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Originally published as JCO Early Release 10.1200/JCO.2005.06.146 on January 31 2005 © 2005 American Society of Clinical Oncology. Meta-Analysis to Evaluate the Role of Interferon in Follicular LymphomaFrom St Bartholomew's Hospital, London, UK; University of Minnesota, Minneapolis, MN; Taussig Cancer Center, Cleveland, OH; Centre Jean Bernard, Le Mans, France; University Medical Center, Utrecht, The Netherlands; Wilmot Cancer Center, University of Rochester, Rochester, NY; Georg-August-University, Gottingen, Germany; Hospital Universitario de la Princesa, Madrid, Spain; Ospedale Civile, Venice, Italy; Oncology Hospital, IMSS, Mexico City, Mexico Address reprint requests to A.Z.S. Rohatiner, MD, FRCP, Department of Medical Oncology, St Bartholomew's Hospital, 45 Little Britain, London, EC1A 7BE, United Kingdom; e-mail: ama.rohatiner{at}cancer.org.uk
PURPOSE: To determine whether interferon (IFN) -  2, when given with or following chemotherapy, influences response rate, remission duration, and survival in newly diagnosed patients with follicular lymphoma.
PATIENTS AND METHODS: Ten phase III studies evaluating the role of IFN-
RESULTS: The addition of IFN-
CONCLUSION: When given in the context of relatively intensive initial chemotherapy, and at a dose
Interferon (IFN) was introduced into the treatment of follicular lymphoma following observation of activity in L1210 leukemia1 and AKR lymphoma,2 but with limited understanding of its mode of action. Phase II studies (using an empirical dose and schedule derived from the original Scandinavian osteogenic sarcoma trial3) in low-grade lymphoma, resulted in response rates of 30% to 50%, regardless of the source of IFN- 2.4-11 Such responses were, however, almost always incomplete and, in general, short lived. Activity having been demonstrated, the concept of synergy between IFN and conventional cytotoxic drugs was tested and confirmed in murine models of leukemia12 and lymphoma,13 in human breast cancer xenografts in nude mice,14 and in patients with follicular lymphoma known to be refractory to chemotherapy.15,16
A series of randomized studies followed, in newly diagnosed patients with a spectrum of histologic subtypes, evaluating the use of IFN- In addition to the variation in histologic subtype engendered by the inclusion of patients with any type of low-grade lymphoma (though the majority of patients in fact had follicular lymphoma), there were also differences in eligibility criteria. Some studies were very permissive, allowing enrollment of not only patients who had a specific indication for treatment, but also of those who did not. Conversely, others, for example the GELA (Groupe d'Etudes des Lymphomes de l’Adulte) study,19,20 focused on patients deemed to have an adverse prognosis (by GELA criteria), while one study included only patients in whom a complete remission (CR) had been achieved with prior chemotherapy.27
As a consequence of this heterogeneity (in both patient population and entry criteria), there are major discrepancies in the results, even when only studies with a similar design are considered. Therefore, for this meta-analysis, only patients with follicular lymphoma were included. The aim was to determine whether IFN-
Studies At the inception of the project, review of the published literature (and of completed analyses presented in abstract form) led to identification of eight phase III studies of newly diagnosed patients with "low-grade" or, specifically, follicular lymphoma. A protocol was written and distributed to individual authors and groups, who were then asked to provide updated (ie, updated from the original publication or analysis for that study) individual patient information, which was transmitted electronically to us (W.G.). Data were checked and only patients described as having follicular lymphoma were selected for inclusion in the analysis. Central review of pathology was not undertaken. On this basis, an initial meta-analysis was conducted and presented.30 Data from two studies that had not been published at that time were subsequently made available.24,28 The present meta-analysis, therefore, comprises the results for patients included in ten phase III studies.
