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Treatment strategies in limited stage follicular NHL

Best Practice & Research Clinical Haematology, 2, 24, pages 179 - 186

Limited stage (I–II) follicular lymphoma is an uncommon entity, since most patients with this disease have generalized adenopathy (stage III) or bone marrow involvement (stage IV). Although patients who present with stage III–IV disease often are considered to be incurable, ∼50% of patients with limited disease will enjoy long-term freedom-from progression, usually following treatment with radiation therapy. Relapse among these patients is uncommon after 10 years and exceedingly rare after 15 years. Radiation treatment is generally restricted to the involved nodal region(s) with modest (∼5 cm.) extension proximally and distally. Radiation dose is generally 30 Gy, but may be boosted slightly (36 Gy total) in the presence of bulky disease. Randomized clinical trials have been insufficiently powered to define the value of any additional treatment beyond radiation therapy, although single arm studies suggest a benefit to the addition of chemotherapy. There have been no reported experiences with chemo-immunotherapy or radioimmunotherapy. Patients should be monitored during follow up to identify transformation to a more aggressive lymphoma.

Keywords: follicular lymphoma, radiation therapy, limited stage lymphoma.

Introduction

Limited stage follicular non-Hodgkin’s lymphoma (FL) is not a common entity. The relative frequency of “limited” vs. “generalized” FL will depend on the definition of “limited” as well as the intensity of staging investigations that are performed at the time of diagnosis. Limited disease generally implies stage I–II, although some clinical scenarios of stage II disease, e.g. >3 nodal sites or extensive abdominal disease may often be considered to be generalized.

Goffinet et al. [1] reported a series of 206 patients with “nodular” lymphoma who underwent intensive clinical investigations. 31% had stage I–II disease based on physical exam and imaging studies only. After bone marrow biopsy and staging laparotomy/splenectomy (in marrow negative patients) only 12% remained with stage I–II disease.

As the quality of imaging studies improves and new imaging modalities become available, the proportion of patients with early stage disease also declines. For example, Wirth et al. [2] reported on the impact of 14FDG-PET imaging. Forty-two patients were identified who were thought to have stage I–II disease after CT imaging and bone marrow biopsy. However, 31% (13/42) of these patients were upstaged to stage III–IV following PET imaging.

Finally, as many as 65–80% of patients with presumed stage I–II disease may have circulating t(14;18)-positive cells in the peripheral blood [3] or Bcl-2/IgH+ cells in the peripheral blood or bone marrow[4] and [5]. Whether this reflects systemic disease is not clear, since these cells may clear with just local therapy[4] and [5]. But the implication of all of these observations is that truly “localized” presentations of follicular lymphoma are not common. With an annual total number of new cases of follicular lymphoma in the US <20,000 [6] , it is likely that <2000 have localized presentations.

This fact also accounts for the deficiency of large reports (>100 patients) in the literature that detail the outcomes of treatment. The few reports of sufficient magnitude have often accrued those patients over more than two decades, with variable treatment and follow up protocols. It also explains the lack of prospective randomized clinical trials (although attempts have been made). The only randomized trial (radiotherapy +/− chlorambucil) that has included a significant number of patients (105) was reported from the British Lymphoma National Investigation (BNLI) as a subset analysis of a larger trial that included patients with diffuse or follicular histology [7] .

Given the paucity of clinical trials, treatment policies have been based on large institutional experiences, which in turn have been transformed into guidelines by organizations such as the National Cancer Center Network (NCCN) [8] and the European Society for Medical Oncology (ESMO) [9] .

Prognostic factors influencing treatment selection

It is not clear how potential prognostic factors should influence selection of therapy. Analyses of individual data sets often reflect inherent selection biases and potential influence of specific therapies. Survival outcomes commonly correlate with age [10], [11], and [12] and often stage [12] . Relapse-free survival, freedom-from treatment failure or freedom-from progression may be linked to age[10] and [12], stage[12] and [13], or tumor size [13] ; [11] . Treatment type (e.g., radiation therapy alone vs. combined modality therapy; involved field vs. extended field irradiation) may influence relapse outcomes [10] ; [14] but rarely has an impact on survival [13] ; [11] ; [14] .

