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Treatment of Patients With Metastatic Renal Carcinoma With a Combination of Subcutaneous Interleukin-2 and Interferon Alfa With or Without Fluorouracil

From the Centre L. Bérard, Lyon; Centre O. Lambret, Lille; Centre E. Marquis, Rennes; Centre R. Gauducheau, Nantes; Institut G. Roussy, Villejuif; Centre Hospitalier Lapeyronie, Montpellier; and Institut P. Calmettes, Marseille, France.

Address reprint requests to S. Négrier, MD, Medical Oncology Department, Centre Léon Berard, 28 rue Laënnec, 69373 Lyon Cedex 08, France; email negrier{at}lyon.fnclcc.fr

	ABSTRACT

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PURPOSE: Subcutaneous recombinant interleukin-2 (rIL-2) and recombinant interferon alfa-2a (rIFN-2a) have been used extensively in the treatment of metastatic renal cancer. Most results, coming from noncontrolled phase II trials, showed inconsistent rates of response. More recently, the addition of fluorouracil (FU) was proposed to improve the efficacy of these regimens.

PATIENTS AND METHODS: The role of a subcutaneous combination of rIL-2 and rIFN-2a with or without FU was investigated. Patients were randomly assigned to receive a combination of rIL-2 and rIFN-2a at weeks 1, 3, 5, and 7 or the same combination together with a continuous infusion of FU at weeks 1 and 5. The major end points of this multicenter, randomized trial were progression-free survival, response rate, and toxicity. Overall survival was a secondary end point. Tumor responses were reviewed by an independent committee. Analysis of the results was performed on an intention-to-treat basis.

RESULTS: One hundred thirty-one patients were enrolled. There was no difference in toxicity between the arms, and no toxic death was observed. One partial response was observed in arm A and five in arm B. Progression-free survival did not differ between the arms, and rates at 1 year were 12% and 15% in arms A and B, respectively. No statistically significant differences were detected in any end point.

CONCLUSION: The subcutaneous combination of rIL-2 and rIFN-2a with or without FU does not benefit patients with metastatic renal carcinoma. Neither of these regimens can be recommended as standard treatment. The results of the subcutaneous cytokine regimen seem disappointing.

	INTRODUCTION

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APPROXIMATELY 50% of patients with renal cell carcinoma develop metastatic disease. The median survival of these patients is approximately 1 year, and the probability of survival at 2 years is 10% or less in most series.¹ Metastatic renal cell carcinoma (MRCC) is resistant to conventional chemotherapy.^2,3 Spontaneous regressions have been reported in some patients, which suggests a role of host immunity in antitumor response.^4,5 Recombinant interleukin-2 (rIL-2) and recombinant interferon alpha-2a (rIFN-2a) have shown reproducible effects in patients with MRCC, at least in terms of tumor response.^6-9 However, intravenous (IV) rIL-2 with or without lymphokine-activated killer cells has been associated with severe side effects.^6-9 Several strategies have been proposed for improving the antitumor activity of rIL-2 and for reducing its toxicity.

Regimens using subcutaneous rIL-2 with or without subcutaneous rIFN-2a seem far less toxic, and response rates obtained in phase II trials were encouraging.^10-13 However, no results of large randomized trials are available.

Experimental studies have demonstrated some evidence of synergism between chemotherapeutic agents, notably fluorouracil (FU) and rIFN-2a.¹⁴ Some clinical data are available for the combination of rIL-2, rIFN-2a, and FU in MRCC, and several phase II trials showed encouraging response rates in the range of 15% to 45%.^15-19 On the basis of the results of the interim analysis of a phase II trial that combined subcutaneous rIL-2, rIFN-2a, and FU (results that, unfortunately, were not confirmed at final analysis²⁰ ), the Groupe Français d’Immunothérapie set up a randomized trial to evaluate this regimen. The trial compared response rate, toxicity, and progression-free and overall survival of this combination with those of subcutaneous rIL-2 and rIFN-2a alone for patients with MRCC.

