Is Observation Dead in Follicular Lymphoma? Still Appropriate

Given the incurable yet indolent nature of follicular lymphoma (FL) and the lack of a survival benefit seen with the early treatment of patients with a low tumor burden, watchful waiting has been the predominant strategy for treating asymptomatic patients with newly diagnosed FL for more than 2 decades. The success and tolerability of rituximab for the treatment of this disease, however, has led to challenges for this treatment paradigm and the consideration of early upfront treatment with rituximab monotherapy, with or without rituximab maintenance. These strategies have resulted in improvements in quality of life with a low incidence of toxicity and have led some to practice changes. However, based on uncertainty about how early treatment affects response to second treatment, the differential cost of treatment, and the lack of a survival benefit, observation remains an appropriate and viable strategy for select patients.

Abstract

Given the incurable yet indolent nature of follicular lymphoma (FL) and the lack of a survival benefit seen with the early treatment of patients with a low tumor burden, watchful waiting has been the predominant strategy for treating asymptomatic patients with newly diagnosed FL for more than 2 decades. The success and tolerability of rituximab for the treatment of this disease, however, has led to challenges for this treatment paradigm and the consideration of early upfront treatment with rituximab monotherapy, with or without rituximab maintenance. These strategies have resulted in improvements in quality of life with a low incidence of toxicity and have led some to practice changes. However, based on uncertainty about how early treatment affects response to second treatment, the differential cost of treatment, and the lack of a survival benefit, observation remains an appropriate and viable strategy for select patients.

NCCN: Continuing Education

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This activity has been designated to meet the educational needs of physicians and nurses involved in the management of patients with cancer. There is no fee for this article. No commercial support was received for this article. The National Comprehensive Cancer Network (NCCN) is accredited by the ACCME to provide continuing medical education for physicians.

NCCN designates this journal-based CME activity for a maximum of 1.0 AMA PRA Category 1 Credit(s)™. Physicians should claim only the credit commensurate with the extent of their participation in the activity.

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This activity is accredited for 1.0 contact hour. Accreditation as a provider refers to recognition of educational activities only; accredited status does not imply endorsement by NCCN or ANCC of any commercial products discussed/displayed in conjunction with the educational activity. Kristina M. Gregory, RN, MSN, OCN, is our nurse planner for this educational activity.

All clinicians completing this activity will be issued a certificate of participation. To participate in this journal CE activity: 1) review the learning objectives and author disclosures; 2) study the education content; 3) take the posttest with a 66% minimum passing score and complete the evaluation at http://education.nccn.org/node/62684; and 4) view/print certificate.

Release date: March 6, 2015; Expiration date: March 6, 2016

Learning Objectives

Upon completion of this activity, participants will be able to:

  • Review the pros and cons of early treatment versus observation in the management of patients with FL

  • Discuss the potential benefits of chemoimmunotherapy as initial treatment for the management of patients with FL

  • Identify the indications of therapy in patients requiring treatment for FL

“I will get by, I will survive!” This lyric from the Grateful Dead is relevant to the patient with asymptomatic follicular lymphoma (FL). If the goal of management of patients with advanced-stage FL is survival, then observation for many newly diagnosed patients is not dead. Most patients with advanced-stage indolent FL are not cured with current available therapies. The question that has been posed is whether observation is dead in FL. More specifically, in the era of rituximab-based treatment, should no patients go untreated? This article reviews the indications for therapy, results of randomized trials of observation versus treatment with chemotherapy, and more recent studies of observation versus treatment with rituximab, and discusses why observation is still a viable option for selected patients.

The deferring of initial treatment, also referred to as watch and wait, was originally reported from Stanford University in 1979 and updated in 1984.1,2 The reasons for this approach stemmed from the lack of effective therapy to cure the disease, coupled with the indolent behavior of FL. In these patients, the median time to first therapy was 31 to 36 months, and approximately 20% of patients did not require therapy at 17-year follow-up. Compared with a cohort of patients treated on protocol at diagnosis, no difference was seen in 5-year overall survival (OS) after initial observation, and the median OS for patients initially observed was 11 years, and perhaps better depending on histology. Moreover, in these studies, approximately 30% of patients with FL had spontaneous remissions. The indications for therapy for FL have largely not changed in 30 years, and include local symptoms from and compromise of normal organ function from progressive or bulky disease, B symptoms, symptomatic extranodal disease, cytopenias, and an increased pace of disease growth. The reports from Stanford suggested that more than 50% of patients could be observed. Another important observation from these studies was that the risk of histologic transformation was similar in patients who were observed and those receiving immediate therapy. Therefore, for more than 2 decades, patients who had no clear indications of therapy were generally observed.

Without question, the optimal way to determine whether there are advantages to early treatment for asymptomatic patients with no clear indications for treatment are randomized controlled trials evaluating observation versus therapy. Three randomized trials have compared observation versus immediate chemotherapy (Table 1).35 These trials compared chemotherapy regimens of different intensities versus observation followed by chemotherapy at progression. The largest trial of observation in FL included 309 patients with asymptomatic stage III or IV indolent lymphoma, with 66% having FL.3 Patients were either treated immediately with chlorambucil or observed, and then treated with chlorambucil at progression. The findings of this study, at a median follow-up of 16 years, found no significant difference in OS or cause-specific survival between patients treated initially and those observed initially. The median time of observation was 31 months, and 19% did not require therapy at 10 years of observation, very similar to the Stanford experience reported more than 2 decades earlier. More importantly, the time to second therapy, from initial randomization, was significantly longer in patients who were initially observed (median time, 66 vs 43 months; P=.01). Similar findings have been reported by Brice et al4 in patients with low tumor burden. Moreover, when treatment was needed, delay in treatment did not adversely impact response to treatment, with response rates of 78% and 70% after initial treatment with prednimustine and interferon-α, respectively, and 70% after deferred treatment, which was most commonly combination chemotherapy with cyclophosphamide, doxorubicin, teniposide, prednisone, and interferon. In fact, this regimen was only associated with a 50% to 64% response rate when used at relapse after initial treatment with prednimustine or interferon-α compared with 70% in the deferred treatment group, with similar time to second progression of 21 to 23 months for all 3 groups. OS did not differ among the groups. Therefore, the watch and wait approach has been often adopted for asymptomatic patients, although most eventually need treatment.