The follicular lymphoma international prognostic index (FLIPI) [15] includes multiple factors (age, Ann Arbor stage, hemoglobin, LDH, and number of involved nodal sites) and was developed as a predictor of prognosis for patients with advanced stage disease. Patients with 0–1 adverse factor are at “low risk”, those with 2 adverse factors are at “intermediate risk” and those with ≥3 factors are at “high risk” for relapse. Plancarte et al. [16] analyzed a series of 48 patients with stage I–II follicular lymphoma and categorized them according to the FLIPI. Patients with intermediate risk disease had a much higher relapse risk than those with low risk disease; however, 88% of patients had low risk disease and only 12% had intermediate risk disease (no patient had high risk disease). So the FLIPI is not very discriminatory for patients with apparently localized disease.

The general correlation of survival with age and failure of treatment type to influence survival outcomes is likely related largely to deaths from intercurrent disease, which may exceed deaths from lymphoma in this generally favorable group of patients [10] . In any case, the presence of intercurrent disease must be considered in treatment selection.

The following sections deal with outcomes that have been reported for different treatment modalities.

Treatment options

Radiation therapy alone

The largest experiences in the treatment and follow up of patients with limited stage follicular lymphoma have been those utilizing radiation therapy alone. For example, there are 3 series that have reported outcomes of >100 patients treated in this fashion ( Table 1 ). In most cases, these reports include patients treated as long ago as the 1970s[7], [10], and [17]. The implication is that histologic classifications have changed and staging procedures have varied. Among the different series (and within series over the course of time) there are differences in the extent of the radiation fields and doses employed and variable inclusion of the small proportion of patients with follicular lymphoma, grade 3 (follicular large cell or nodular histiocytic in older classifications). Nevertheless, despite these issues, certain generalizations can be made regarding those variables.

Table 1 Follicular lymphoma, stage I–II radiation therapy alone.

Center N Stage FFR/DFS (yrs) Survival (yrs)
PMH [34] 460 I–II 41% (10) 62% (10)
BNLI [7] 208 I 49% (10) 64% (10)
Stanford [10] 177 I–II 44% (10) 64% (10)

FFR-Freedom-from-Relapse; DFS-Disease Free Survival; PMH-Princess Margaret Hospital; BNLI-British National Lymphoma Investigation.

Extent of radiation fields

The general conclusion has been that limited (involved/slightly extended) fields are sufficient as primary management. Some series have included patients treated with either limited or more extensive (e.g. total lymphoid) irradiation[10], [13], and [18]. Although improvements may be seen in freedom-from-relapse, differences in survival have not been demonstrated. Given this observation, as well as the potential increase in risk for radiation-related complications with larger fields, the general recommendation for primary radiation management has been to treat limited fields.

The exact extent of those fields may be difficult for the radiation oncologist to define, i.e., how conformal can the dose be? Many of the larger series initially used classical definitions of involved field, which would include all of the lymph nodes in the clearly defined “regions” of the Ann Arbor classification system [19] . This was especially the approach prior to the introduction of computed tomographic (CT) imaging, however, even in that earlier era, the extent of subdiaphragmatic fields could be designed more precisely with the aid of a lymphogram. Although CT imaging allows the identification of abnormally enlarged nodes, it is likely that adjacent non-enlarged nodes are also involved, which was documented in the “lymphogram era” as nodes that were not enlarged but had abnormal internal architectural patterns, often adjacent to clinically enlarged nodes.

18FDG-PET imaging holds some promise in helping to identify the involved nodes, even distant nodes that would revise the overall management plan [2] . However, there remains the issue of nodes that are “at risk”, i.e., minimally involved nodes that may be negative on PET imaging. In addition, some investigators have reported a problem with false negative PET scans in the follicular lymphomas. The conclusion is therefore that the radiation treatment fields should not be limited to the PET+ or anatomically enlarged nodes, but should be extended a bit beyond that, perhaps by as much as ∼5 cm, proximally and distally.

The concept of “involved node” irradiation has been applied to the management of patient with limited stage Hodgkin lymphoma [20] . This clearly should not apply to patient with limited stage follicular lymphoma. Firstly, patients with Hodgkin lymphoma are treated with combined modality therapy, so occult disease in PET negative, CT negative nodes would be managed by the systemic component of therapy. Secondly, as noted above, the likelihood of involvement of nearby nodes in the follicular lymphomas is too great to be ignored.

