Background Recombinant human interleukin-2 (aldesleukin) andrecombinant human interferon alfa can induce notable tumor regressionin a limited number of patients with metastatic renal-cell carcinoma.We conducted a multicenter, randomized trial to determine theeffect of each cytokine independently and in combination, andto identify patients who are best suited for this treatment.
Methods Four hundred twenty-five patients with metastatic renal-cellcarcinoma were randomly assigned to receive either a continuousintravenous infusion of interleukin-2, subcutaneous injectionsof interferon alfa-2a, or both. The main outcome measure wasthe response rate; secondary outcomes were the rates of event-freeand overall survival. Predictive factors for response and rapidprogression were identified by multivariate analysis.
Results Response rates were 6.5 percent, 7.5 percent, and 18.6percent (P<0.01) for the groups receiving interleukin-2,interferon alfa-2a, and interleukin-2 plus interferon alfa-2a,respectively. At one year, the event-free survival rates were15 percent, 12 percent, and 20 percent, respectively (P = 0.01).There was no significant difference in overall survival amongthe three groups. Toxic effects of therapy were more commonin patients receiving interleukin-2 than in those receivinginterferon alfa-2a. Response to treatment was associated withhaving metastasis to a single organ and with receiving the combinedtreatment. The probability of rapid progression of disease wasat least 70 percent for patients with at least two metastaticsites, liver metastases, and a period of less than one yearbetween the diagnosis of the primary tumor and the appearanceof metastases.
Conclusions Cytokines are active in a few patients with metastaticrenal-cell carcinoma. The higher response rate and longer event-freesurvival obtained with a combination of cytokines must be balancedagainst the toxicity of such treatment.
Metastatic renal-cell carcinoma is refractory to chemotherapy,and median survival is usually less than a year.1,2,3,4 Performancestatus, number of metastatic sites, time from diagnosis of theprimary tumor to the discovery of metastases, and weight lossare important prognostic factors.1,5,6 In 1985 and 1987, Rosenberget al.7,8 reported that recombinant human interleukin-2 (aldesleukin)caused dramatic shrinkage of tumors, particularly in patientswith metastatic renal-cell carcinoma. These results sparkedthe development of cytokine treatment in oncology. The pronouncedtoxic effects described in the initial reports from trials involvinga high-dose bolus of interleukin-2 prompted the developmentof other regimens, such as the continuous infusion of interleukin-2or subcutaneous injections of interleukin-2 plus interferonalfa.9,10
In 1990 interleukin-2 and interferon alfa were approved forthe treatment of metastatic renal-cell carcinoma in most WesternEuropean countries. However, the results available at that timewere discordant and were based on nonrandomized phase 2 studies.11,12,13,14,15,16
In this setting, the Groupe Français d'Immunothérapieinitiated a randomized trial to determine the effect of interleukin-2and interferon alfa-2a on metastatic renal-cell carcinoma. Becausethese cytokines can cause dramatic and durable tumor regressionin some patients, the group considered a randomized trial withan untreated control group to be unethical. In this trial patientswere treated with recombinant human interleukin-2, recombinanthuman interferon alfa-2a, or both cytokines.
Methods
Selection of Patients
Patients between 18 and 65 years of age were eligible if theyhad histologically confirmed, clearly progressive metastaticrenal-cell carcinoma that could be measured in two dimensions;an Eastern Cooperative Oncology Group (ECOG) performance statusno higher than 1; and normal blood cell counts, normal bilirubinlevels, and creatinine levels below 1.7 mg per deciliter (150µmol per liter). Patients were excluded if they had brainmetastases (confirmed by computed tomography [CT]), cardiacdysfunction (confirmed by electrocardiography and echocardiography),a contraindication to the use of vasopressor agents, activeinfection, previous treatment with interleukin-2 or interferonalfa, chemotherapy or radiotherapy in the six weeks before enrollment,or current treatment with corticosteroids. Patients with a historyof organ transplantation, other cancer, or seizure disorderwere excluded. Pregnant or lactating women were also ineligible.The base-line workup consisted of brain, thoracic, abdominal,and pelvic CT and bone scanning. The number of organs with metastaseswas determined in each patient before randomization, and theorgans involved were recorded as lung (including pleura), liver,bone, or other (with details of the site).
Patients who required nephrectomy were invited to enter thetrial only after they had undergone the operation. We recommendedthat patients who had only one metastasis have the metastasissurgically removed. The protocol was approved by the ethicscommittee of the Centre Léon Bérard in Lyons incompliance with French law. Voluntary, written informed consentwas obtained from all patients.
Treatment
Randomization, with stratification according to center, wasperformed by an interactive computerized procedure at the studydata-monitoring center. All data were prospectively monitoredon site. Details of ineligible patients were recorded, togetherwith the main reason for exclusion. Eligible patients were randomlyassigned to receive either intravenous recombinant human interleukin-2alone (group 1), subcutaneous recombinant human interferon alfa-2aalone (group 2), or intravenous interleukin-2 combined withsubcutaneous interferon alfa-2a (group 3).
