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Subcutaneous Interleukin-2 and Interferon Alfa Administration in Patients With Metastatic Renal Cell Carcinoma: Final Results of SCAPP III, a Large, Multicenter, Phase II, Nonrandomized Study With Sequential Analysis Design—The Subcutaneous Administration Propeukin Program Cooperative Group

Jean-Marc Tourani, Christian Pfister, Nicole Tubiana, Mahmoud Ouldkaci, Gilles Prevot, Virginie Lucas, Stéphane Oudard, Maxime Malet, Paul Cottu, Jean-Marc Ferrero, Didier Mayeur, Olivier Rixe, Xu-Shan Sun, Olivier Bernard, Thierry Andre, Christophe Tournigand, Xavier Muracciole, Joelle Guilhot

From the Service d’Oncologie Médicale and Unité de Biostatistique, Fédération de Cancérologie et d’Hématologie, Hôpital J. Bernard, Poitiers; Service d’Urologie, Hôpital Charles Nicolle, Rouen; Service d’Oncologie et de Radiothérapie, Hôpital Dupuytren, Limoges; Service d’Urologie, Hôpital Bicêtre, Le Kremlin Bicêtre; Unité d’Oncologie et de Radiothérapie, Hôpital du Hasenrain, Mulhouse; Unité d’Oncologie Médicale, Hôpital la Source, Orléans; Service d’Oncologie Médicale, Hôpital Georges Pompidou; Service d’Oncologie Médicale, Hôpital Saint Louis; Service d’Oncologie et de Radiothérapie, Hôpital d’Instruction des Armees Val de Grâce; Service d’Oncologie Médicale, Hôpital Tenon; and Service de Médecine Interne, Hôpital Saint Antoine, Paris; Service d’Oncologie Médicale, Hôpital de Pau, Pau; Service d’Oncologie Médicale, Centre A. Lacassagne, Nice; Service de Médecine Interne B; Hôpital A. Mignot, Le Chesnay; Service d’Oncologie et de Radiothérapie, Hôpital Claude Bernard, Metz; Unité d’Oncologie et de Radiothérapie, Hôpital A. Boulloche, Montbéliard; and Service de Radiothérapie, Hôpital La Timone, Marseille, France.

Address reprint requests to Jean-Marc Tourani, MD, Oncology Unit, Centre Hospitalier Universitaire Poitiers, BP 577, 86021 Poitiers Cedex, France; e-mail: jm.tourani{at}chu-poitiers.fr.

	ABSTRACT

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Purpose: This outpatient multicenter trial tested the hypothesis that subcutaneous administration of an interleukin-2 (IL-2)/interferon alfa (IFN) combination produces a response rate greater than 20% in patients with renal cell carcinoma (RCC).

Patients and Methods: Patients with metastatic RCC received a 12-week induction treatment with subcutaneous IL-2 (5 days/wk, 9 and 18 million U/d)/IFN (3 days/wk, 6 million U/d). After evaluation, patients with objective response or stable disease were randomly assigned to maintenance treatment or short consolidation treatment.

Results: Lack of benefit was shown at the 12th sequential analysis, and the trial was closed. At the end of the induction period, 26 (21%) of 122 patients had objective responses (including six complete responses). Thirty-three patients (27%) developed severe toxicity requiring dose reductions, delayed treatment, or treatment termination. Survival rates at one, two, and four years were 63%, 38%, and 17%, respectively. Three-year survival was 20% in patients with two poor prognosis factors and 37% in patients with one or no poor prognosis factors (P = .016). Three-year survival was significantly better (P < 10^-3) in patients with erythrocyte sedimentation rate less than 35 mm (43%) compared with those with 1-hour sedimentation rate greater than 35 mm (19%).

Conclusion: This study confirms the importance of prognostic factors when initiating cytokine immunotherapy in patients with metastatic RCC and underlines the prognostic value of erythrocyte sedimentation rate before treatment initiation. Nonetheless, this subcutaneous IL-2/IFN combination does not improve response rate or survival compared with subcutaneous IL-2 alone, although a definitive conclusion cannot be drawn in the absence of a randomized study comparing the two treatments.

