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Journal of Clinical Oncology, Vol 18, Issue 24 (December), 2000: 4009-4015
© 2000 American Society for Clinical Oncology

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

By Sylvie Négrier, Armelle Caty, Thierry Lesimple, Jean-Yves Douillard, Bernard Escudier, Jean-François Rossi, Patrice Viens, Frédéric Gomez, for the Groupe Français d’Immunothérapie, Fédération Nationale des Centres de Lutte Contre le Cancer

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
TOP
 ABSTRACT
INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
 DISCUSSION
 APPENDIX Other Trial...
 REFERENCES
 
PURPOSE: Subcutaneous recombinant interleukin-2 (rIL-2) and recombinant interferon alfa-2a (rIFN{alpha}-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{alpha}-2a with or without FU was investigated. Patients were randomly assigned to receive a combination of rIL-2 and rIFN{alpha}-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{alpha}-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
TOP
 ABSTRACT
 INTRODUCTION
PATIENTS AND METHODS
 RESULTS
 DISCUSSION
 APPENDIX Other Trial...
 REFERENCES
 
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{alpha}-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{alpha}-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{alpha}-2a.14 Some clinical data are available for the combination of rIL-2, rIFN{alpha}-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{alpha}-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{alpha}-2a alone for patients with MRCC.


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



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  		Fig 1. Scheme of the treatment schedules.

 
All patients received subcutaneous administration of rIL-2 (Proleukin, Chiron Therapeutics, Suresnes, France), 9 x 106 IU/d for 6 days per week at weeks 1, 3, 5, and 7, and rIFN{alpha}-2a (Roferon, Produits Roche, Neuilly, France), 6 x 106 IU/d thrice a week at weeks 1, 3, 5, and 7 (Arms A and B). In arm B, FU was administered by continuous infusion (IV) for 5 days at 600 mg/m2/d at weeks 1 and 5.

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 {chi}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
TOP
 ABSTRACT
 INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
DISCUSSION
 APPENDIX Other Trial...
 REFERENCES
 
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{alpha}-2a, 0 responses in 21 patients, v rIL-2 + rIFN{alpha}-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.


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  		Table 1. Patients’ Characteristics According to the Treatment Group
 
There was no statistically significant difference between the characteristics of the two groups. However, some parameters were not well-balanced. Notably, the number of patients with multiple metastatic sites or with a short interval between primary tumor and occurrence of metastases, which are both important prognostic factors in this disease, were more frequent in the group without FU.

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{alpha}-2a administered between the two groups. Overall, a large majority of patients received 80% or more of the planned doses.


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  		Table 2. Numbers and Percentages of Patients Who Received >= 80% of the Planned Doses According to the Randomized Treatment
 
Most side effects consisted of an impairment of general status as well as digestive disorders. Some grade 3 and a few grade 4 toxicities were reported, and details are given in Table 3. The type and incidence of these toxicities were similar in the two groups. Because of toxicity, treatment was discontinued for six patients in each group during the first cycle (in both groups, five of six treatments were interrupted before the third week of treatment). No toxic death was observed.


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  		Table 3. Grades 3 and 4 Toxicities (World Health Organization grades) According to Treatment Group (maximal grade 3 or 4 per patient)
 
Treatment Responses
The probability of tumor response is listed in Table 4. No complete response was observed in either arm. There was one PR in arm A and five in arm B. There was no significant difference between the two arms (P = .1).


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  		Table 4. Tumor Responses According to the Treatment Group
 
The median follow-up of the population was 23 months. Progression-free and overall survival curves are shown in Figs 2 and 3. Progression-free survival rates at 1 year were 12% in arm A and 15% in arm B. Overall survival rates at 1 year were 53% in arm A and 52% in arm B. The differences between the curves were not statistically significant.



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  		Fig 2. Progression-free survival according to the treatment group.

 


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  		Fig 3. Overall survival according to the treatment group.