Patients
Treatment Treatment in terms of chemotherapy regimen and the dose, schedule, and timing of IFN- 2 is summarized in Table 2, by Study Group (or country of origin when a formal group was not involved). In six of the studies, IFN-2 was given as part of initial therapy17-24,29; in four studies, it was given only as maintenance therapy25-28; and in four studies, patients could be randomly assigned to receive it throughout.17,18,24,29
Chemotherapy. Chemotherapy regimens were categorized by the intensity of chemotherapy as follows: studies utilizing relatively "less intensive" chemotherapy are defined as those that used chlorambucil, cyclophosphamide, or cyclophosphamide/vincristine/prednisolone (CVP) as initial therapy (Table 2). Those studies that used an anthracycline or mitoxantrone-based combination regimen were deemed "more intensive" (Table 2).
Interferon.
The dose of IFN-
Meta-Analyses: Methodology
In brief, for response, the expected number of responses was calculated for each trial arm, assuming no difference in response rate between the two arms. This was then compared with the observed number of responses, and the differences (observed-to-expected ratio [O-E]) calculated for each trial. For survival and remission duration, the expected number of events (deaths or recurrences) in each arm, assuming no difference between the treatments, was derived for each trial. This was then compared with the observed number of events and the differences (O-Es) calculated. For response, survival, and remission duration, these O-E figures were then summed over the whole set of trials to form a grand total. The variance of the individual estimates was also derived and summed, giving a variance and a standard deviation (SD) for the grand total. The number of SDs (z) by which the grand total differs from zero gives an estimate of the significance of any effect. The O-Es were also tested for heterogeneity to see whether the scatter of results was unexpected. (The sum of [O-E]2/variance should be distributed as
For response, survival, and remission duration, the size of any treatment effect, specifically the typical odds ratio (TOR), was simply estimated as exp(z/SD), with approximate 95% CI expressed as exp (z/SD ± 1.96/SD). CIs for the individual trials were calculated in the same fashion. The TORs and their CIs for each trial, together with the grand total, are shown in Figures 1-7. The size of the solid squares is proportional to the amount of information each trial contains. Because many individual trials are displayed, 99% CIs are shown for the individual trials. For the overall result, 95% CIs are given (represented by the open diamonds in the figures). These odds ratios were converted into 5- and 10-year differences in survival and remission duration as follows: the odds ratio, Or, is related to the hazard ratio,
Four of the 10 studies had a double randomization, as listed in Table 2. Clearly, for each of these studies, only a proportion of randomly assigned patients initially reached the second randomization (for a variety of reasons including toxicity, patient refusal, and death). Those failing to reach the second randomization had a worse survival than those who did, because of this selection process. Furthermore, the numbers not reaching the second randomization were not necessarily the same as in the two initial randomization groups. For instance, in the UK study, 47 (45%) of 104 patients initially randomly assigned to receive IFN- 2 failed to reach the point of second randomization, compared with 30 (30%) of 100 of those patients initially randomly assigned to the chlorambucil-only arm. Therefore, in these studies, to analyze just those patients who received "any IFN-2" versus the rest of the patients would bias the result, almost certainly in favor of the IFN-2 group. To avoid this problem and to make it possible to perform a meta-analysis of IFN-2 given at any point versus no IFN-2, such studies have been regarded as having two separate strata, ie, comprising patients who reached the second randomization and those who did not. (For the Non-Hodgin's Lymphoma Study Group [NHLSG] study, information on the second randomization was unavailable, and so for this study only the initial randomization was used in the meta-analysis graphs). The remaining three studies are therefore each represented twice on the meta-analysis graphs, reflecting the two different strata.
The survival of the IFN-
Because significant heterogeneity was observed between studies (see Results), further analyses were carried out in an attempt to explain this heterogeneity. A number of hypotheses were generated. The following appeared the most likely to explain the observed differences; that IFN- 2 might increase survival when given: (1) concurrently with, or following, relatively intensive chemotherapy; (2) at a dose equal to or greater than 5 x 106 units; (3) at a cumulative dose in excess of 36 x 106 units over a period of 4 weeks; or (4) with initial chemotherapy rather than as maintenance therapy.