	INTRODUCTION

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RENAL CELL carcinoma (RCC) represents 2% to 3% of all adult cancers. At the time of diagnosis, approximately 30% of patients have metastatic disease and a further 30% to 40% develop metastases in the months or years after nephrectomy.¹ Disease is resistant to hormonal therapy,² chemotherapy,³ and radiotherapy.⁴ The prognosis for patients with metastatic RCC is poor, with a spontaneous median survival of between 5 and 12 months depending on the patient’s initial status (prognostic factors).^5,6

Substantial progress has been made with the use of immunotherapy and cytokines. Interferon alfa (IFN) was the first cytokine used in this pathology. IFN administered subcutaneously gave a response rate of between 5% and 30%.^7–9 A randomized study by the Medical Research Council Renal Cancer Collaborators group showed an improvement in survival in patients with metastatic RCC treated with IFN.¹⁰

Interleukin-2 (IL-2) was then proposed as a treatment for patients with metastatic RCC, by high-dose intravenous bolus or intermediate dose-continuous infusion. These schedules gave a response rate of 15% to 30% with approximately 5% complete response.^11,12 Depending on prognostic factors present at diagnosis, median survival was between 6 and 19 months.⁵ To improve tolerance, several investigators proposed subcutaneous administration, which yielded efficacy comparable to that of intravenous administration, with a response rate of 15% to 29% (including a 2% to 5% complete response rate), with the added benefit of less toxicity and outpatient treatment.^13–15

To improve these results, a number of schedules combining the two cytokines with or without chemotherapy were subsequently developed. Although initial results with the combination of IL-2, IFN, and fluorouracil suggested a response rate of approximately 40%, subsequent response rates reported were less than 20%.^16–20 Moreover, the combination produces increased toxicity and no increase in survival rates.²¹ In an alternative approach, a large randomized study by a French cooperative group (Cancer Renal Cytokine) compared continuous-infusion IL-2 or subcutaneous IFN monotherapy with an intravenous IL-2/IFN combination. This study showed a statistically significant superiority in terms of response for the combination regimen, but this superiority was without survival benefit.²²

On the basis of the results from the Cancer Renal Cytokine program showing that an intravenous IL-2 and subcutaneous IFN combination is superior to monotherapy, our French Subcutaneous Administration Propeukin Program (SCAPP) Cooperative Group wanted to verify whether the IL-2/IFN combination administered subcutaneously is more effective than IL-2 alone by conducting a nonrandomized, sequential analysis design study.

	PATIENTS AND METHODS

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Inclusion Criteria
Patients included in this study had histologically confirmed, evolving metastatic RCC (including clear-cell, chromophobe, and papillary RCCs), with clinically or radiologically assessable disease. The study was approved by the Saint Antoine Hospital (Paris) ethical committee, and written informed consent (including randomization) was obtained from all patients. Exclusion criteria were as follows: age greater than 65 years, serum creatinine greater than 1.25 times normal, brain metastases, previous tumor, World Health Organization Performance Status (PS) greater than 1, previous IL-2 or IFN treatment, or three poor prognosis factors (according to the classification of Palmer et al²³: < 12 months between primary renal tumor diagnosis and appearance of metastasis; > one metastatic site, and PS > 0). Before inclusion, patients underwent a clinical examination; assessment of blood cell count, erythrocyte sedimentation rate (ESR), serum electrolytes, and hepatic, renal, and thyroid functions; chest x-ray; technetium pyrophosphate bone scan; and brain, thoracic, and abdominal computed tomography scanning. Response to treatment was evaluated at the end of the induction treatment period, after short consolidation, or after the second, fourth, and sixth maintenance cycles.

