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Originally published as JCO Early Release 10.1200/JCO.2004.10.086 on March 15 2004 © 2004 American Society of Clinical Oncology. Stage I and II Follicular Non-Hodgkin’s Lymphoma: Long-Term Follow-Up of No Initial TherapyFrom the Division of Oncology, Department of Medicine, Stanford University Medical Center, Stanford, CA Address reprint requests to Ranjana Advani, MD, Division of Oncology, 875 Blake Wilber Dr, Stanford, CA 94305; e-mail: radvani{at}stanford.edu
PURPOSE: To analyze the outcome of no initial therapy in stage I and II follicular small-cleaved (FSC) and follicular mixed (FM) non-Hodgkin’s lymphoma (NHL) on overall survival, time to treatment, incidence and course of transformation, and cause of death. PATIENTS AND METHODS: This was a retrospective analysis. Criteria for selection were patients with stage I and IIA FSC and FM (grades 1 and 2) NHL with therapy deferred for at least 3 months after diagnosis and a minimum follow-up of 1 year. RESULTS: Forty-three patients were identified (11 stage I, 32 stage II), with a median age of 58 years. Reasons for no initial therapy included: physician choice (n = 20), large abdominal radiation field required (n = 10), advanced age (n = 7), concern for xerostomia (n = 4), or patient refusal (n = 2). At a median follow-up of 86 months, 27 patients (63%) had not been treated. The median time to treatment in the remaining 16 patients was 22 months. Four of 16 patients transformed to a higher-grade lymphoma. Nine patients died—six due to progressive lymphoma. Estimated survivals at 5, 10, and 20 years were 97%, 85%, and 22%, respectively. CONCLUSION: In selected stage I and II follicular NHL patients, deferred therapy is an acceptable approach, as more than half of our patients remained untreated at a median of 6 or more years, and survival was comparable to that seen in reports with immediate treatment.
In the WHO classification, indolent follicular lymphomas are characterized as grades 1 and 2.1 These entities were previously referred to as follicular small-cleaved (FSC) and follicular mixed (FM) low-grade lymphoma in the Working Formulation.2 Compared with other non-Hodgkin’s lymphomas (NHLs), the indolent follicular lymphomas are characterized by prolonged survival.3,4 Despite initial complete remission (CR) in advanced disease following single alkylating agents, combination chemotherapy, or combined modality treatment, a continuous rate of relapse is observed.5,6 On this basis, advanced-stage follicular lymphoma is considered incurable. In our institutional experience, patients managed with no initial therapy had survivals similar to historical controls who received immediate therapy.7 Thereafter, three randomized phase III trials have confirmed that immediate treatment confers no survival benefit.8-10 Thus, a policy of conservative management, deferring treatment until disease progression, has become an accepted option for selected patients with advanced disease. For patients with limited disease, defined as stage I and II, radiotherapy (XRT) has been considered the standard management.11 In a report from Stanford University on 177 patients with stage I or II FSC or FM histology treated with XRT, the median survival was 13.8 years with 5-, 10-, 15-, and 20-year survival rates of 82%, 64%, 44%, and 35%, respectively.12 Similar results were reported in other studies utilizing XRT alone.13-15 Because deferred therapy yields survival comparable with immediate treatment for advanced-stage disease, and the overall survival (OS) is relatively long, no initial therapy may be considered in selected, asymptomatic patients with stage I and II disease. We present here a retrospective analysis of 43 patients with early-stage disease for whom therapy was deferred after consultation at Stanford University. The objectives of this study were to analyze the outcome of no initial therapy in stage I and II FSC and FM lymphoma on OS, time to treatment (TTT), incidence of and outcome after transformation, and causes of death.