 

   DISCUSSION
TOP
 ABSTRACT
 INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
 DISCUSSION
APPENDIX Other Trial...
 REFERENCES
 
Most of the previously reported rIL-2 trials in MRCC used IV rIL-2 (high-dose bolus injections or continuous infusion).6-8,24 These initial results were encouraging, but the severity of side effects restricted this approach to intensive care or inpatient facilities. The putative additive effect of rIL-2 and rIFN{alpha}-2a, which has been suggested by some experimental data,25 was also demonstrated in the large randomized Cancer du Rein et Cytokines (CRECY) trial, at least in terms of tumor response.26

Because of the toxicity of IV rIL-2, subcutaneous regimens were developed. The initial report of a combination of subcutaneous rIL-2 and rIFN{alpha}-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{alpha}-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{alpha}-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{alpha}-2a in MRCC.


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  		Table 5. Results of Phase II Trials Using the Combination of rIL-2, rIFN{alpha}-2, and FU in Patients With MRCC
 
As hypothesized by Ravaud et al,20 the low response rates obtained in the present study could be related to the schedule of treatment that we have used. In most other studies, these combinations were administered more or less continuously, over a 5- to 6-week period; here, we used an intermittent schedule that included 1 week of rest between each treatment course to try to maximize tolerance of the regimen.

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{alpha}-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{alpha}-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
TOP
 ABSTRACT
 INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
 DISCUSSION
 APPENDIX Other Trial...
REFERENCES
 
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
 
1. Dekernion JB, Ramming KP, Smith RB: The natural history of metastatic renal cell carcinoma: A computer analysis. J Urol 120: 148-152, 1978[Medline]

2. Yagoda A, Abi-Rached B, Petrylak D: Chemotherapy for advanced renal-cell carcinoma: 1983-1993. Semin Oncol 22: 42-60, 1995[Medline]

3. Motzer RJ, Bander NH, Nanus DM: Renal-cell carcinoma. N Engl J Med 335: 865-875, 1996[Free Full Text]

4. Gleave ME, Elhilali M, Fradet Y, et al: Interferon gamma-1b compared with placebo in metastatic renal-cell carcinoma. Canadian Urologic Oncology Group. N Engl J Med 338: 1265-1271, 1998[Abstract/Free Full Text]

5. Fairlamb DJ: Spontaneous regression of metastases of renal cancer: A report of two cases including the first recorded regression following irradiation of a dominant metastasis and review of the world literature. Cancer 47: 2102-2106, 1981[Medline]

6. Rosenberg SA, Lotze MT, Muul LM, et al: A progress report on the treatment of 157 patients with advanced cancer using lymphokine-activated killer cells and interleukin-2 or high-dose interleukin-2 alone. N Engl J Med 316: 889-897, 1987[Abstract]

7. West WH, Tauer KW, Yannelli JR, et al: Constant-infusion recombinant interleukin-2 in adoptive immunotherapy of advanced cancer. N Engl J Med 316: 898-905, 1987[Abstract]

8. Négrier S, Philip T, Stoter G, et al: Interleukin-2 with or without LAK cells in metastatic renal cell carcinoma: A report of a European multicentre study. Eur J Cancer Clin Oncol 25: S21-S28, 1989 (suppl 3)

9. Fossa SD, Martinelli G, Otto U, et al: Recombinant interferon alpha-2a with or without vinblastine in metastatic renal cell carcinoma: Results of a European multi-center phase III study. Ann Oncol 3: 301-305, 1992[Abstract/Free Full Text]

10. Atzpodien J, Korfer A, Franks CR, et al: Home therapy with recombinant interleukin-2 and interferon-alpha 2b in advanced human malignancies. Lancet 335: 1509-1512, 1990[Medline]

11. Figlin RA, Belldegrun A, Moldawer N, et al: Concomitant administration of recombinant human interleukin-2 and recombinant interferon alpha-2A: An active outpatient regimen in metastatic renal cell carcinoma. J Clin Oncol 10: 414-421, 1992[Abstract/Free Full Text]

12. Ravaud A, Négrier S, Cany L, et al: Subcutaneous low-dose recombinant interleukin-2 and alpha-interferon in patients with metastatic renal-cell carcinoma. Br J Cancer 69: 1111-1114, 1994[Medline]

