Journal of Clinical Oncology, Vol 17, Issue 7
(July), 1999: 2039
© 1999 American Society for Clinical Oncology
Cytokines in Metastatic Renal Cell Carcinoma: Is It Useful to Switch to Interleukin-2 or Interferon After Failure of a First Treatment?
Bernard Escudier,
Christine Chevreau,
Christine Lasset,
Jean Yves Douillard,
Alain Ravaud,
Michel Fabbro,
Armelle Caty,
Jean Francois Rossi,
Patrice Viens,
Jean Pierre Bergerat,
Jacqueline Savary,
Sylvie Négrier,
for the Groupe Français d'Immunothérapie
From the Institut Gustave Roussy, Villejuif; Centre Claudius Régaud, Toulouse; Centre Léon Bérard, Lyon; Centre René Gauducheau, Nantes; Institut Bergonié, Bordeaux; Centre Val d'Aurelle, Montpellier; Centre Oscar Lambret, Lille; CHU, Montpellier; Institut Paoli Calmettes, Marseille; and CHU, Strasbourg, France.
Address reprint requests to Bernard Escudier, MD, Institut Gustave Roussy, 39 rue Camille Desmoulins, 94805 Villejuif, France; email escudier{at}igr.fr
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ABSTRACT
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PURPOSE: Interleukin-2 (IL-2) and interferon alfa-2a (IFN 2a) have some antitumor activity in metastatic renal cell carcinoma either alone or in combination. To determine whether either of these cytokines might be efficient after failure of the other, we analyzed a series of patients treated with either IL-2 or IFN2a as second-line treatment after failure of the other cytokine.
PATIENTS AND METHODS: We recently performed a large multicenter study to determine the respective efficacy of IL-2, IFN2a, or combined treatment in renal cell carcinoma. In this study, patients who progressed on the single-arm treatment could receive the other cytokine in a cross-over trial. IL-2 was administered as a continuous intravenous infusion for 5 days (18 x 106 IU/m2/d), and IFN2a was administered three times weekly at 18 x 106 IU.
RESULTS: A total of 113 patients with progressive disease after first-line treatment received either IFN2a (n = 48) or IL-2 (n = 65). Toxicity during second-line treatment was similar to that observed during first-line treatment. Only four partial responses were observed (one with IFN2a and three with IL-2). All partial responders had a performance status of 0 and lung metastases. Moreover, three of these four patients had stable disease or had responded to first-line therapy. Only one patient with confirmed disease progression after receiving IL-2 subsequently responded to IFN2a.
CONCLUSION: Cross-over after failure of IL-2 or IFN2a is poorly efficient in metastatic renal cell carcinoma, especially when progression has been clearly documented.
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INTRODUCTION
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METASTATIC RENAL CELL carcinoma is refractory to chemotherapy, with a reported median survival duration of 2 to 12 months.1-3 Since the early 1980s, interferon alfa-2a (IFN2a) and interleukin-2 (IL-2) have demonstrated some activity, both alone and in combination, with objective response rates ranging from 5% to 40%.4-9 However, the respective roles of these two cytokines have been poorly investigated, and many questions remain unsolved.
In an attempt to answer some of these questions, the Groupe Français d'Immunothérapie decided to conduct a large trial to determine the role of these approved but expensive cytokines in metastatic renal cell cancer. The first objective of this prospective randomized study (the Cancer Renal Cytokines [CRECY] trial) was to determine the efficacy and toxicity of IFN2a, IL-2, and a combination of both cytokines. Combination of IL-2 and IFN2a was found to have an edge over each cytokine administered independently in terms of objective responses and event-free survival.10 However, toxicity of this combined regimen was high, and overall survival was not different in the three arms.
Another question in the CRECY trial was whether treatment with either IL-2 or IFN2a could be beneficial to patients whose disease progressed after treatment with the other cytokine. To address this question, the study was designed so that patients who experienced progression in the IL-2– or IFN2a-alone arms of the trial could switch to the alternative arm. Here we report the results of this study.