Of course, there are other factors that may be important in the definition of the extent of the radiation fields. Limited stage follicular lymphomas rarely involve the mediastinal nodes and the mediastinum may be safely blocked, even in patients with supraclavicular disease. This eliminates concern about potential radiation-related toxicity to the heart, coronary arteries, or lungs. Occasional women present with isolated femoral lymph node disease. In the pre-menopausal setting, care should be taken to avoid treatment of the ipsilateral ovary; however, if treatment of the iliac nodes is required, an ipsilateral laparoscopic directed oophoropexy may be performed. Special caution should be taken in the treatment of disease in head/neck sites. It is desirable to minimize treatment of the salivary glands, to avoid xerostomia. In some cases, special techniques of radiation therapy, such as intensity modulated radiotherapy (IMRT) may be required to provide maximal sparing, and should be used. Rare instances of follicular lymphoma involving the orbital adnexal structures (conjunctiva, lacrimal gland, etc.) may be treated with quite restricted fields [21] . Primary cutaneous follicular lymphoma may be treated with a direct electron field with ∼1.5 cm margins.

Radiation dose

The radiation dose used for the management of early stage follicular lymphoma has generally been in the range of 30–36 Gy (the higher dose for bulky disease). Fuks and Kaplan analyzed the recurrence rates within 174 fields in 38 patients with stage I–IV “nodular lymphocytic poorly differentiated lymphoma” and found a 5-year local control rate of ∼95% when doses ≥35 Gy were used [22] . Bush et al. [23] , from Princess Margaret Hospital showed that local control could be achieved in more than 90% of patients with stage IA–IIA disease when doses of 25–30 Gy were applied [23] . More recently, the UK NCRN conducted a trial comparing 24 Gy (12 × 2 Gy) vs. 40–45 Gy (2 Gy fractions). The primary endpoint was local control at one month. The results have been reported only in abstract form, but there was no difference in local control between the two doses at the one month evaluation time [24] .

2 Gy × 2

Of importance to the management of patients with follicular lymphoma, in general, and not covered elsewhere in this monograph, is the concept of very low dose (2 Gy × 2) involved field irradiation. Follicular lymphomas are notable for their exquisite radiosensitivity and very effective palliation can be achieved with doses as low as 4 Gy (2 Gy × 2). Ganem et al [25] first proposed the use of this regimen and reported an objective response in 89% of 27 patients so treated. Haas et al. [26] treated 98 patients with follicular lymphoma, more than half of whom (52%) had disease >5 cm. The overall response rate was 92% (complete response rate = 61%). After achieving a complete response, the median time to local progression was 42 months. This concept has not been applied as initial therapy to patients with stage I–II disease, but is provocative.

Treatment results

The largest series report remarkable similar outcomes ( Table 1 ). 10-year measures of “cure” (freedom-from-relapse, disease free survival) are 40–50% and 10-year survival is 60–65%. Series with the longest follow up demonstrate a decrease in relapse risk with time, with relapse after 10 years being quite unlikely [7], [10], and [17]. When relapse occurs, it is usually in untreated lymph nodes and often detected initially by physical exam [27] . Disease may often be limited at the time of relapse, with 70% of patients having “relapse stage” I–II disease, and the bone marrow is involved <10% of the time when sampled at relapse [27] . 20–30% of patients will show evidence of histologic transformation at the time of or shortly following relapse[11] and [27]. The median survival following relapse is 5.3–12.8 years and 10-year survival is 35%-53% in different series[11] and [27] and the prognosis following relapse is related to “relapse stage” and presence of transformation [27] .

Combined modality therapy (Radiation plus chemotherapy)

Second in frequency only to series employing radiation therapy alone are reports using combined radiation therapy and chemotherapy. Generally, these have been studies in which combined modality therapy was being tested against radiation therapy alone. Radiation was given first, followed by chemotherapy. Unfortunately, due to the scarcity of this disease in early stage, only one trial has been reported that accrued more than 40 patients!

The BNLI conducted a limited disease trial between 1974 and 1980. Patients with Ann Arbor Stage I–II disease were treated with involved field radiotherapy to 35 Gy. Patients were randomized to no further therapy (n = 55) vs. chlorambucil 0.2 mg/kg/day orally for 8 weeks, followed by 0.1 mg/kg/day for 16 weeks (n = 50). No significant differences in relapse-free survival or overall survival were detected between the two arms of the trial [7] .

The fact that chlorambucil was the adjuvant agent used in this trial has led to the discounting of its results by some. Other randomized trials that have used cyclophosphamide, vincristine and prednisone (CVP) +/− doxorubicin (CHOP) have had insufficient accrual to inform any conclusion. However, a more recent attempt at an international trial has been inaugurated by the Trans Tasman Radiation Oncology Group (TROG) in which patients are randomized to treatment with involved field irradiation alone (30–36 Gy) or involved field followed by 6 cycles of CVP [28] .