We used the Stanford University Lymphoma Database, in which data are recorded for all lymphoma patients referred to the Division of Oncology since 1960, for this retrospective analysis. Criteria for selection included patients with stages I and IIA, FSC and FM (grades 1 and 2) NHL managed with no initial therapy and a minimum follow-up of 1 year. For the purpose of this study, we defined no initial therapy as no treatment for at least 3 months after diagnosis. The medical records on all patients were reviewed for accuracy of staging, pathology, treatment, and survival. The pathologic data were confirmed at Stanford University at presentation in all but one patient. Consistent with the changing classification of lymphomas during the three decades of patient follow-up, the pathologic data on the first four patients were initially reported according to the earlier Rappaport classification and were subsequently reclassified according to the Working Formulation.2 The more recent cases were classified per the Revised European American Lymphoma/WHO classification.1 All patients had a bone marrow examination, CBC, computed tomography scan of the abdomen and pelvis and/or lower extremity lymphogram, and a chest radiograph. Lactic dehydrogenase level was available in 40 of 43 patients. Patients were staged using the Ann Arbor criteria.16 Only one patient underwent a laparotomy, and this was as a diagnostic procedure. Clinical features were expressed according to the International Prognostic Index (IPI).17 We retrospectively categorized the indications for treatment as progression (pain, B symptoms, significant palpable adenopathy, organ dysfunction, or radiologic evidence of significant tumor growth) or transformation (change in pathology) from FSC or FM (grade 1 or 2) histology to a predominantly diffuse mixed or diffuse large-cell type. Fourteen patients were followed-up exclusively at Stanford, and 29 were managed primarily by referring physicians. Forty-one of 43 patients and/or their referring physicians were personally contacted via telephone for information regarding treatment, progression, transformation, and survival. Two patients were lost to follow-up, and their survival was censored based on their last documented follow-up date. OS and TTT were calculated from the date of diagnosis using Kaplan-Meier methods.18 All causes of death were included in the OS analysis.
Between June 1969 and July 2000, 133 patients with stage I or II FSC or FM lymphoma were identified in the database. Of these, 45 patients (34%) met the specified criteria of no therapy for at least 3 months after diagnosis. The medical records on 43 of 45 patients were available and form the basis of this report. Four cases were identified between 1969 and 1979; 12, between 1980 and 1990; and 27, from 1991 to 2000. The characteristics of the study patients are shown in Table 1. Twenty-three had FSC, and 20 had FM lymphoma. There were 11 (26%) stage I patients and 32 (74%) stage II patients. Twenty-two patients presented with supradiaphragmatic disease (eight stage I, 14 stage II), and 21 had subdiaphragmatic disease (three stage I, 18 stage II). The median age was 58 years (range, 30 to 76 years), with 19 female and 24 male patients. Seventeen patients (40%) were older than 60 years of age. Two patients had B symptoms at presentation, and none had bulky (> 5 cm) disease. Seven patients (16%) had extranodal sites of involvement, including gastrointestinal (n = 3), parotid (n = 2), thyroid (n = 1), and tonsil (n = 1). The IPI was 1, in 15 of 17 patients older than 60 years, and 0, in 24 of 26 patients younger than 59 years, consistent with their low risk. In three patients, the IPI could not be calculated, as the lactic dehydrogenase level was not available. Five patients had complete excision of their disease.
The reasons for deferring treatment were varied, as indicated in Table 2. In 16 patients (37%), therapy was deferred because of concern for potential complications of radiation. These concerns were based on (1) disease in the abdomen or pelvis requiring a large field or pelvic radiation with potential bone marrow toxicity (n = 10); (2) disease in the high neck with potential xerostomia (n = 4); and (3) a history of prior radiation due to unrelated cancers (n = 2). Seventeen patients (40%) had no initial treatment based on physician or patient preference, and 10 patients (23%) had no initial therapy based on advanced age or comorbid conditions.
With a median follow-up of 86 months (range, 17 to 280 months), the estimated median survival was 19 years. The proportions of patients alive at 5, 10, 15, and 20 years were 97%, 85%, 58%, and 22%, respectively (Fig 1). There were no differences in survival based on stage, histology, age (< 60 years v > 60 years), or presentation above or below the diaphragm. Nine patients died, and all deaths occurred in patients treated for progressive or transformed disease. Six deaths were due to progressive lymphoma, and one death each was due to metastatic colon cancer and a motor vehicle crash. In one case, the cause of death was unknown.
Figure 2 shows that 27 patients (67%) have not been treated for their disease to date. At a median follow-up of 6 or more years, more than half of patients have not received treatment for significant disease progression or transformation. The proportions of patients estimated to be observed without treatment at 5, 10, and 15 years were 76%, 56%, and 48%, respectively. Sixteen patients (37%) received XRT and/or chemotherapy, with a median TTT of 21.5 months (range, 7 to 280 years). Retrospectively determined indications for treatment included significant disease progression in 12 patients, and transformation in four patients (three diffuse large cell and one diffuse mixed). The median TTT for patients with progression of their follicular lymphoma was 22 months (range, 11 months to 12.5 years). Eight patients progressed in initial sites, and four patients progressed distantly. Six patients were treated with XRT and six were treated with chemotherapy (five with cyclophosphamide + vincristine + prednisone [CVP], or chlorambucil; and one with cyclophosphamide + daunorubicin + vincristine + prednisone [CHOP]). The median survival of the subgroup of patients treated for progression of follicular lymphoma was 8.3 years after diagnosis.