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PATIENTS AND METHODS
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Patient Selection
Eligibility criteria for the CRECY trial have been reported elsewhere.10 Briefly, patients with metastatic renal cell cancer, aged 18 to 65 years, with measurable metastatic disease and adequate organ functions were deemed eligible. Patients whose disease progressed during or after treatment with IL-2 or IFN2a alone could be switched to the other cytokine arm. This cross-over was allowed either after immediate progression or when progression occurred later during follow-up (in patients whose disease was initially stable or who relapsed after an initial objective response). However, patients had to be able to receive intravenous IL-2 when the cross-over was proposed.
Treatment
Randomization of first-line treatment was stratified by center using an interactive computerized procedure. All data were prospectively monitored on site. Eligible patients were randomly assigned to receive either intravenous IL-2 alone (arm 1), IFN2a alone (arm 2), or IL-2 combined with IFN2a (arm 3). The treatment arms have been described previously.10 IL-2 (Proleukin; Chiron Therapeutics, Suresnes, France) was administered as a 5-day continuous intravenous infusions at a dose of 18 x 106 IU/m2/d (four cycles). IFN2a (Roferon; Roche, Neuilly sur Seine, France) was administered subcutaneously at a dose of 18 x 106 IU/d three times weekly for 10 weeks as induction treatment and for 13 additional weeks as maintenance treatment.
IL-2 or IFN2a was administered in the cross-over study according to the same schedule used in arms 1 and 2. Clinical response was evaluated at week 10 and was based on adequate computed tomography examinations.
Supportive Care
Patients assigned to receive intravenous IL-2 had a central venous catheter inserted, and prophylactic antibiotherapy, usually intravenous quinolone, was recommended. Patients also received acetaminophen (1 g every 4 hours); when necessary, indomethacin (25 mg every 6 hours) to reduce febrile reactions; cimetidine or misoprostol to prevent gastrointestinal bleeding; diphenhydramine for pruritus; and antidiarrheal agents. In addition, antiemetics, anxiolytics, and sedative agents were administered when required. Colloids were used initially to treat hypotension, followed by vasopressive agents, usually dopamine, when necessary.
Dose Modification and Toxicity Monitoring
The World Health Organization scoring system was used to classify the toxicities.11 Treatment was stopped for refractory hypotension (eg, resistant to intravenous vasopressive treatment) or for any toxic event  grade 3. Patients with life-threatening or persistent severe toxicities received no further trial treatment. Therapy was resumed at the original doses when toxicities resolved to  grade 1. The doses were reduced, usually halved, only if a new episode of grade 3 toxicity occurred. A specific warning was sent to all investigators after reports of unusual or unexpected adverse reaction. In addition, all grade 4 toxicity reports were reviewed by the toxicity review committee to assess whether the treatment was responsible for the toxicity.
Response Assessment
World Health Organization response criteria11 were used to determine tumor response. Objective response (> 50% tumor regression) included partial and complete responses. Tumor sizes 10 weeks after treatment started were compared with tumor dimensions during the 2 weeks before treatment. Patients with at least stable disease and who were on maintenance therapy had their tumors measured at week 25.
The charts of all patients enrolled onto this cross-over study were reviewed by an external blinded review committee12 when an objective response or stable disease was reported by the investigator. The objective of this review was to assess the true response rate and verify the disease status when the switch from one treatment to the other was decided.
Statistical Analysis
The main end point of the study was response rate. Secondary end points were disease stabilization, event-free survival (defined as time to death or disease progression), and overall survival. Survival curves were calculated using the Kaplan-Meier method13 and were compared by the log-rank test.14
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RESULTS
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Treatment Characteristics and Toxicity
First-line treatment was administered to 132 and 146 patients in arms 1 and 2, respectively. Of these patients, 113 were subsequently enrolled onto the cross-over study: 48 received IFN2a after failure of IL-2, and 65 received IL-2 after failure of IFN2a. The characteristics of the patients enrolled onto the cross-over study are listed in Table 1. Both groups of patients were comparable. In contrast, patients who were enrolled onto the cross-over study were significantly different from those who were not in terms of performance status and weight loss (Table 2). These differences could partly explain why patients with progressive disease were not switched to the other treatment arm. Interestingly, centers with a large recruitment (> 10 patients) enrolled more patients onto the cross-over study than smaller centers.