In studies within the past decade, progression-free survival and OS of previously untreated patients has been significantly improved by the inclusion of rituximab in treatment regimens.6,7 Impressive results have been reported for previously untreated patients receiving rituximab alone for induction therapy followed by maintenance.8 Martinelli et al8 (SAK 35/98 study) reported that nearly half of the previously untreated patients were free of progression 8 years after

Table 1

Randomized Studies of Watch and Wait Versus Intervention for Low-Tumor-Burden Follicular Lymphoma

Table 1
rituximab induction and 4 maintenance doses. With the excellent results after antibody therapy alone for many patients who needed therapy, a recent randomized trial9 has evaluated initial treatment with rituximab, with or without maintenance, or watchful waiting for asymptomatic patients with low-tumor-burden FL. This study by Ardeshna et al9 raised the question of whether patients who typically are observed should be treated, and therefore whether observation should no longer be an option. In this multicenter study, 379 patients were randomized to watchful waiting, rituximab induction alone (R/R), or rituximab induction followed by 2 years of maintenance (R/M). The rituximab followed by observation, or R/R, arm closed early based on results of other studies demonstrating the progression-free survival benefit of R/M followed by induction with rituximab monotherapy.8

However, the SAKK 35/98 trial was not specific to patients with low tumor burden, and many of these patients had a typical indication for treatment. In contrast, results from the RESORT trial,10 which compared R/R and R/M specifically in patients with low-tumor-burden FL, showed no difference in time to treatment failure between the arms. These results argue against the early closure of the R/R arm in the Ardeshna study. Most patients in both arms of the RESORT study (86% for R/R and 95% for R/M) did not require cytotoxic chemotherapy during the 3-year follow-up. Proponents of early treatment with rituximab for low-tumor-burden FL argue that this compares favorably with the median time to treatment failure with a watch and wait approach, which has been 31 to 36 months.

Although in the Ardeshna randomized study of watch and wait versus R/M a significant difference was seen in the time to not needing new therapy for the watch and wait group compared with the patients undergoing R/M (46% vs 88%), many of the watchful waiting patients would be candidates for single-agent rituximab at disease progression.9 Thus, this does not mean that half of these patients will require cytotoxic chemotherapy within 3 years. The patients treated with R/M had significant improvements in quality of life scores compared with those treated with watchful waiting, specifically with respect to mental adjustments to cancer, the ability to cope with illness, and the degree of worry about future treatment over time. Although the 2 groups differed significantly with respect to these outcome measures at 7-month follow-up, a small percentage of patients reported severe anxiety (9% vs 13%) or a deterioration in their mental adjustment to, or ability to cope with, their illness. No difference in histologic transformation or OS was observed. Finally, 12 grade 3/4 adverse events were seen in the patients who received rituximab, including neutropenia, infections, and infusion reactions.

The Ardeshna et al9 study raises the question of whether asymptomatic patients with low-tumor-burden FL should receive R/M. Given the challenge of making OS an end point in a disease with a long natural history, a reasonable surrogate end point for this study would be time to second therapy for both the initially observed and the rituximab-treated groups. If there was a significant difference in time to second therapy, then there might be justification for earlier use of R/M. Because other key end points, specifically OS and incidence of histologic transformation, are not improved by R/M, this strategy is hard to recommend. Although quality of life was more favorable in those treated with R/M, the proportion of patients with severe anxiety and worry was still small in the watchful waiting group, and an R/M strategy is not a “free lunch.” Increased adverse events, cost of treatment, and uncertainty about whether patients treated with R/M would respond differently to second treatment cast doubt on whether there is any true benefit to starting therapy early in patients who would otherwise not warrant treatment.

The authors have disclosed that they have no financial interests, arrangements, affiliations, or commercial interests with the manufacturers of any products discussed in this article or their competitors.

EDITOR

Kerrin M. Green, MA, Assistant Managing Editor, JNCCN—Journal of the National Comprehensive Cancer Network

Ms. Green has disclosed that she has no relevant financial relationships.

CE AUTHORS

Deborah J. Moonan, RN, BSN, Director, Continuing Education, has disclosed that she has no relevant financial relationships.

Ann Gianola, MA, Manager, Continuing Education Accreditation & Program Operations, has disclosed that she has no relevant financial relationships.

Kristina M. Gregory, RN, MSN, OCN, Vice President, Clinical Information Operations, has disclosed that she has no relevant financial relationships.

Rashmi Kumar, PhD, Senior Manager, Clinical Content, has disclosed that she has no relevant financial relationships.

Hema Sundar, PhD, Oncology Scientist/Senior Medical Writer, has disclosed that she has no relevant financial relationships.

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Correspondence: Arnold S. Freedman, MD, Dana-Farber Cancer Institute, 450 Brookline Avenue, Boston, MA 02215. E-mail: Arnold_Freedman@dfci.harvard.edu

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