Treatment Schedule
The induction period lasted 12 weeks. During this period, patients received subcutaneous IL-2 (Aldesleukin; Chiron, Amsterdam Zuidoost, the Netherlands), 9 million units twice daily for 5 consecutive days, in the first and the seventh weeks. In the second, fourth, fifth, eighth, 10th, and 11th weeks, IL-2 was administered at 9 million units twice daily on days 1 and 2, followed by 9 million units once daily on days 3, 4, and 5. IFN (Roferon; Roche Products, Paris, France) was administered in the evening at 6 million units on days 1, 3, and 5 during each week of IL-2 treatment. The third, sixth, ninth, and 12th weeks were treatment-free. Toxicity of treatment was evaluated during each of these four treatment-free weeks with a clinical examination and an assessment of blood cell count, serum electrolytes, and renal and hepatic functions. For patients developing grade 3 or 4 cytokine-related toxicities, IL-2 and IFN doses were decreased to 9 million U/d and 3 million U/d respectively, until the end of the treatment.

After evaluation of response to induction treatment and a 2-week rest period, and in the absence of tumor progression and unacceptable toxicity (despite dose reductions), patients with partial response or stable disease were randomly assigned to short consolidation or maintenance treatment. This random assignment was stratified by tumor response at the completion of the induction period. In the consolidation arm, patients received cytokines in the first, second, fourth, and fifth weeks, and the third week was treatment-free. IL-2 was given during the first week at 9 million units twice daily for 5 consecutive days, and the second, fourth, and fifth weeks at 9 million units twice daily on days 1 and 2, followed by 9 million units once daily on days 3, 4, and 5. IFN was administered in the evening at 6 million units on days 1, 3, and 5 during each week of IL-2 treatment. In the maintenance arm, patients received a maximum of seven cycles of 2 weeks of treatment followed by 3 weeks of rest. During each week of treatment, patients received 9 million units of IL-2 on days 1 through 5 and 6 million units of IFN on days 1, 3, and 5 in the evening. Clinical and biologic toxicity occurring during the maintenance period was evaluated at each cycle. To prevent pyretic reactions, paracetamol was administered together with IL-2 and IFN (500 mg orally every 4 to 6 hours).

End Points
Clinical response and toxicity were evaluated according to World Health Organization criteria. Duration of response was calculated from the beginning of treatment. Progression-free survival refers to responding patients (complete or partial response) and patients with stable disease at the end of the induction treatment; this was calculated from the response date up to the date of disease progression.

Statistical Analysis
Based on the results observed with programs using IL-2 alone given by subcutaneous route, the main objective of this trial was to test the hypothesis that an IL-2/IFN combination would lead to a response rate greater than 20%. For a true response rate of 30%, a fixed-sample size, nonrandomized study would require 156 patients, given a type I error rate of 0.05 and a power of 90%. Therefore, to meet ethical requirements, a sequential approach was used allowing early termination of the study with clear evidence of efficacy or the lack thereof. Among the various multistage designs for nonrandomized trials, we chose the extension for phase II trials of the triangular test, initially proposed by Whitehead and Jones for phase III trials.²⁴ This sequential group method allows analyses to be performed whenever a group of new patients is evaluated, with the same favorable statistical properties of strictly sequential methods and an easier implementation. A simulation study showed that, compared with the single-stage design, the triangular test allows a large decrease in sample size irrespective of response rate.

The triangular test is a true decision-making method and uses a sequential plan defined by two perpendicular axes. The horizontal axis corresponds to the V statistics, which represent the information accumulated since the beginning of the trial. The vertical axis corresponds to the Z statistics, which represent the benefit from the treatment as compared with the theoretical response rate. Two boundaries delineate a continuation region that depends on the theoretical response rate and type I and II errors as well as frequency of the sequential analyses defined in terms of the number of patients included between two sequential analyses.

In practice, after the inclusion of each group of patients, the two statistics V and Z are calculated from the data, and the point (V, Z) is plotted on the sequential plan, determining the sample path. As long as the sample path stays in the continuation region, the trial is continued. When the sample path crosses one of the boundaries, the trial is closed: crossing the lower boundary means that the regimen is not efficient, whereas crossing the upper boundaries means that the regimen is efficient. Because the continuation region is closed, the number of patients is limited and the maximum number of patients can be computed when the trial is designed. Considering the response rate usually reported with IL-2 alone given subcutaneously in patients with metastatic RCC,^13–15 a response rate less than 20% was considered insufficient and, according to the results reported with combinations of IL-2 and IFN with or without fluorouracil,^25,26 we considered that a response rate equal to 30% would be a clinically meaningful improvement. Using a type I error of 0.05 and a power of 90%, with sequential analyses every 10 patients, the equations of the boundaries were computed (Fig 1).