In group 1, recombinant human interleukin-2 (Proleukin, ChironTherapeutics, Paris) was administered as a five-day continuousintravenous infusion at a dose of 18x106 IU per square meterof body-surface area per day. This regimen has been widely usedin Europe since interleukin-2 received a product license. Thetreatment schedule consisted of two induction cycles and fourmaintenance cycles, with a three-week rest period between cycles.Each induction cycle consisted of two five-day courses of interleukin-2infusion separated by a six-day break. Each maintenance cycleconsisted of a five-day infusion followed by three weeks ofno therapy.
In group 2, recombinant human interferon alfa-2a (Roferon, Roche,Paris) was given subcutaneously at a dose of 18x106 IU per daythree times a week for 10 weeks as induction treatment and for13 additional weeks as maintenance treatment.
In group 3, interleukin-2 was administered exactly as in group1; in addition, interferon alfa-2a at a dose of 6x106 IU perday three times a week subcutaneously was given during the twointerleukin-2 induction cycles and during each interleukin-2maintenance cycle. This regimen had been previously validatedby our group in a pilot study (unpublished data).
Patients without disease progression at the time response wasevaluated (week 10) received maintenance treatment. In the eventof progression of disease, patients in groups 1 and 2 couldreceive the other cytokine (crossover).
Supportive Care
Patients assigned to receive interleukin-2 had a central venouscatheter inserted, and the use of prophylactic antibiotics,usually an intravenous quinolone, was recommended.17 The patientsalso received acetaminophen (1 g every four hours) and, if necessary,indomethacin (25 mg every six hours) to reduce febrile reactions;cimetidine or misoprostol to prevent gastrointestinal bleeding;diphenhydramine for pruritus; and antidiarrheal agents. In addition,antiemetic drugs, anxiolytic agents, and sedatives were administeredwhen required. Colloids were used for the initial treatmentof hypotension, followed by vasopressor agents, usually dopamine,if necessary.
Dose Modification and Monitoring of Toxicity
The World Health Organization scoring system was used to classifytoxic effects of therapy.18 Treatment was stopped if hypotensionresistant to intravenous vasopressor treatment occurred or ifthere was any toxic event of grade 3 or higher. Patients withlife-threatening or persistent, severe toxic reactions receivedno further treatment with the trial drugs. In other patients,treatment was resumed at the original doses when the toxic effectsimproved to grade 1 or less. The doses were reduced, usuallyhalved, if a new episode of toxic effects of grade 3 or moreoccurred. When unusual or unexpected adverse reactions werereported, a specific warning was sent to all investigators.In addition, all reports of grade 4 toxicity were reviewed bya committee to assess whether the treatment caused the sideeffect.
Assessment of Response
The World Health Organization criteria18 were used to determinetumor response. An objective response (more than 50 percentreduction in the sum of the sizes of all lesions) included bothpartial and complete responses, judged by comparing tumor sizesby CT 10 weeks after the start of treatment with those measuredin the 2 weeks before treatment. Tumors were measured at week25 in patients who had at least stable disease and who had receivedmaintenance treatment. All cases of tumor regression, even thoseclassified as minor responses by the investigators, and doubtfulcases were reviewed by an external committee consisting of threeradiologists and two physicians who were blinded to the patients'treatment assignments.19 Rapid progression was defined as progressionoccurring within the first 10 weeks of treatment (progressionwas defined as a 25 percent increase in the size of one lesionor the appearance of a new lesion).
Statistical Analysis
The major end point was the rate of response. The secondaryend points were event-free survival, defined as survival withoutdisease progression, and overall survival. Survival curves werecalculated by the Kaplan–Meier method20 and compared bythe log-rank test.21
An independent methods review committee evaluated the resultsof an interim analysis after the enrollment of 31 patients pergroup to verify the efficacy of each treatment. The predefinedcriterion for stopping the trial was a response rate of lessthan 10 percent in one group, together with a difference ofat least 15 percent from the treatment group with the closestresults to that group. The methods committee recommended continuationof the study as a phase 3 trial to allow the comparison of overallsurvival between group 1 or 2 (in which the two cytokines couldbe administered sequentially in a crossover fashion) and group3 (in which both cytokines were administered at the same time).It was calculated that 138 patients per group were needed fora difference of at least 20 percent in overall survival to bedetected, with set at 5 percent and at 10 percent.
Univariate analysis and multivariate stepwise logistic-regressionanalysis were performed with the Logistic procedure of the SASstatistical software package (SAS Institute, Cary, N.C.) toidentify prognostic factors for response and rapid progression.
Results
Characteristics of the Patients
From March 1992 to July 1995, 425 patients with metastatic renal-cellcarcinoma were enrolled in the study; 138 were randomly assignedto the interleukin-2 group, 147 to the group receiving interferonalfa-2a, and 140 to the group receiving interleukin-2 plus interferonalfa-2a. During the same period, 722 patients were consideredineligible, because of an ECOG performance status of 2 or higher(25 percent), age below 18 or above 65 years (17 percent), organdysfunction (13 percent), brain metastases (12 percent), previoustreatment (11 percent), refusal by the patient (6 percent),or miscellaneous reasons (16 percent).