One large non-randomized trial has been reported by Seymour et al. [29] . They treated 85 patients with stage I–II follicular lymphoma with 3 cycles of chemotherapy followed by involved field irradiation (30–40 Gy) followed by 7 additional cycles of chemotherapy. The chemotherapy was cyclophosphamide, vincristine, prednisone, and bleomycin (COP-Bleo); however, patients with extra-nodal involvement, bulky disease (≥5 cm.), or an elevated LDH also received doxorubicin (CHOP-Bleo). They reported a 10-year freedom-from treatment failure of 76% and survival of 82%. These are both substantially better than results noted above for radiation therapy alone; however, this was not a randomized trial and similar results have not been reported by others.

Other than single agent chlorambucil and CVP or CHOP-like combinations, there have been no reports of other single agents or combinations of drugs in conjunction with radiation therapy in the management of limited stage follicular lymphoma.

Chemotherapy alone

There are no series that have reported on the results of treatment with chemotherapy alone for limited stage follicular lymphoma. It is likely that some patients, especially those with bulky or extensive stage II disease, have been included in large series that have reported outcomes for treatment with chemotherapy alone. But the proportion of these patients in any series is very small and results have not been analyzed separately.

Rituximab

Rituximab is used commonly in the management of patients with advanced stage follicular lymphoma – either alone or in combination with chemotherapy (see Chapter 8). However, there are no reports of it being used alone, or in combination with radiation, for limited stage disease. Its use in conjunction with irradiation does hold some appeal. Experimental work demonstrates that radiation exposure can induce CD20 surface expression on B-cells, which perhaps would make the irradiated nodes more sensitive to the effects of rituximab [30] .

Radioimmunotherapy (RIT)

Bexxar and Zevalin, which link anti-CD20 to a radioisotope, are used in advanced stage follicular lymphoma (see Chapter 14). As is the case for chemotherapy alone, some patients in large series have had bulky or extensive stage II disease, but these have not been analyzed separately.

Interferon

Interferon has been used as a maintenance therapy for patients with stage III–IV disease who achieve a complete response to chemotherapy. It has not been used as an adjuvant following radiation therapy for limited disease.

Total Body Irradiation (TBI)

Low dose total body irradiation has been used in the management of patients with stage III-IV follicular lymphoma. The experience in stage I–II disease is limited. However, Richaud et al. [31] reported on a series of 26 patients treated with combined low dose total body and involved field irradiation. Patients with limited disease received 0.75 Gy TBI (0.15 Gy × 5) followed by a 2 week break followed by another course of 0.75 Gy TBI (0.15 Gy × 5) followed by a 4 week break followed by 40 Gy involved field irradiation (2 Gy × 20). The complete response rate to the 1.5 Gy TBI alone was >90%! The 5-year survival and freedom-from-relapse were both 60%, not unlike what is expected following involved field irradiation alone; however, the response rate to low dose TBI deserves note. This concept has been incorporated into a randomized clinical trial in the European Organization for the Research and Treatment of Cancer (EORTC).

Observation (No initial therapy)

Observation is a common method of management for patients with advanced stage asymptomatic follicular lymphoma. Studies fail to show a survival advantage for similar patients treated at the outset. This is a reasonable management approach for patients with advanced disease, who are generally thought to be incurable. It is more controversial as a concept in limited disease, since nearly half of these patients can be cured with radiation therapy.

There are 2 reports of no initial therapy in limited stage follicular lymphoma. Soubeyran et al. [32] studied 43 patients with stage I follicular lymphoma that had been completely resected. 26 patients, accrued over an 11 year period, were selected for a “wait-and-see” policy. These patients were those had the lowest suspicion of residual disease. With a median follow up of 6.3 years, 13/26 (50%) of the patients had relapsed, 6 locally and 7 distantly.

From Stanford, Advani et al. [33] reported on 43 patients with stage I–II follicular lymphoma accrued over a 31year period in whom a policy of no initial therapy was followed. Patients were included in this analysis if they required no treatment during the first three months of observation, i.e., did not manifest disease progression or develop symptoms during that time. All patients had disease <5 cm. The median time to requiring treatment (for disease progression, pain, transformation, B symptoms, or organ dysfunction) was nearly two years. The median survival was 19 years, but difficult to compare with other management strategies because of the selection criteria.

