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© 2000 American Society for Clinical Oncology
The Curious Case of the Baffling BiologicalNational Cancer Institute , Bethesda, MD
The temptation to form premature theories upon insufficient data is the bane of our profession. S. Holmes1
In solving a problem of this sort, the grand thing is to be able to reason backward. S. Holmes2 FIRST CAME THE solution, then came the problem. More than two decades ago, the results of several small series that tested varying doses and schedules of different preparations of interferon (IFN) suggested activity for this agent in the low-grade non-Hodgkin’s lymphomas (NHL).3-5 These preliminary, encouraging observations resulted in a kaleidoscope of randomized trials that were conducted to better characterize the role of this drug. IFN was eventually approved by the United States Food and Drug Administration for low-grade NHL in combination with aggressive chemotherapy largely on the basis of data from the Groupe d’Etude des Lymphomes Folliculaires (GELF).6 Their study accrued 242 assessable patients with follicular NHL and a high tumor burden. They were treated with a regimen consisting of doxorubicin, cyclophosphamide, teniposide, and prednisone, either alone or with concurrent IFN, which was continued for 18 months. The advantages in response rate (85% v 69%), event-free survival (34 v 19 months), and overall survival at 3 years (86% v 69%) all favored the group of patients who received IFN, and the results remained significantly different with additional follow-up.7 However, there were at least nine completed randomized trials that studied the role of IFN either during induction,8 as maintenance therapy,9-11 or in both settings.6,12-15 The results were strikingly inconsistent, leaving the role for this agent more baffling than it would seem. Attempting to define the place for IFN, Rohatiner et al16 (data updated through the kindness of A. Rohatiner, MD) conducted a meta-analysis using the 1,671 newly diagnosed patients from the various randomized IFN trials. In five studies, the chemotherapy was considered to be less intensive, defined as not including an anthracycline or anthracene agent.11-15 In these studies, there was no evidence for any benefit from IFN. In contrast were the results of the analysis of the four trials of more intensive treatment.7-10 Although there was still no improvement in the response rate when IFN was added to the chemotherapy agents, there was a consistent, but not uniform, prolongation of time to disease progression. Moreover, there was a significant survival advantage in favor of the IFN arms (14% at 5 years and 22% at 8 years), although this benefit was limited to patients who had responded to their induction regimen with either a complete or partial response. The conclusion was that IFN played a role in responsive patients who were receiving more intensive chemotherapy. Just when we thought that the mystery was solved, the article by Fisher et al17 published in this issue of the Journal of Clinical Oncology confounds the issue once again. This Southwest Oncology Group (SWOG) study, one of the largest to date, accrued 571 previously untreated patients with stage III or IV low-grade NHL. The patients received a minimum of six courses of chemotherapy with prednisone, methotrexate, doxorubicin, cyclophosphamide, etoposide, mechlorethamine, vincristine, and procarbazine, with involved-field radiation to convert partial responses with a negative bone marrow to a complete remission. Responding patients were then randomized to IFN for 2 years or to observation. There was no difference in progression-free or overall survival. So, how do we reconcile these divergent results? Unfortunately, the answer is not elementary: no two trials were created equal, and, therefore, none are readily comparable. There are differences in patient-associated factors: eligible histologies (follicular v follicular + others); patient risk factors that predict outcome (eg, bulky disease, extranodal involvement, lactate dehydrogenase, disease-related symptoms, age). There are also differences in treatment-associated factors, including IFN type, dose, and schedule; whether the agent was administered to all patients or only to the responders; and the percentage of patients who were actually able to complete the full course of IFN therapy. And, I am sure there are a number of other factors yet to be identified. The International Prognostic Index was developed to standardize definitions of risk groups, and recently recommended response criteria ensure that response definitions are consistent.18,19 Unfortunately, all of these studies were initiated before these guidelines were published, and the necessary data were not available on sufficient numbers of patients to enable comparisons among most of them. The case becomes more curious as we examine the clues from the GELF trial, which is the only large published study to show a survival advantage with IFN, and the current negative SWOG trial. There is no reason to expect that one of these chemotherapy regimens would be better than the other. The most significant distinction between the two studies is that the GELF trial included the only one of the more intensive regimens in which IFN was administered both during induction and maintenance therapy. The GELF