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Originally published as JCO Early Release 10.1200/JCO.2008.16.1398 on July 28 2008 © 2008 American Society of Clinical Oncology.
Follicular Lymphoma, Survival, and Rituximab: Is It Time to Declare Victory?
Stanford University Medical Center, Stanford, CA Seemingly an unattainable goal in the 20th century, prolongation of survival has long been the Holy Grail of clinical investigation in follicular lymphoma. In fact, single institutional data over a 30-year time period from Stanford University were frequently cited as evidence for the lack of progress.1 All that has changed. Reports of change in follicular lymphoma survival first appeared in the form of retrospective analyses in Journal of Clinical Oncology. Swenson et al2 assessed U.S. population data, citing an improvement in overall survival of 1.8% per year among patients diagnosed from 1983 to 1999. They speculated that the advance was due to the sequential application of effective therapies and improved supportive care.2 Improvements in survival were reported in each of three eras of Southwest Oncology Group therapeutic trials conducted from 1974 to 2000, and the highest 4-year overall survivals were achieved with chemotherapy plus anti-CD20 antibody.3 The authors attributed the 10% gain in survival for patients treated from 1988 to 1994—the prerituximab era—to effective sequential treatment options, because there was no advantage in progression-free survival after initial therapy in this era. Similarly, significant gains in overall survival in stage IV follicular lymphoma were reported in a retrospective analysis from the M. D. Anderson Cancer Center during a 25-year period.4 In this report, the efficacy of both initial and subsequent treatments was credited for the progress. Recently, new data from Stanford University demonstrated longer overall survivals in patients diagnosed after 1986.5 Again, this progress was attributed to effective sequential treatments because no prolongation in the time to progression after initial therapy was observed. In this issue of JCO, Marcus et al6 describe a survival benefit for patients with advanced stage follicular lymphoma requiring therapy, based on their initial treatment. In a randomized controlled trial, 4-year overall survival rates were 83% for rituximab, cyclophosphamide, vincristine, and prednisone (R-CVP) and 77% for CVP (P = .03). These data are concordant with two German phase III trials in which rituximab plus chemotherapy was tested against chemotherapy alone for remission induction. Although the German trials also incorporated interferon or high-dose therapy with autologous transplantation as consolidation, the described survival benefits are of similar magnitude. Collectively, do these results lead to the conclusion that primary therapy including rituximab prolongs overall survival and the corollary that rituximab as initial treatment is superior to the sequential use of rituximab at a later time in the disease course? Let's review the data more carefully. It should be noted that each of the three cited European trials had early primary end points relative to the conventional progression-free survival end point. Patients who did not achieve partial response after four treatment cycles were considered treatment failures in the Marcus study. Patients achieving less than partial remission went off-study after four cycles of chemotherapy in the trial of Hiddemann et al, 7 and patients achieving less than partial remission after six cycles of chemotherapy were scored as treatment failures in the trial of Herold et al.8 Theoretically, survival bias could be introduced in favor of the chemotherapy-only arms if patients immediately crossed over to rituximab or initiated another highly effective second-line treatment, whereas the bias could be unfavorable in the chemotherapy-only arms if patients were managed conservatively with observation or less effective treatments. To address the question whether the initial use of rituximab confers a survival advantage over its sequential use, information on the type and timing of second-line therapy is needed. Although rituximab was approved for relapsed follicular lymphoma in the United States in 1997, it may not have been fully available for second-line use in combination in all the countries participating in the R-CVP versus CVP until after 2004, according to Marcus et al.6 This lack of accessibility may explain why just one third of patients treated for relapse after CVP received rituximab as secondary therapy. Unfortunately, as such, the results from this trial cannot fully address the question of sequence. The authors state that the survival differences—76% of patients treated with rituximab at first relapse compared to 64% of patients treated otherwise—did not achieve statistical significance; but this is a sizeable disparity, and there was little power to observe a significant survival difference based on the sample size. The enormity of the difficulty in demonstrating a survival difference in follicular lymphoma with a true cross-over design has been recently demonstrated by Ladetto et al.9 In this Italian multicenter study, highly unfavorable follicular lymphoma patients were randomly assigned to cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) plus rituximab or a high-dose sequential chemotherapy with rituximab regimen with autologous transplantation. Patients experiencing disease progression after CHOP plus rituximab crossed-over to the high-dose arm. Despite a large difference in failure-free survival (61% v 28% at 4 years; P < .001) in favor of high-dose treatment, no survival difference was observed (P = .7), leading the authors to conclude that the more intensive approach was better used as second-line treatment, based on the toxicity profile.9 Because follicular lymphoma is a heterogeneous disease, clinical trial results must be interpreted in context. Each of the randomized rituximab and chemotherapy versus chemotherapy