	PATIENTS AND METHODS

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Patients
All patients were required to have histologically confirmed and measurable progressive MRCC, age between 18 and 80 years, and Eastern Cooperative Oncology Group score 1. They had normal blood cells counts, normal bilirubin level, creatine level less than 180 µmol/L, normal cardiac function, and life expectancy of at least 12 weeks. Patients who required corticosteroids were excluded. Patients were not eligible if they had untreated and/or progressive brain metastases, serious active infections, positivity for human immunodeficiency virus test or hepatitis B surface antigen, history of an organ allograft, previous treatment with cytokines, or other malignancies.

Pretreatment work-up included clinical history and physical examination, hematologic and biochemical parameters, computed tomography scan of the chest, abdomen, and brain, and radioisotope bone scan. Written informed consent was obtained before randomization from every patient. The trial was approved by the ethics committee in Lyon according to French law.

Treatment Plan (Fig 1)
Registration and randomization of eligible patients were performed at the data monitoring center by an interactive computerized procedure according to the predetermined randomization sequence and after stratification by center. Patients were treated according to the treatment schedule shown in Fig 1.

View larger version (13K): [in this window] [in a new window]   Fig 1. Scheme of the treatment schedules.

The first week of each course was generally given to patients who were admitted to the hospital. Subsequent treatment could be given at home or in the outpatient clinic, depending on tolerance to the therapy. Response to therapy was evaluated after the first cycle at weeks 9 and 20.

This original schedule of treatment was designed to maximize tolerance by including 1 week of rest between each treatment course. Two consecutive cycles of 8 weeks each were planned for all patients except those who progressed during the first course or in the case of unacceptable toxicity. Additional cycles were not planned but could have been performed depending on each investigator’s decision.

Treatment Evaluation
Evaluation of tumor response, including computed tomography scan of the chest and abdomen and a bone scan, if previously abnormal, was performed after completion of each treatment cycle. Toxicity was assessed according to standard World Health Organization criteria.²¹

Response rates were calculated according to World Health Organization criteria.²¹ Briefly, a complete response required the disappearance of all evidence of tumor for a minimum of 4 weeks from the first date of documentation. A partial response (PR) was defined as a 50% or greater decrease in the sum of the products of the two longest perpendicular diameters of all measurable lesions for at least 4 weeks with no simultaneous progression of any assessable disease or the appearance of new lesions. Patients who had less than a PR or an increase of less than 25% in the sum of cross-sectional areas without simultaneous progression of any assessable lesion or appearance of any new lesions were classified as having stable disease. Progression of disease was defined as an increase of more than 25% in the sum of cross-sectional areas or the development of new lesions. The results of the successive bone scans were considered as progressive disease in the case of the appearance of new spots, stable if not, and complete regression in the case of disappearance of all spots only. These results were integrated into the overall evaluation of the tumor response.

All cases of objective response claimed by the investigators were reviewed by an independent evaluation committee. Survival was calculated from the start of treatment to the date of last follow-up or the date of death. Progression-free survival was calculated from the start of treatment to the date of last follow-up or the date of progression.

Statistical Analysis
Primary end points were progression-free survival, response rate, and toxicity. Overall survival was a secondary end point. Two analyses were initially planned. The first analysis was to assess and compare response rates after 21 patients were recruited to each group. If one of the groups had had a response rate less than 10% and if a difference greater than 15% in response rate was observed between the two groups, the study would have been stopped.²² If not, the trial could continue as a phase III study. The final planned sample size was then 91 patients in each group, on the basis of detection of a 15% difference in progression-free survival between the two arms (15% v 30% at 1 year) with a two-sided test, an alpha risk of 5%, and a power of 80%.²³ Since both treatments given during the trial corresponded to routine treatment regimens for these patients, the accrual of the patients was not planned to be put on hold while performing the interim analysis.

All analyses were performed on an intention-to-treat basis. Categorical variables were compared using the ² test or Fisher’s exact test. Analysis of progression-free survival and overall survival was performed by the Kaplan-Meier actuarial method, and differences between arms were assessed by the log-rank test.