Response The addition of IFN- 2 to initial chemotherapy did not significantly influence response rate overall (2P = .41). The estimated difference in percentage response rate was –2% (ie, in favor of the no IFN group; 95% CI, –6% to 3%; Fig 1), though there was considerable heterogeneity between studies (2P = .005), and a highly significant benefit from IFN-2 was observed in the GELA study (2P = .006).
Survival
Further inspection of the data raised the four hypotheses listed in the Patients and Methods section; these hypotheses were investigated further. Analyzing each of the four hypotheses separately, for patients receiving relatively intensive initial therapy, IFN- 2 used at any point was associated with prolongation of survival (2P = .00005; Fig 3; 5-and 10-year survival differences being 11% [95% CI, 6% to 16%] and 15% [95% CI, 8% to 23%], respectively. In contrast, for patients receiving less intensive initial therapy (ie, alkylating agents or CVP), there was no significant improvement in survival (2P = .93; Fig 4).
Considering the individual dose of IFN- 2, for patients receiving 5 x 106 units or more per dose, there was a highly significant increase in survival (2P = .000002; Fig 5; 5- and 10-year survival differences being 15% [95% CI, 9% to 21%] and 20% [95% CI, 12% to 28%], respectively). Conversely, for patients receiving less than 5 x 106 units per dose, there was no effect on survival (2P = .75; data not shown).
Similarly, in terms of the monthly dose of IFN- 2 administered, for patients receiving more than 36 x 106 units over 4 weeks, there was a significant improvement in survival (2P = .000008; Fig 6; 5- and 10-year survival differences being 18% [95% CI, 10% to 25%] and 23% [95% CI, 14% to 33%], respectively), compared with no significant effect when IFN-2 was used at the typical dose of 3 x 106 units 3x weekly, (equivalent to 36 x 106 units per 4 weeks; 2P = .43; data not shown).
For studies in which IFN- 2 was given initially together with chemotherapy, there was a significant improvement in survival (2P = .004; data not shown; 5- and 10-year survival differences being 7% [95% CI, 2% to 12%] and 9% [95% CI, 3% to 15%], respectively), compared with no significant effect in studies in which it was given only as maintenance (2P = .20; data not shown). In the latter group, the only study that demonstrated an effect was the Mexican study, which was, again, an outlier. Excluding this study reduced the significance to 2P = .98. It should be noted that none of the latter four results are significantly altered by the exclusion of the data from the Mexican study. For instance, for patients receiving 5 x 106 units or more per dose, there was still a highly significant increase in survival (2P = .0002; data not shown). The odds reduction was 37% ± 10% (hardly different than with the inclusion of the Mexican study's data), and 5- and 10-year survival differences were also largely unaffected, being 13% (95% CI, 6% to 20%) and 17% (95% CI, 8% to 25%), respectively. The other three comparisons show similar small differences from the equivalent analyses that included the Mexican data (data not shown). This is because, though the Mexican study shows a relatively large survival difference, it is a relatively small study, and the significance and magnitude of the meta-analysis differences are influenced more by the studies with larger numbers of patients, such as those conducted by the Eastern Cooperative Oncology Group (ECOG) and GELA. Plotting the hazards as they change over time, as described in Patients and Methods, showed a pattern of increasing hazard over time (Fig 9). There is a big rise in risk of death from not having received IFN during the 3- to 4-year period after entry, and though the risk reduces slightly thereafter, it is maintained at least up to 7 years from entry, and probably beyond. Although there may be some random element to this pattern, it is very clear that the risk increases over time from entry. It therefore appears that IFN produces an effect that is maintained, or even increases, over time. This was confirmed by a weighted correlation of adjacent yearly hazards that gave a correlation coefficient of r = 0.60 (2P = .04). Thus the 10-year survival estimates are probably slight underestimates of the true difference (by approximately 25%, so the overall reported 10-year survival difference of 8% is probably closer to 10%), and this is confirmed by inspection of the adjusted survival graph (Fig 8) and survival estimates taken from it, which show this slightly larger difference (the adjusted survival curve methodology does not assume proportional hazards33 and can therefore produce these estimates). The 5-year survival estimates appear to be much more accurate, being in the middle of the survival range for this analysis. It should be noted that the departure from proportional hazards is not sufficient to invalidate the findings of the study; its main effect is to create a slight underestimate of the 10-year survival figures.