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Table 2. Characteristics of Patients in Arms 1 and 2 According to Whether They Were Enrolled Onto the Cross-over Study
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The mean interval between progression and the cross-over was 25.5 days (range, 0 to 542 days) after IFN2a and 20 days (range, 0 to 741 days) after IL-2. Among the 113 patients enrolled, disease progressed early in 73 (65%) after induction treatment (week 10), in 28 (25%) after maintenance therapy (week 25), and in 12 (10%) during follow-up without treatment.
The actual dose of cytokine received during the cross-over was 64% for IL-2 (n = 65) and 79% for IFN2a (n = 48). These total received doses were comparable to those received during first-line treatment in arms 1 (61%; n = 132) and 2 (86%; n = 146). The toxicities that occurred during the cross-over study are listed in Table 3 and were not different from those usually encountered. There was no significant difference between these toxicities and those observed during the first-line treatment (data not shown). Two toxicity-related deaths occurred in the IL-2 arm: (1) severe hypotension with ventricular fibrillation during the third IL-2 cycle (day 4) occurred in a patient with diffuse metastatic disease (lung, liver, mediastinum, bones) in whom deterioration of performance status to grade 4 had occurred during initial therapy with IFN2a; and (2) severe gastrointestinal bleeding at home 9 days after the end of the second course of IL-2 occurred in a patient in whom disease had progressed rapidly, with diffuse liver and retroperitoneal metastases (IFN2a was stopped after 5 weeks).
Response to Treatment
All 113 patients were considered assessable for response by the review committee. There were no complete responses. Partial responses (confirmed by the review committee) were observed in four patients: one who was switched to IFN2a and three who were switched to IL-2 (Table 4). The characteristics of these four responders are listed in Table 5. It should be noted that all but one patient either had stable disease (n = 2) or were transient responders with first-line treatment before the cross-over. Interestingly, all of these responders had a performance status of 0 and mainly had lung metastases. The durations of response were 2, 3, 10, and 18 months, respectively.
Survival
There was no difference in survival between the two groups, with a median survival of 18 months in the IFN2a arm and of 19 months in the IL-2 arm. Similarly, median survival of the 113 patients who were entered onto the cross-over trial was the same as that of the 140 patients who received the combination of IL-2 and IFN2a as first-line treatment (19 and 17 months, respectively).
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DISCUSSION
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A combination of IL-2 and IFN2a is the more efficient means to induce an objective response and increase event-free survival in patients with metastatic renal cell carcinoma.10 However, this combined treatment is highly toxic and does not increase overall survival. Therefore, it was crucial to determine whether IL-2 and IFN2a could be administered alone and sequentially when a first-line treatment with a single cytokine had failed.
In this study, 113 patients (> 285 treated ) were switched to the other cytokine after failure of first-line treatment. They represent only 39.6% of the patients randomized to arms 1 and 2 of the CRECY study. A large number of patients whose disease progressed during initial treatment were not entered onto the cross-over study. Although the reason for noninclusion was not recorded, we can reasonably assume that rapid deterioration of general conditions and toxicity of initial treatment were the main reasons. The fact that 65 patients were switched to IL-2 after IFN2a (v 48 switched to IFN2a after IL-2) is compatible with this assumption. Lastly, some investigators who were less involved in the study may have forgotten this part of the CRECY trial; the difference in enrollment in the cross-over study and the inclusion rate of the center suggest that this is a plausible explanation.