Management strategies in limited stage follicular lymphoma

It is important to confirm the pathologic diagnosis (follicular lymphoma, grade 1–2) and to ensure complete staging. A complete physical exam and routine blood evaluations (complete blood count, differential, platelet count; comprehensive metabolic panel and lactate dehydrogenase [LDH]) should be complemented by a PET-CT scan. Bilateral random bone marrow biopsies should be obtained to rule out stage IV disease.

For patients who remain stage I–II, the main consideration should be given to treatment with limited irradiation to a dose of ∼30 Gy. This is the main management option noted in the clinical guidelines from the European Society for Medical Oncology (ESMO) [9] and is the preferred treatment option in the practice guidelines published by the National Comprehensive Cancer Network (NCCN) [8] . Patients with “bulky” stage I–II disease may be candidates for combined chemo-radiation programs.

Radiation fields should be based upon results of PET-CT imaging and designed to include the involved nodes with ∼5 cm. margins proximally and distally and 1–1.5 cm. margins in other directions. The most accepted dose is ∼30 Gy, perhaps boosting to 35–36 Gy in the presence of initially “bulky” disease. Daily doses are in the range of 1.5–2 Gy. Given the low total dose, radiation treatments can usually be safely administered with opposed field techniques. Concepts of treatment such as intensity modulated radiotherapy rarely provide additional benefit and in some cases may lead to increased risk due to the larger volume of tissue that is irradiated (albeit to lower dose).

More tailored radiation fields are indicated for rare extra-nodal presentation of disease such as the conjuctiva and skin. In superficial sites such as these, treatment is usually administered with low energy electrons (∼6 MeV), to similar doses as noted above.

Absolute contraindication to the use of radiation therapy for these patients is unusual. However, rare patients with intercurrent disease may have relative contraindications. For example, patients with Sjogren disease experience xerostomia and xerophthalmia. These patients may have low thresholds for developing more severe manifestations of these symptoms secondary to radiation. Based on limited experience cited above, one might consider “watch and wait” programs or even 2 Gy × 2, if treatment is mandated. Experience using chemotherapy alone or chemo-immunotherapy (addition of rituximab) is insufficient to endorse either of those approaches.

Patients with very bulky abdominal disease may be considered for treatment programs analogous to those utilized in stage III–IV disease, or one may follow systemic therapy with local consolidative irradiation. This is consistent with ESMO and NCCN treatment guidelines.

Following the completion of therapy, repeat imaging is appropriate to confirm response to therapy. This may be limited to a CT scan of the involved body region (or PET-CT if PET scan was performed pre-treatment).

Routine surveillance following therapy is indicated, but there is substantial variation in the recommended frequency, types of examinations, etc. A physical exam with special attention to the lymph node regions and abdomen is reasonable every 4–6 months, with blood work at least once a year. Laboratory evaluation should include thyroid function studies if neck irradiation was a component of the initial treatment. The value of repeat imaging during the follow up period is unknown. Many practitioners will repeat a CT or PET-CT scan annually until year 5. Identification of new disease should prompt a biopsy to rule out transformation. If relapse occurs in the absence of transformation management must be individualized and may include observation, local radiation, or systemic therapy.

Summary

Limited stage (I–II) follicular lymphoma is an uncommon entity, since most patients with this disease present with generalized adenopathy (stage III) or bone marrow involvement (stage IV). Although patients who present with stage III–IV disease often are considered to be incurable, ∼50% of patients with stage I–II disease will enjoy long-term freedom-from progression, usually following treatment with radiation therapy. Relapse is uncommon after 10 years and exceedingly rare after 15 years. Radiation treatment is generally restricted to the involved nodal region(s) with modest (∼5 cm.) extension proximally and distally. Radiation dose is generally 30 Gy, but may be boosted slightly (36 Gy total) in the presence of bulky disease. Randomized clinical trials have been insufficiently powered to define the value of any additional treatment beyond radiation therapy, although single arm studies suggest a benefit to the addition of chemotherapy. There have been no reported experiences with chemo-immunotherapy or radioimmunotherapy. Selected patients may be candidates for simple observation or treatment with very low dose irradiation. Patients should be monitored during follow up to identify transformation to a more aggressive lymphoma.

Conflict of interest statement

None to declare.

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Footnotes

Department of Radiation Oncology, 875 Blake Wilbur Drive, Room CC-G224, Stanford University, Stanford, CA 94305, USA

Tel.: +1 650 723 5510; Fax: +1 650 498 6922.