View larger version (15K): [in this window] [in a new window]   Fig. 1. Sample path of the triangular test with early termination of the 12th sequential analysis. Z represents benefit from the treatment as compared with the theoretical response rate.

	RESULTS

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Stopping Rule
The trial started in July 1997 and sequential analyses were performed after every 10 newly evaluated patients. In August 2000, at the 12th analysis involving 120 patients with 26 responses, the sample path crossed the lower boundary of the continuation region, indicating that this IL-2/IFN regimen does not achieve a response rate significantly greater than 20% (Fig 1). Thus patient inclusion was stopped, and the final analysis is based on the 122 patients included at that time.

Patient Characteristics
Between July 1997 and August 2000, 128 patients with metastatic RCC from 62 French centers were included in the study. Six patients did not fulfill the inclusion criteria and were subsequently excluded (brain metastases, n = 1; age > 65 years, n = 3; PS greater than 1, n = 2). The baseline characteristics of the 122 remaining patients are summarized in Table 1. Ninety men and 32 women were entered with a mean age of 55 years (range, 20 to 65 years). PS was 0 in 105 patients (86%) and 1 in 17 patients (14%). Ninety-six percent of patients had undergone nephrectomy, and 17% had undergone prior surgery for metastatic disease (n = 5), radiotherapy (n = 14), or chemotherapy (n = 2). Forty-nine patients (40%) presented with metastatic disease at diagnosis of renal cancer, whereas metastases appeared during the first year of follow-up in 34 patients (28%), during the second year in 19 patients (16%), or during the third year or later in 20 patients (16%). Fifty-four patients (44%) had a single metastatic site. Among the 122 included patients, 14 patients (11%) had no poor prognosis factors, 50 patients (41%) presented with one factor, and 58 patients (48%) presented with two of these poor prognosis factors. Tumor histology is reported for 114 patients, and the Führman histo-prognostic grade was evaluated in 92 patients. During the accrual period, 82 screened patients with metastatic RCC were not included because of a PS 2, three poor prognosis factors (39 patients), brain metastases (15 patients) or age greater than 65 years (28 patients).

Table 2 lists toxicity observed during the induction period. The mean value of serum creatinine was 119 µmol/L (minimum, 67 µmol/L; maximum, 183 µmol/L; SD, 41.2 µmol/L) before treatment initiation, and 137 µmol/L (minimum, 81 µmol/L; maximum, 439 µmol/L; SD, 58.7 µmol/L) at the end of induction (P = .34). Thyroid dysfunction was observed in six patients (two patients with biologic hypothyroidism and four patients with biologic hyperthyroidism). All these disturbances disappeared within a few weeks of treatment completion. During the induction period, 27 patients (22%) lost more than 10% of their initial weight. Five patients (4%) required RBC transfusions because of grade 3 anemia. During the induction period, two treatment-related deaths occurred. One patient with well-developed pulmonary metastases experienced acute respiratory insufficiency in the fourth week of treatment. The other patient died during the ninth week of treatment after developing severe infection.

Maintenance or Consolidation Treatment
Of the 58 patients with partial response (20 patients) or stable disease (38 patients) at completion of the induction treatment, 24 patients were randomly assigned to maintenance treatment (nine patients with partial response and 15 patients with stable disease), and 25 patients were assigned to short consolidation treatment (10 patients with partial response and 15 with stable disease). For the nine remaining patients, the treatment was interrupted because of unacceptable toxicity during induction period (four cases) or patient’s decision (five cases). Tumor response observed after the induction treatment was never improved, either during maintenance period or at completion of consolidation treatment.

Maintenance treatment was interrupted for disease progression (nine patients), toxicity (one patient), or patient request (one patient). Table 3 lists the number of maintenance cycles given to patients. Four patients in the maintenance schedule had dose decreases or delays of 1 to 2 weeks because of grade 3 side effects. Table 4 lists toxicity observed during the maintenance phase. Two patients with partial response and seven patients with stable disease at the end of the induction period experienced disease progression during the maintenance period.