The toxicity of IL-2 or IFN2a when given as second-line treatment seems to be similar to that observed during first-line treatment. As observed in the CRECY trial, deaths related to IL-2 toxicity occurred in patients with a poor performance status and diffuse metastatic disease. Therefore, severe toxicity occurs mainly in patients who are unlikely to benefit from treatment and who should be spared the discomfort of further cytokine studies.10
The overriding result of this study is the fact that few patients responded to treatment. To our knowledge, this is the first large study to assess the efficacy of IL-2 or IFN2a as second-line treatment. Lissoni et al15 previously reported that IL-2 alone induced four partial responses in 13 patients previously treated with IFN2a. However, this was a small series with very limited information on the status of responders before the start of IL-2. In our study, all suspected responses or even stabilization were vetted by the tumor response evaluation committee, and the disease status before the start of cross-over was then carefully verified.12 During this review, all three responders with IL-2 did, in fact, have stable disease (n = 2) or an initial partial response (n = 1) at the time of the cross-over. In contrast, in the patient who responded to IFN2a, disease progressed rapidly (after two cycles of IL-2). The main characteristics of these responders indicate that most of the good prognostic factors16,17 were present: good performance status, absence of weight loss, previous nephrectomy, a long metastasis-free interval, and metastases predominantly in the lungs.
In conclusion, second-line treatment with IL-2 or IFN2a after failure of first-line therapy with a single cytokine is feasible, with toxicity comparable to that of initial treatment. Objective responses were rare and occurred in patients with good prognostic factors. In contrast, patients whose disease progressed rapidly during first-line treatment were unlikely to benefit from additional cytokine treatment. Further studies are warranted to determine whether such a cross-over is able to increase survival in selected patients who have experienced a long period of stabilization or have relapsed after an initial response.
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AKNOWLEDGMENT
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We thank Lorna Sainte Ange for careful revision of the manuscript.
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APPENDIX
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In addition to the authors, the following investigators and centers from the Groupe Français d'Immunothérapie also participated in this study: Bernard Coronel, Hôpital E. Herriot, Lyon; Daniel Baume, Institut P. Calmettes, Marseille; Joël Fleury, Centre J. Perrin, Clermont-Ferrand; Jean-Marc Ferrero and André Thyss, Centre A. Lacassagne, Nice; Rémi Delva, Centre P. Papin, Angers; Nicole Tubiana-Mathieu, Hôpital de la Timone, Marseille; Pierre Fargeot and Bruno Coudert, Centre G.F. Leclerc, Dijon; Thierry Lesimple, Centre E. Marquis, Rennes; Thierry Dorval, Institut Curie, Paris; Marie-Brigitte Orgerie, Hôpital Minjoz, Besançon; Thierry Conroy, Centre A. Vautrin, Nancy; Alain Goupil, Centre R. Huguenin, Saint-Cloud; Elhani Khenifar, Hôpital Saint-Jacques, Besançon; Bruno Audhuy, Centre Hospitalier, Colmar; and Jean-Christophe Eymard, Institut J. Godinot, Reims, France.
Members of the tumor response evaluation committee: Liliane Ollivier, Institut Curie, Paris; Donatella Di Stefano-Louineau, Institut P. Calmette, Marseille; and Philippe Thiesse, Centre L. Bérard, Lyon, France.
Members of the toxicity review committee: Thierry Vial, Hôpital E Herriot, Lyon; Gérard Nitenberg, Institut G. Roussy, Villejuif; and Serge Robard, Centre R. Gauducheau, Nantes, France.
Members of the methodology review committee: Hélène Sancho-Garnier, Centre Val d'Aurelle, Montpellier; Jean-Pierre Boissel, Hôpital Cardiologique, Lyon, France; and Marc Buyse, International Institute for Drug Development, Brussels, Belgium.
From the data monitoring and statistical center: Karine Pignard, Michel Drevon, and Franck Chauvin, Centre L. Bérard, Lyon; and Nathalie Rodrigo and Jean Maupas, Association pour la Promotion de la Recherche et de l'Evaluation Theràpeutique (APRET), Lyon, France.
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ACKNOWLEDGMENTS
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Supported by grants from the Association pour la Recherche contre le Cancer.
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NOTES
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The Groupe Français d'Immunothérapie is part of the Fédération Nationale des Centres de Lutte Contre le Cancer; the names of additional investigators are listed in the Appendix.
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Submitted September 24, 1998;
accepted March 12, 1999.
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ABSTRACT
INTRODUCTION