and SWOG studies used the same IFN preparation, with a schedule of 5 million units three times a week for 18 months in the former and 2 MU/m2 three times a week for 2 years in the latter. The GELF trial included follicular histologies only, whereas the SWOG protocol admitted patients with small lymphocytic lymphoma, but these comprised only 8% of the group. The median ages of the patients were similar: 52 years in the GELF trial and 49 years in the SWOG study. An estimate of the distribution of International Prognostic Index subgroups in the GELF and SWOG trials suggests that they are comparable: low, 37% versus 51%; low-intermediate, 36% versus 36%; high-intermediate, 19% versus 10%; and high, 3% versus 3%, respectively. It is difficult to imagine how these rather modest differences between these two trials could lead to such a major disparity in outcomes. But what about the great arbiter—the meta-analysis? Unfortunately, these calculations are not without their own difficulties. An interesting study was published in 1995 that included 40 phase III trials published in prestigious journals, involving more than 1,000 patients.20 The authors compared the results of a meta-analysis with the subsequent large randomized trial. They found that the meta-analysis failed to predict the results of randomized trials 35% of the time. Indeed, for 46% of the discrepancies, a positive meta-analysis was followed by a negative randomized trial. The IFN meta-analysis will soon be revised to include the SWOG data: it will be interesting to see what effect the large amount of negative SWOG data will have on those previously significant differences. Nevertheless, whatever the results of the new meta-analysis, they will be of little more than historic interest. Physicians must seriously consider whether to recommend this agent to their NHL patients with its significant expense and toxicities when it takes a meta-analysis to suggest benefit, yet still no curative potential. What is clear is that there already have been enough randomized chemotherapy-IFN trials: the SWOG study had better be the last of them! The new century finds us with a more appealing dilemma: How do we best evaluate the abundance of new and exciting agents that are rapidly becoming available for clinical trials of the low-grade NHL? Perhaps the greatest enthusiasm has been stimulated by the current generation of monoclonal antibodies, including rituximab (Rituxan; IDEC Pharmaceuticals Corp, San Diego, CA, and Genentech, Inc, South San Francisco, CA), iodine-131 tositumomab (Bexxar; Coulter Pharmaceutical, Inc, Palo Alto, CA), yttrium-90 ibritumomab (Zevalin; IDEC Pharmaceuticals Corp), and alemtuzumab (Campath-1H; Millennium Pharmaceuticals, Inc, Cambridge, MA)21-25; vaccines26,27; and antisense therapy.28 Unique new chemotherapy drugs being evaluated include compound GW506U78, depsipeptide, arsenic trioxide, flavopiridol, UCN-01, angiogenesis inhibitors, and many others.29-34 Hopefully, the various phase III trials involving these agents will be designed and coordinated in such a fashion so that the results can be compared, and, therefore, the conclusions will be less ambiguous than with IFN. It is an exciting time in clinical research for NHL. Hopefully, rational development of combinations of the new chemotherapy and biologic agents will finally solve the case of the incurable low-grade NHL. REFERENCES 1. Doyle AC: The Valley of Fear. The Strand Magazine, September 1914 2. Doyle AC: A Study in Scarlet. Beeton’s Christmas Annual, 1887 3. Merigan TC, Sikora K, Breeden JH, et al: Preliminary observations on the effect of human leukocyte interferon in non-Hodgkin’s lymphoma. N Engl J Med 299:1449-1553, 1978[Medline] 4. Foon KA, Sherwin SA, Abrams PG, et al: Treatment of advanced non-Hodgkin’s lymphoma with recombinant leukocyte A interferon. N Engl J Med 311:1148-1152, 1984[Abstract] 5. O’Connell MJ, Colgan JP, Oken MM, et al: Clinical trial of recombinant leukocyte A interferon as initial therapy for favorable histology non-Hodgkin’s lymphomas and chronic lymphocytic leukemia: An Eastern Cooperative Oncology Group pilot study. J Clin Oncol 4:128-136, 1986[Abstract]
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Fisher RI, Dana BW, LeBlanc M, et al: Interferon alfa consolidation after intensive chemotherapy does not prolong the progression-free survival of patients with low-grade non-Hodgkin’s lymphoma: Results of the Southwest Oncology Group randomized phase III study #8809. J Clin Oncol 18:2010-2016, 2000
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LeLorier J, Grégoire G, Benhaddad A, et al: Discrepancies between meta-analyses and subsequent large randomized, controlled trials. N Engl J Med 337:536-542, 1997 21. McLaughlin P, Grillo-López AJ, Link BK, et al: Rituximab chimeric anti-CD20 monoclonal antibody therapy of relapsed indolent lymphoma: Half of patients respond to a four-dose treatment program. J Clin Oncol 16:2825-2833, 1998[Abstract] 22. Vose JM, Zelenetz AD, Rohatiner A, et al: Iodine 131 tositumomab for patients with follicular non-Hodgkin’s lymphoma (NHL): Overall clinical trial experience by histology. Blood 94:89a, 1999 (abstr 387)
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Copyright © 2000 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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