View larger version (10K): [in this window] [in a new window]   Fig. 2. Probability of survival.

	DISCUSSION

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IFN administered subcutaneously, alone or in combination with vinblastine, gives response rates between 5% and 30% in metastatic RCC patients.^8,9 A multicenter, randomized trial (IFN v medroxyprogesterone acetate) recently showed that activity of IFN translates into a statistically significant survival advantage.¹⁰

There is conflicting evidence concerning the advantage of the IL-2/IFN combination over IL-2 alone. Atkins et al³² reported no benefit when IFN was added to high-dose intravenous bolus IL-2. On the other hand, Dutcher et al³³ and Vogelzang et al³⁴ observed a response rate comparable to that of high-dose intravenous therapy in two multicenter trials combining subcutaneous IL-2 and IFN. Response duration, however, for these combinations may be shorter, as reported.^33,35 In a randomized multicenter trial comparing continuous intravenous infusion IL-2 versus subcutaneous IFN versus both, response rates after 10 weeks were 6.5% with IL-2, 7.5% with IFN, and 18.6% with the combination.²² However, no difference in overall survival was observed, possibly because of the cross-over allowed between the two monotherapy arms in the event of tumor progression. Thus currently, although the IL-2/IFN combination administered intravenously can improve the response rate, it is not clear whether subcutaneous administration of the combination therapy improves its effectiveness in terms of response and survival compared with the subcutaneous administration of IL-2 alone.

This multicenter, nonrandomized, sequential trial assessed the efficacy of simultaneous administration of an IL-2/IFN combination given subcutaneously for 12 weeks. The trial was closed after the 12th sequential analysis (120 patients) when the test indicated that the program did not allow a response rate greater than 20%. Of the 122 patients treated, 26 patients achieved an objective response, with six complete responses. One-, 2-, and 4-year survival rates in the 122 patients were 63%, 38%, and 17%, respectively. This subcutaneous combination generated significant toxicity that necessitated dose modification, delay, or termination of the treatment in 29% of patients. Short consolidation or maintenance treatment was administered to 49 patients with partial response or with stable disease but did not improve tumor responses obtained at the end of the induction, an observation already shown in our previous studies.^15,21 Moreover, no difference in terms of survival was found between the two groups, although this could be due to insufficient patient numbers.

We used prognostic factors identified by Palmer et al²³ in a program using intravenous IL-2. No difference in terms of response was observed according to each of the prognostic factors or the number of poor prognosis factors, taking into account that patients with a very poor prognostic profile—that is, with at least three poor prognosis factors—were excluded from the study. However, among the patients who had one or no poor prognosis factors or who had a PS of 0, survival was significantly improved. ESR seems to be a biologic prognostic factor of interest.^36–38 In our study, patients with an ESR of less than 35 mm had a 3-year survival rate of 43%, whereas those who had an ESR greater than 35 mm at the start of treatment had a 19% 3-year survival rate. This simple and inexpensive test may be as relevant as more sophisticated biologic prognostic parameters, such as soluble IL-2R³⁹ or IL-6.⁴⁰

Our results are similar to those of other phase II trials combining subcutaneous IL-2 and IFN, with response rates between 12% and 25%.^35,41,42 These response rates are comparable to those obtained with IL-2 alone. The statistical methodology used in our study (triangular test) concluded that there was an absence of benefit compared with IL-2 monotherapy, which gives a response rate of 20%.

Between 1993 and 1994, 39 metastatic RCC patients were included in a phase II trial (SCAPP I) of subcutaneous IL-2 alone at daily doses varying between 9 million units and 18 million units according to the same schedule as in the SCAPP III program.¹⁵ Seven (18%) of 39 patients had an objective response (95% CI, 8% to 34%). The 1-, 2-, and 4-year survival rates were 63%, 36%, and 15%, respectively. Thus the response and survival distributions obtained with the SCAPP III program are comparable to those observed in SCAPP I. Moreover, for apparently identical efficacy, the toxicity seen here with the SCAPP III program, judged by dose reductions, delays, or treatment terminations (29%), is greater than that observed with the SCAPP I program (15%).