13. Atzpodien J, Lopez Hanninen E, Kirchner H, et al: Multiinstitutional home-therapy trial of recombinant human interleukin-2 and interferon alfa-2 in progressive metastatic renal cell carcinoma. J Clin Oncol 13: 497-501, 1995[Abstract/Free Full Text]

14. Kase S, Kubota T, Watanabe M, et al: Recombinant human interferon alpha-2a increases 5-fluorouracil efficacy by elevating fluorouridine concentration in tumor tissue. Anticancer Res 14: 1155-1159, 1994[Medline]

15. Sella A, Kilbourn RG, Gray I, et al: Phase I study of interleukin-2 combined with interferon-alfa and 5-fluorouracil in patients with metastatic renal cell cancer. Cancer Biother 9: 103-111, 1994[Medline]

16. Ellerhorst JA, Sella A, Amato RJ, et al: Phase II trial of 5-fluorouracil, interferon-alpha and continuous infusion interleukin-2 for patients with metastatic renal cell carcinoma. Cancer 80: 2128-2132, 1997[Medline]

17. Hofmockel G, Langer W, Theiss M, et al: Immunochemotherapy for metastatic renal cell carcinoma using a regimen of interleukin-2, interferon-alpha and 5-fluorouracil. J Urol 156: 18-21, 1996[Medline]

18. Joffe JK, Banks RE, Forbes MA, et al: A phase II study of interferon-alfa, interleukin 2 and 5 fluorouracil in advanced renal cell carcinoma: Clinical data and laboratory evidence of protease activation. Br J Urol 77: 638-639, 1996[Medline]

19. Atzpodien J, Kirchner H, Franzke A, et al: Results of a randomized clinical trial comparing SC interleukin-2, SC alpha-2A-interferon and bolus 5 fluorouracil against oral tamoxifen in progressive metastatic renal cell carcinoma patients. Proc Am Soc Clin Oncol 16: 326a, 1997 (abstr 1164)

20. Ravaud A, Audhuy B, Gomez F, et al: Subcutaneous interleukin-2, interferon alpha 2a, and continuous infusion of fluorouracil in metastatic renal cell carcinoma: A multicenter phase II trial. J Clin Oncol 16: 2728-2732, 1998[Abstract]

21. Miller AB, Hoogstraten B, Staquet M, et al: Reporting results of cancer treatment. Cancer 47: 207-214, 1981[Medline]

22. Simon R, Wittes RE, Ellenberg SS: Randomized phase II clinical trials. Cancer Treat Rep 69: 1375-1381, 1985[Medline]

23. Rubinstein LV, Gail MH, Santner TJ: Planning the duration of a comparative clinical trial with loss to follow-up and a period of continued observation. J Chronic Dis 34: 469-479, 1981[Medline]

24. Atkins MB, Sparano J, Fisher RI, et al: Randomized phase II trial of high-dose interleukin-2 either alone or in combination with interferon alfa-2b in advanced renal cell carcinoma. J Clin Oncol 11: 661-670, 1993[Abstract]

25. Von Rohr A, Ghosh AK, Thatcher N, et al: Immunomodulation during prolonged treatment with combined interleukin-2 and interferon-alpha in patients with advanced malignancy. Br J Cancer 67: 163-171, 1993[Medline]

26. Négrier S, Escudier B, Lasset C, et al: Recombinant human interleukin-2, recombinant human interferon alfa-2a, or both in metastatic renal-cell carcinoma. N Engl J Med 338: 1272-1278, 1998[Abstract/Free Full Text]

27. Vogelzang NJ, Lipton A, Figlin RA: Subcutaneous interleukin-2 plus interferon alfa-2a in metastatic renal cancer: An outpatient multicenter trial. J Clin Oncol 11: 1809-1816, 1993[Abstract/Free Full Text]

28. Dutcher JP, Atkins M, Fisher R, et al: Interleukin-2-based regimen therapy for metastatic renal cell cancer: The Cytokine Working Group experience, 1989-1997. Cancer J Sci Am 3: S73-78, 1997 (suppl 1)