The time to transformation in the four treatment-naive patients ranged from 14 months to 23.3 years. All had supradiaphragmatic presentations (two stage I and two stage II) and all transformed in supradiaphragmatic sites (two neck, one orbit, and one scalp). Three patients received CHOP chemotherapy with one CR and two partial remissions. The patient with an isolated scalp lesion was treated with local excision only. The median survival for the four previously untreated transformed patients was 119 months after diagnosis and 71 months after transformation. An additional five patients had "posttherapy transformations," with three following XRT and two after chemotherapy. All five patients with posttherapy transformation were treated with doxorubicin-containing combination chemotherapy, with two achieving a CR. No plateau was observed in the estimated overall risk of transformation, with four cases occurring between 14 and 26 months and five between 7.8 to 23.3 years after diagnosis. Overall, for the entire group, the transformation incidence during the entire observation period was 21% (n = 9), with a median time to transformation of 7.8 years (range, 14 months to 24 years) and an overall median survival of 10.1 years (range, 17 months to 23 years) after diagnosis for patients who transformed.
No initial therapy, often referred to as watchful waiting, is commonly recommended for patients with advanced stage FSC and FM lymphomas. To assess this approach in early-stage patients, we analyzed our institutional experience throughout 31 years. The median survival was 19 years, with a median follow-up of 86 months. More than half (27 of 43 patients) of patients in our study group were diagnosed during the period from 1991 to 2000, possibly reflecting the increased adoption of watchful waiting in advanced-stage patients. The estimated OS rates at 5, 10, and 20 years were 97%, 85%, and 22%, respectively. Sixteen patients (37%) received treatment during the follow-up period, with 12 for disease progression and four for transformation to a higher-grade lymphoma. These data suggest that no initial therapy for lymphoma is an acceptable approach in selected FSC and FM patients with early-stage disease. No randomized trials have compared immediate irradiation or chemotherapy with no initial therapy for patients with stages I and II disease. In fact, to our knowledge, this report is the first of deferred therapy in patients with early-stage follicular NHL. Soubeyran et al19 reported their experience with a watchful waiting policy for 26 patients with stage I follicular NHL in CR after surgical resection. At a median follow-up of 6.3 years, six patients experienced local progression, and seven patients relapsed at distant sites. This group of patients, who were completely resected, is distinct from the patient population of our study, in which the majority had stage II disease, with only five patients (12%) rendered disease-free by surgery. The reported literature for stage I and II indolent NHL has included small lymphocytic lymphomas and follicular grade 3 (large-cell) lymphoma, together with grade 1 and 2 patients. Both XRT alone and combined modality approaches were reported. Radiation techniques and fields that were used varied, resulting in difficulty in comparison across studies. With this caveat and differences in patient selection in mind, the OS in our report did not differ from other retrospective reports utilizing XRT, such as reported by investigators at the Princess Margaret Hospital,13 the Royal Marsden Hospital14 and the British National Lymphoma Investigation15 (Table 3). Median survival rates in the current report are not inferior to a previous retrospective analysis from our institution, in which stage I and II FSC and FM lymphoma patients were treated with radiation therapy12 (Table 4). At 5, 10, 15, and 20 years, survival estimates were 82%, 64%, 44%, and 35%, respectively, in that series. In the former Stanford University XRT report, 56% of the irradiated patients relapsed within 10 years. The authors interpreted the low number of relapses between 10 and 20 years as suggestive evidence that a proportion of patients might be cured of their disease. The current report also has long median follow-up, but includes a greater proportion (74% v 42%) of patients with stage II disease. Despite more extensive disease at diagnosis in the group receiving no initial therapy, OS rates were similar in both reports. In the former XRT report, patients older than 40 years, especially those older than 60 years, had significantly higher death rates than age- and sex-matched population controls. Patients in the no initial therapy series had a median age of 58 years, with 17 patients older than 60 years; no comparisons were made with a control population.