To confirm this finding, the meta-analyses were repeated using only data from the patients who had already survived 3 years (because the hazard is close to zero for the first 3 years, which is different from its later values), and the basic findings were unaltered; if anything the results tended to be more significant, and with less heterogeneity between studies.
Remission Duration
These results demonstrate that the addition of IFN- 2 to conventional chemotherapy as part of initial therapy for newly diagnosed patients with follicular lymphoma does not result in any improvement in response rate. However, the meta-analysis confirms that IFN-2 does prolong remission duration and overall survival, and also prolongs survival and remission duration under specific circumstances that relate to the intensity of the chemotherapy used, the dose of IFN-2, or both. The point at which IFN-2 is given, ie, as part of initial therapy rather than as maintenance therapy, also appears to influence outcome. There was no survival difference following only maintenance IFN-2 therapy (except in the Mexican study).
To summarize, overall, there was an effect of IFN- The difference in survival (Figs 8 and 9) increases over time. The survival effect appears to be a late effect, and the difference between the curves may therefore widen further with longer follow-up. This is in keeping with the difference in remission duration, which shows a consistent effect from about 1 year onwards, with a difference of at least 10% at 10 years. This might be expected to translate eventually into a similar size of survival difference, as is becoming apparent in the survival curve.
It is important to recognize that the data on which the meta-analysis is based reflect protocol dose and not actual dose administered. Originally, it had been the intention to analyze the results using the dose given (of both chemotherapy and of IFN- The prolongation in survival in the context of relatively more intensive chemotherapy is unlikely to be simply a reflection of an increase in the intensity of the chemotherapy. Intensification of treatment in follicular lymphoma has increased remission duration34 but not survival.35-43 An earlier meta-analysis based on data from 8 studies (as published in manuscript or abstract form) also showed significantly better 5-year survival and longer progression-free survival at 3 and 5 years for patients with low-grade lymphoma who received IFN in randomized trials.44 Furthermore, the advantage was most marked in studies using anthracycline-containing induction chemotherapy. It is of interest that despite the methodology being very different (in that the present study used individualized updated patient data), the main conclusions are in fact the same.
Thus, the meta-analysis results support the use of IFN-
The following authors or their immediate family members have indicated a financial interest. No conflict exists for drugs or devices used in a study if they are not being evaluated as part of the investigation. Research funding: A.Z.S. Rohatiner, Schering-Plough; P. Solal-Celigny, Schering-Plough. For a detailed description of this category, or for more information about ASCO's conflict of interest policy, please refer to the Author Disclosure Declaration and Disclosures of Potential Conflicts of Interest found in Information for Contributors in the front of each issue.
We are very grateful to all the data managers at individual hospitals and of the cooperative groups who contributed data, and thank Margaret Cresswell for preparing the manuscript. Andrew Lister and Ama Rohatiner are supported by Cancer Research UK. The authors are affiliated with the following organizations: Cancer and Leukemia Group B (CALGB), B. Peterson; Eastern Cooperative Oncology Group (ECOG), B. Peterson, E. Borden; Groupe d’Etudes des Lymphomes de l’Adulte (GELA), P. Solal-Celigny; European Organisation for Research and Treatment of Cancer (EORTC), A. Hagenbeek; Southwest Oncology Group (SWOG), R.I. Fisher; German Low Grade Lymphoma Study Group (GLSG), M. Unterhalt; LNH-PRO, R. Arranz.
Supported in part by a grant from Schering-Plough. Authors' disclosures of potential conflicts of interest are found at the end of this article.
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Copyright © 2005 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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ABSTRACT
INTRODUCTION
5 million units (2P = .000002), (3) at a cumulative dose 
2n – 1 if the scatter is random, where n is the number of studies.) 
, by the equation 