	RESULTS

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Patients’ Characteristics
One hundred thirty-one patients were enrolled from October 1995 to June 1996 in 24 institutions. The results of the interim analysis indicated that a limited number of patients had responded to treatment (ie, rIL-2 + rIFN-2a, 0 responses in 21 patients, v rIL-2 + rIFN-2a + FU, three PRs in 21 patients). The trial was closed prematurely at the request of participating investigators because of the low overall response rate. Because of an unexpectedly high accrual rate, 131 patients were already enrolled at the time of closure.

The main characteristics of the 131 patients according to the treatment arm are listed in Table 1. A total of six patients were retrospectively found to be ineligible: five in arm A because of low performance status (Eastern Cooperative Oncology Group score > 1) and one in arm B because of a nontreated brain metastasis. Two patients did not receive any treatment (one in each arm): the one with the brain metastasis and another, who died of disease progression 13 days after inclusion and before starting treatment. All of these patients were included in the analysis of the results.

Treatment Administration and Toxicity
Table 2 lists details of treatment administration and indicates the number of patients who received at least 80% of the planned doses. There was no significant difference in the amount of rIL-2 and that of rIFN-2a administered between the two groups. Overall, a large majority of patients received 80% or more of the planned doses.

View this table: [in this window] [in a new window]   Table 2. Numbers and Percentages of Patients Who Received 80% of the Planned Doses According to the Randomized Treatment

View larger version (12K): [in this window] [in a new window]   Fig 2. Progression-free survival according to the treatment group.

View larger version (12K): [in this window] [in a new window]   Fig 3. Overall survival according to the treatment group.

	DISCUSSION

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Because of the toxicity of IV rIL-2, subcutaneous regimens were developed. The initial report of a combination of subcutaneous rIL-2 and rIFN-2a indicated mild toxicity and a high response rate of 36%.¹⁰ Subsequently, different treatment schedules using subcutaneous cytokines were tested and confirmed the improvement in tolerance but with lower rates of response.^12,13,27,28 Because some experimental data had shown an enhancement of the antitumor effect of cytokines when associated with chemotherapeutic agents such as FU, such combinations were tested in patients with MRCC. The results of the initial phase II trials were encouraging, with response rates ranging from 35% to 48%.^15-19,29 Our group set up trials to investigate this type of combination, first, as a phase II trial,²⁰ which initially gave satisfactory response rates at interim analysis, then as a randomized, controlled trial to determine the role of FU in this setting.

To our knowledge, this is the first report of a randomized trial addressing the question of the addition of FU to rIL-2 and rIFN-2a in the treatment of MRCC. Despite small differences in the characteristics of the two groups, we do not detect any advantage in response rate or progression-free survival or overall survival in favor of one treatment regimen. In agreement with the final results of the previous phase II trial with rIL-2, rIFN-2a, and FU,²⁰ the response rates obtained here were unexpectedly low.

The accrual of patients was not put on hold while performing the interim analysis. This explains why 131 patients were already enrolled at the time of trial closure. Two major possibilities may explain the discrepancy between our results and those of some previous reports: the difference in doses and schedules and a different patient selection. We summarize in Table 5 the results, doses, and schedules of previously published trials using FU, rIL-2, and rIFN-2a in MRCC.

View this table: [in this window] [in a new window]   Table 5. Results of Phase II Trials Using the Combination of rIL-2, rIFN-2, and FU in Patients With MRCC

However, the dose-intensity may be more relevant than the schedule of treatment. Effectively, when compared with others, the dose-intensity of our regimen is slightly lower. To verify the existence of a correlation between dose-intensity and response rate, our group further conducted a phase II trial with a different subcutaneous regimen of rIL-2 and rIFN-2a. The doses and schedule were identical to what we had previously used in the randomized CRECY trial,²⁶ except that rIL-2 was given by subcutaneous injections instead of an IV infusion. This represents a high dose-intensity of cytokines, but again, the response rate was disappointing (ie, five PRs or complete responses in 67 patients, with a response rate of 7%).³² As a consequence, we think that patient selection may be more likely responsible for the differences in response rates than the schedules or doses of treatments.