Recently Seymour et al20 updated results on their combined-modality therapy with cyclophosphamide, vincristine, and prednisolone + bleomycin or CHOP + bleomycin, and 30- to 40-Gy involved field XRT in patients with early-stage follicular NHL. At a median follow-up of 10 years, the TTT failure and OS were 72% and 80% respectively. These excellent TTT failure results are superior to those previously reported with XRT alone. However, both myelodysplasia/acute leukemia (n = 2) and solid tumors (n = 12) were reported following this combined modality treatment. The OS at 10 years in our no initial therapy group, 85%, compares favorably (Table 4) with the M.D. Anderson experience, and only one of 43 patients developed a second malignancy (colon cancer) during the observation period. This patient had been treated with CHOP and XRT for a transformation. The rate of transformation in the current group, 21%, is similar to that reported in other series.21 Transformation occurred as early as 14 months and as late as 24 years after diagnosis. In four of nine patients, transformation was the first event that prompted treatment with excision, irradiation, or combined-modality therapy. The median survival of these four patients (from diagnosis of follicular lymphoma) was 15 years, comparable to a prior report from Stanford.22 Therefore, no initial therapy does not seem to be associated with an increased rate of transformation, nor adversely influence the outcome of treatment for transformation, consistent with our prior observations.3 More than half of the patients in this report have not yet been treated and all untreated patients are alive. These patients clearly benefited from a conservative management approach. However, a minority of patients demonstrated a less favorable disease course, including transformation as early as 14 months after diagnosis. There continue to be large gaps in our understanding of disease progression in follicular lymphoma. Although the IPI and the more recent follicular lymphoma international prognostic index provide prognostic information, these clinical tools are quite limited.17,23 Cytogenetic studies have demonstrated that many patients with follicular lymphoma have multiple karyotypic abnormalities at diagnosis beyond the characteristic t(14;18) translocation.24,25 In particular, deletions of chromosome 6 have been identified as conferring an unfavorable prognosis.26 Investigators have also suggested that the subset of follicular lymphoma patients without a t(14;18) translocation as identified by the major breakpoint or minor cluster regions have different outcomes.27 Further efforts directed toward understanding the molecular biology of follicular lymphoma in large patient cohorts should provide additional insight into clonal evolution and transformation.28,29 As with chronic lymphocytic leukemia, it may be possible to identify subsets with a more aggressive clinical course that could benefit from early intervention.30 In conclusion, survival in selected patients with early-stage FSC and FM lymphoma does not seem to be compromised when a no initial therapy approach is substituted for conventional therapies. With the anticipation of a long median survival, quality of life is an important consideration for these patients who wish to avoid early and late adverse treatment effects. This may be particularly true for patients with comorbid conditions or with disease that would require irradiation of a large volume and/or critical normal tissues. The number of potential therapeutic options for treatment of follicular lymphomas has increased in recent years.31-33 Investigational strategies with curative intent and acceptable morbidity should be pursued, but an extended period of follow-up will be required to assess the impact on OS and quality of life. Although the optimal management of early-stage FSC and FM lymphoma remains undefined, we consider no initial therapy to be an acceptable option for selected patients.
The authors indicated no potential conflicts of interest.
We are very grateful to Bert Lum, Beth McCormick, and John Allen, all of whom provided technical assistance. We also acknowledge Drs Roger Warnke and Ronald Dorfman, who reviewed the pathology data at the initial consultation at Stanford.
Supported in part by National Institutes of Health grant No. CA34233. Presented at the 8th International Conference on Malignant Lymphomas, Lugano, Switzerland, June 12-15, 2002. Authors’ disclosures of potential conflicts of interest are found at the end of this article.
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31. Cohen Y, Solal-Celigny P, Polliack A: Rituximab therapy for follicular lymphoma: A comprehensive review of its efficacy as primary treatment, treatment for relapsed disease, re-treatment and maintenance. Haematologica 88:811-823, 2003
32. Witzig TE, Flinn IW, Gordon LI, et al: Treatment with ibritumomab tiuxetan radioimmunotherapy in patients with rituximab-refractory follicular non-Hodgkin’s lymphoma. J Clin Oncol 20:3262-3269, 2002
33. Kaminski MS, Zelenetz AD, Press OW, et al: Pivotal study of iodine I 131 tositumomab for chemotherapy-refractory low-grade or transformed low-grade B-cell non-Hodgkin’s lymphomas. J Clin Oncol 19:3918-3928, 2001 Submitted October 10, 2003; accepted February 4, 2003.
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Copyright © 2004 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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ABSTRACT
INTRODUCTION