In conclusion, the SCAPP III program, which combined IFN and subcutaneous IL-2, does not seem to improve the results observed in the SCAPP I trial using the same subcutaneous IL-2 schedule without IFN. One of the objectives of the randomized trial in the national Programme d’Evaluation des Cancers du Rein Sous Cytokines program in collaboration with the Federation Nationale des Centres Lutte Contre le Cancer, started in 2000, is to define whether subcutaneous combination of IL-2/IFN (according to this SCAPP III schedule) is superior in terms of survival when compared with monotherapy with subcutaneous IFN or IL-2 (according to the SCAPP I schedule).

	AUTHORS’ DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST

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The authors indicated no potential conflicts of interest.

	APPENDIX

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The following investigators also participated in this study: Philippe Ayela, Service d’Oncologie, Hôpital de Lourdes, Lourdes; Michael Azagury, Service de Médecine Interne B, Hôpital de St Germain, St Germain en Laye; Gérard Benoit, Service d’Urologie, Hôpital Bicêtre, Le Kremlin Bicêtre; Catherine Boaziz, Unité d’Oncologie Médicale, Centre de Cancérologie Paris Nord, Sarcelles; Jean-Louis Bonnal, Service de Cancérologie, Hôpital V. Provo, Roubaix; Daniel Bonnet, Service de Pneumologie, Hôpital d’Instruction des Armées Laveran, Marseille; Hugues Bourgeois, Service d’Oncologie Médicale, Centre Hospitalier Universitaire de Poitiers, Poitiers; Yvelise Brewer, Service d’Oncologie Médicale, Clinique Ste Catherine, Avignon; Philippe Colin, Unité d’Oncologie Radiothérapie, Clinique Courlancy, Reims; Pierre Colombaud, Service de Chirurgie, Hôpital Dupuytren, Limoges Cedex; Philippe Dalivoust, Service d’Oncologie, Clinique Résidence du Parc, Marseille; Philippe David, Unité de Pneumologie, Hôpital d’Elbeuf, Elbeuf; Jean Domas, Unité d’Oncologie Médicale, Clinique St Pierre, Perpignan; Roger Favre, Service d’Oncologie Médicale, Hôpital La Timone, Marseille; Philippe Grise, Service d’Urologie, Hôpital Charles Nicolle, Rouen; Yvan Krakowski, Unité d’Oncologie Médicale, Hôpital Jean Monnet, Epinal; Dominique Larregain-Fournier, Service d’Oncologie Médicale, Hôpital côte Basque, Bayonne; André Mathieu, Service de Radiothérapie, Clinique des Genêts, Narbonne; Laurent Miglianico, Service de Radiothérapie, Centre St Vincent, St Grégoire; Sana Mrad, Unité d’Oncologie Médicale, Hôpital la Source, Orléans; Gilles Alex Noble, Unité d’Oncologie, Hôpital Castelluccio, Ajaccio; Yves Otmezguine, Service d’Urologie, Hôpital A. Paré, Boulogne; Claude Platini, Service d’Oncologie Radiothérapie, Hôpital Bel Air, Thionville; Christine Piprot, Unité de Radiothérapie, Hôpital Sud, Amiens; Frédérique Rousseau, Service d’Oncologie Médicale, Hôpital R. Dubos, Cergy Pontoise; Hélène Simon, Service de Cancérologie, Hôpital Morvan, Brest; Zoulica Tadrist, Unité d’Oncologie et d’Hématologie, Hôpital d’Aix en Provence, Aix en Provence; and Michel Untereiner, Unité d’Oncologie et de Radiothérapie, Hôpital Claude Bernard, Metz.

	ACKNOWLEDGMENTS

 
We thank Dr Esteban Cvitkovic for his comments and Dr Sarah Mackenzie for her editorial assistance.

	NOTES

 
Supported by a grant from Association pour le Développement et la Recherche Appliquée en Cancérologie, Mignaloux-Beauvoir, France.

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Submitted February 14, 2003; accepted August 11, 2003.

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