29. Tourani JM, Pfister C, Berdah JF, et al: Outpatient treatment with subcutaneous interleukin-2 and interferon alfa administration in combination with fluorouracil in patients with metastatic renal cell carcinoma: Results of a sequential nonrandomized phase II study. Subcutaneous Administration Propeukin Program Cooperative Group. J Clin Oncol 16: 2505-2513, 1998[Abstract]

30. Lopez Hanninen E, Kirchner H, Atzpodien J: Interleukin-2 based home therapy of metastatic renal cell carcinoma: Risks and benefits in 215 consecutive single institution patients. J Urol 155: 19-25, 1996[Medline]

31. Samland D, Steinbach F, Reiher F, et al: Results of immunochemotherapy with interleukin-2, interferon-alpha2 and 5-fluorouracil in the treatment of metastatic renal cell cancer. Eur Urol 35: 204-209, 1999[Medline]

32. Négrier S, Ravaud A, Delva R, et al: Combination of cytokines in metastatic renal cell carcinoma (MRCC), is the subcutaneous (SC) route less active than the intravenous (IV) route? Proc Am Soc Clin Oncol 18: 331a, 1999 (abstr 1273)

33. Henriksson R, Nilsson S, Colleen S, et al: Survival in renal cell carcinoma: A randomized evaluation of tamoxifen vs interleukin 2, alfa-interferon (leucocyte) and tamoxifen. Br J Cancer 77: 1311-1317, 1998[Medline]

34. Jayson GC, Middleton M, Lee SM, et al: A randomized phase II trial of interleukin 2 and interleukin 2-interferon alpha in advanced renal cancer. Br J Cancer 78: 366-369, 1998[Medline]

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




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Better Survival With Interleukin-2-Based Regimens? Possibly Only in Highly Selected Patients
J. Clin. Oncol., April 1, 2004; 22(7): 1174 - 1176.
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J. A. Thompson, R. A. Figlin, C. Sifri-Steele, R. J. Berenson, and M. W. Frohlich
A Phase I Trial of CD3/CD28-activated T Cells (Xcellerated T Cells) and Interleukin-2 in Patients with Metastatic Renal Cell Carcinoma
Clin. Cancer Res., September 1, 2003; 9(10): 3562 - 3570.
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Y. Mizutani, H. Wada, O. Yoshida, M. Fukushima, M. Nonomura, M. Nakao, and T. Miki
Significance of Thymidylate Synthase Activity in Renal Cell Carcinoma
Clin. Cancer Res., April 1, 2003; 9(4): 1453 - 1460.
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S. Negrier, B. Escudier, F. Gomez, J.-Y. Douillard, A. Ravaud, C. Chevreau, M. Buclon, D. Perol, and C. Lasset
Prognostic factors of survival and rapid progression in 782 patients with metastatic renal carcinomas treated by cytokines: a report from the Groupe Francais d'Immunotherapie
Ann. Onc., September 1, 2002; 13(9): 1460 - 1468.
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J. I. Clark, T. M. Kuzel, T. M. Lestingi, S. G. Fisher, P. Sorokin, B. Martone, M. Viola, and J. A. Sosman
A multi-institutional phase II trial of a novel inpatient schedule of continuous interleukin-2 with interferon {alpha}-2b in advanced renal cell carcinoma: major durable responses in a less highly selected patient population
Ann. Onc., April 1, 2002; 13(4): 606 - 613.
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F. Donskov, H. von der Maase, R. Henriksson, U. Stierner, P. Wersall, H. Nellemann, K. Hellstrand, K. Engman, and P. Naredi
Outpatient treatment with subcutaneous histamine dihydrochloride in combination with interleukin-2 and interferon-{alpha} in patients with metastatic renal cell carcinoma: results of an open single-armed multicentre phase II study
Ann. Onc., March 1, 2002; 13(3): 441 - 449.
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S. D. Fossa and E. Skovlund
Interim Analyses in Clinical Trials: Why Do We Plan Them?
J. Clin. Oncol., December 15, 2000; 18(24): 4007 - 4008.
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