Indeed, if we compare the characteristics of the patients enrolled onto the present trial with those enrolled by the same group of investigators into the CRECY trial, there are some differences in prognostic factors. Patients who did not undergo nephrectomy, had three or more metastatic sites, and developed metastases within 1 year after diagnosis of the renal tumor were more commonly seen in the present trial. In addition, we know that whereas four patients per month were enrolled onto the CRECY trial, 15 patients per month were judged ineligible. In the present trial, 15 patients per month were recruited.

Obviously, the investigators, probably influenced by the relatively low toxicity of the subcutaneous regimen of cytokines, considered a much larger number of patients as candidates for this treatment. These results emphasize two important points. First, phase II studies with limited numbers of selected patients have limited generalizability and often give high response rates. The results of our randomized trial, as well as those of two other controlled trials of cytokines, have, in contrast, given disappointing results in these patients.^33,34 Second, if subcutaneous regimens of cytokines are easily manageable, their administration to large populations with a low degree of patient selection, as is usually the case in routine practice, may lead to disappointing results in terms of tumor regression. We think that physicians in charge of this type of patient must be informed of that risk, especially if they give these treatments outside a clinical trial.

In conclusion, the addition of FU to the subcutaneous rIL-2–rIFN-2a combination does not have sufficient activity against MRCC to warrant its use. Moreover, our results indicate that subcutaneous regimens of cytokines, at least in the present schedule, have low activity. They also emphasize the influence of patient selection on the results of trials and, as a consequence, the risk of obtaining disappointing results when treatments are given on a routine basis with a much lower degree of patient selection.

	NOTE ADDED IN PROOF

 
In this trial, the accrual of patients was not planned to be put on hold because both treatments were considered possible treatment regimens for these patients. Under these particular circumstances, we never considered exposing our patients to a vain and hazardous treatment. Moreover, we did not prevent them from receiving any effective therapeutic alternative, which, unfortunately, was not available for these patients. An unexpectedly high accrual rate may explain why so many patients had already been enrolled at the time of trial closure. This consequence had not been fully appreciated by the investigators before the beginning of the trial, but it was finally considered as a major drawback. As a consequence, the organization of the Groupe Français d’Immunothérapie has been modified in order to definitively rule out such a possibility. We declared, by way of a written statement, that the accrual of patients in subsequent trials will be stopped when an interim analysis must be performed, whether it has been planned or not. In addition, a monthly report of patients’ enrollment must be provided to the board of investigators.

	APPENDIX Other Trial Participants

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Investigators: M. Fabbro, Centre Val d’Aurelle, Montpellier; C. Chevreau, Centre C. Régaud, Toulouse; R. Delva, Centre P. Papin, Angers; B. Coudert and P. Fargeot, Centre F. Leclerc, Dijon; J Fleury, Centre J. Perrin, Clermont-Ferrand; T. Conroy, Centre A. Vautrin, Nancy; Y. Merrouche, Centre hospitalier Minjoz, Besançon; C. Linassier, Centre hospitalier Bretonneau, Tours; A. Goupil, Centre R. Huguenin, Saint-Cloud; J.C. Eymard, Institut J Godinot, Reims; A. Ravaud, Fondation Bergonié, Bordeaux; T. Dorval, Institut Curie, Paris; J.M. Ferrero, Centre A. Lacassagne, Nice; O. Boulat, Centre hospitalier, Avignon; M. Mousseau, Centre hospitalier Michallon, Grenoble; L. Mignot, Hôpital Foch, Suresnes; H. Orfeuvre, Centre hospitalier, Bourg-en-Bresse, France.

Response evaluation committee: L Ollivier, Institut Curie, Paris; D. di Stefano-Louineau, Institut P. Calmettes, Marseille; P. Thiesse, Centre L. Bérard, Lyon, France.

Data monitoring and statistical center: Karine Lengagne, Michel Drevon, and Franck Chauvin, Centre Léon Bérard, and Nathalie Rodrigo and Jean Maupas, Association pour la Promotion et la Réalisation des Essais Thérapeutiques, Lyon, France.

	REFERENCES

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION APPENDIX Other Trial... REFERENCES

 
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Submitted August 26, 1999; accepted July 7, 2000.

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