic transformation' and "Histologic transformation of follicular lymphoma".)

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Management of follicular lymphoma".)

INFORMATION FOR PATIENTS — UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." The Basics patient education pieces are written in plain language, at the 5^th to 6^th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10^th to 12^th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.

Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.)

●Basics topics (see "Patient education: Follicular lymphoma (The Basics)")

●Beyond the Basics topics (see "Patient education: Follicular lymphoma in adults (Beyond the Basics)")

SUMMARY AND RECOMMENDATIONS

●Pretreatment evaluation – Follicular lymphoma (FL) is the second most common type of non-Hodgkin lymphoma.

A pretreatment 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. Enrollment in clinical trials should be encouraged. (See 'Pretreatment evaluation' above.)

●Choice of therapy – Treatment of FL depends on the stage of disease at presentation and histologic grade (algorithm 1) (see 'Our approach' above):

•Stage I FL – For most patients with stage I FL, we suggest radiation therapy (RT) to a dose of 24 Gy in 2 Gy fractions delivered with curative intent rather than treatment with chemoimmunotherapy, immunotherapy, or an initial period of observation (Grade 2C). If significant morbidity is expected from RT based on the location and distribution of the tumor, or if the patient chooses against RT, a management approach similar to that used for stage III or IV FL is a reasonable alternative. (See 'Radiation therapy (RT)' above.)

•Stage II FL – For most patients with stage II FL, we prefer a management approach similar to that used for stage III or IV FL rather than initial RT. This preference is based on observational studies that suggest cure with RT is less likely in this population. Other clinicians offer RT to a subset of these patients. (See "Initial treatment of stage II to IV follicular lymphoma", section on 'Stage II FL'.)

The recommendations above pertain to patients with histologic grade 1, 2, or 3a FL; patients with grade 3b FL are treated with regimens used for other clinically aggressive lymphomas. (See 'Grade 3 FL' above.)

While the recommendations presented here apply to most patients with FL, modifications to this approach are necessary when FL arises in children, in certain extranodal locations (eg, primary intestinal FL, primary cutaneous FL), and when FL-type cells are found incidentally without true lymph node involvement (ie, "in-situ" FL). (See 'Special situations' above.)

●Response evaluation – Patients are evaluated after treatment with laboratory studies and imaging with FDG PET/CT in addition to a history and physical examination to determine response to therapy. Patients attaining a complete or partial remission are followed at periodic intervals for disease progression. Patients who fail to achieve a partial remission are treated as refractory disease. (See 'Evaluation of response to therapy' above and 'Surveillance for relapse' above.)

ACKNOWLEDGMENT — The UpToDate editorial staff acknowledges the late Peter M Mauch, MD, for his past work as an author for this topic.