phase III trials excluded patients without indications for immediate treatment. In a fourth European trial, the FL2000 study conducted by French investigators, high tumor burden patients randomly assigned to rituximab plus chemotherapy and interferon enjoyed significantly longer event-free survival (P < .001).10 However, only the subset of high-risk patients by the follicular lymphoma prognostic index had significantly longer overall survivals, compared to chemotherapy and interferon alone. In the United States Eastern Cooperative Oncology Group 1496 trial, rituximab was given as a maintenance treatment after CVP. Progression-free survival was markedly prolonged with maintenance rituximab (P < .001) in this trial, but overall survival significantly favored maintenance rituximab only in the high tumor burden subset.11 In concert, the data suggest that primary treatment with rituximab plus chemotherapy in follicular lymphoma patients who require therapy leads to longer overall survival, particularly in higher risk disease and if the use of subsequent rituximab (or other highly effective therapy) is delayed or uncertain. But of far greater importance are that patients with follicular lymphoma are living longer than ever and that rituximab is a major contributor to this accomplishment. In part, longer survivals observed in patients diagnosed before the rituximab era can be attributed to better education of physicians and patients, earlier recognition and treatment of histologic transformation, new therapies offered at relapse, and better supportive care. For patients diagnosed before 1997 and living long enough, rituximab, radioimmunotherapy, nonmyeloablative transplantation, and other new agents have contributed to longer survival. Rituximab represents the most important advance in the treatment of B-cell lymphoma in the past 30 years. Even without an observed survival advantage, the magnitude of the delay in disease progression with primary combined chemotherapy and rituximab justifies its use for patients with follicular lymphoma needing treatment. It is time to declare a giant leap forward for patients with follicular lymphoma. But it is premature to declare victory. That will come when we produce an individualized treatment approach, hopefully leading to cure, that preserves life expectancy and the quality of life for patients diagnosed with follicular lymphoma. AUTHOR'S DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST Although all authors completed the disclosure declaration, the following author(s) indicated a financial or other interest that is relevant to the subject matter under consideration in this article. Certain relationships marked with a "U" are those for which no compensation was received; those relationships marked with a "C" were compensated. For a detailed description of the disclosure categories, or for more information about ASCO's conflict of interest policy, please refer to the Author Disclosure Declaration and the Disclosures of Potential Conflicts of Interest section in Information for Contributors. Employment or Leadership Position: None Consultant or Advisory Role: Sandra J. Horning, Genentech Inc (C) Stock Ownership: None Honoraria: Sandra J. Horning, Roche Research Funding: Sandra J. Horning, Genentech Expert Testimony: None Other Remuneration: None NOTES published online ahead of print at www.jco.org on July 28, 2008 REFERENCES 1. Horning SJ: Natural history of and therapy for the indolent non-Hodgkin's lymphomas. Semin Oncol 20:75-88, 1993[Medline] 2. Swenson WT, Wooldridge JE, Lynch CF, et al: Improved survival of follicular lymphoma patients in the United States. J Clin Oncol 23:5019-5026, 2005 3. Fisher RI, LeBlanc M, Press OW, et al: New treatment options have changed the survival of patients with follicular lymphoma. J Clin Oncol 23:8447-8452, 2005 4. Liu Q, Fayad L, Cabanillas F, et al: Improvement of overall and failure-free survival in stage IV follicular lymphoma: 25 years of treatment experience at The University of Texas M. D. Anderson Cancer Center. J Clin Oncol 24:1582-1589, 2006 5. Tan D, Rosenberg SA, Levy R, et al: Survival in follicular lymphoma: The Stanford experience, 1960-2003. Blood 110:3428A, 2007 6. Marcus RE, Imrie K, Solal-Celigny P, et al: Phase III study of rituximab plus CVP compared to CVP alone in patients with previously untreated advanced follicular lymphoma. J Clin Oncol 26:4579-4586, 2008 7. Hiddemann W, Kneba M, Dreyling M, et al: Frontline therapy with rituximab added to the combination of cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) significantly improves the outcome for patients with advanced-stage follicular lymphoma compared with therapy with CHOP alone: Results of a prospective randomized study of the German Low-Grade Lymphoma Study Group. Blood 106:3725-3732, 2005 8. Herold M, Haas A, Srock S, et al: Rituximab added to first-line mitoxantrone, chlorambucil, and prednisolone chemotherapy followed by interferon maintenance prolongs survival in patients with advanced follicular lymphoma: An East German Study Group Hematology and Oncology study. J Clin Oncol 25:1986-1992, 2007 9. Ladetto M, De Marco F, Benedetti F, et al: Prospective, multicenter randomized GITMO/IIL trial comparing intensive (R-HDS) versus conventional (CHOP-R) chemoimmunotherapy in high-risk follicular lymphoma at diagnosis: The superior disease control of R-HDS does not translate into an over-all survival advantage. Blood 111:4004-4013, 2008 10. Salles G, Mounier N, De Guibert S, et al: Final analysis of the GELA-GOELAMS FL2000 study with a 5-year follow-up. Blood 110:792A, 2007[CrossRef] 11. Hochster HS, Weller E, Gascoyne RD, et al: Maintenance rituximab after CVP Results in superior clinical outcome in advanced follicular lymphoma (FL): Results of the E1496 phase III trial. Blood 106:349A, 2005 Related Article
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Copyright © 2008 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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