There were no statistically significant differences in patientcharacteristics among the three treatment groups (Table 1).Most patients (77 percent) had a performance-status score of0, and most (93 percent) had undergone nephrectomy. After reviewof the data, 7 of the 425 patients were found not to fulfillthe eligibility criteria; 11 patients did not receive any cytokinetreatment. These patients were included in the intention-to-treatanalysis.
The induction treatment was given to 132, 146, and 136 patientsin groups 1, 2, and 3, respectively, and 29, 59, and 47 patients,respectively, received maintenance treatment. The mean percentagesof each agent delivered during the induction treatment (includingboth dose reductions and discontinuations of treatment) were61 percent (groups 1 and 3) for interleukin-2, and 86 percentand 72 percent (groups 2 and 3, respectively) for interferonalfa-2a. After the failure of their initial treatment, 48 patientsinitially assigned to interleukin-2 received interferon alfa-2a,and 65 initially assigned to interferon alfa-2a received interleukin-2.No unusual degree of toxicity was observed in these patients.
Table 2 shows the grade 3 or 4 adverse events observed in eachtreatment group during induction cycles. More adverse eventswere observed in the groups given interleukin-2 (groups 1 and3) than in the group given interferon alfa-2a alone (group 2),but there were no significant differences in the number of adverseevents between the group given interleukin-2 alone and the groupgiven interleukin-2 plus interferon alfa-2a, except for grade3 or 4 fever, which was more common with the combined treatment(P = 0.02). Fever and hypotension were the most common adverseevents in the two groups receiving interleukin-2. All patientsrecovered and returned to their pretreatment status with respectto these adverse events.
Table 2. Grade 3 or 4 Adverse Events Observed during Induction Treatment.
During the treatment periods, or within a month following atreatment course, 22 patients (5.2 percent) died from causesunrelated to renal-cell carcinoma: 13 patients (9.4 percent)in group 1, 1 (0.7 percent) in group 2, and 8 (5.7 percent)in group 3. These patients were significantly more likely tohave had low performance-status scores at the start of treatment(P = 0.01), metastasis-free intervals of less than one yearfrom diagnosis (P = 0.01), weight loss of at least 10 percentbefore treatment (P = 0.004), and doses of interleukin-2 belowthe median dose received by all the patients given interleukin-2(P = 0.03).
Response to Treatment
Patients who had received at least five days of treatment withinterleukin-2 or four weeks with interferon alfa-2a were assessedto determine whether their disease had responded to treatment.Among the 425 patients randomly assigned to treatment, 44 couldnot be evaluated for a response by the review committee. Elevenof these patients received no cytokine treatment, the treatmentof 10 was interrupted soon after it began because of severetoxic reactions, 13 died before their tumors had been evaluated,6 had not been evaluated within two months after the planneddate, and 4 were excluded because of methodologic problems.
In the intention-to-treat analysis, the proportions of patientswith a response at week 10 were as follows: 9 of 138 (6.5 percent)in group 1, 11 of 147 (7.5 percent) in group 2, and 26 of 140(18.6 percent) in group 3 (Table 3). If only the patients whocould be evaluated were included in the analysis, the responserates were 7.7 percent, 7.8 percent, and 21.3 percent for groups1, 2, and 3, respectively.
Table 3. Rates of Tumor Response at Week 10 and Week 25.
In both analyses, the response rates were significantly higher(P<0.01) in the group that received both treatments thanin either of the groups that received only one treatment. Atweek 25, after the completion of maintenance treatment, theresponse rates were 2.9 percent, 6.1 percent, and 13.6 percentin groups 1, 2, and 3, respectively (Table 3). The responserates remained significantly higher (P = 0.001) in the groupreceiving the combined treatment. The response rates among the113 patients who were changed to a different cytokine treatmentafter their cancer failed to respond to the randomly assignedtreatment were in the same ranges as those in the analysis accordingto the initial treatments (data not shown).
Survival
The median follow-up period for the cohort was 39 months. Theevent-free survival rates at one year were 15 percent, 12 percent,and 20 percent in groups 1, 2, and 3, respectively (Figure 1),and were significantly higher in the group receiving the combinedcytokine treatment than in the other two groups (P = 0.01).However, the overall survival rates in the three groups werenot significantly different from one another (P = 0.55 by thelog-rank test), and the median survival times were 12, 13, and17 months, respectively (Figure 2).
Figure 1. Kaplan–Meier Curves for Event-free Survival among Patients in the Three Treatment Groups.
The tick marks represent censored data on patients who were alive without progression of disease. The results shown are from an intention-to-treat analysis. P = 0.01 for the comparison among the groups.
Figure 2. Kaplan–Meier Curves for Overall Survival among Patients in the Three Treatment Groups.
The tick marks represent censored data on patients who were alive or lost to follow-up. The results shown are from an intention-to-treat analysis. P = 0.55 for the comparison among the groups.
Factors Predicting Response
Two statistically independent factors had predictive value fora response to treatment: the number of organs with metastasis(one vs. two or more, P<0.001) and the treatment group (1or 2 vs. 3, P<0.001) (Table 4). Patients with only one metastaticsite who received both cytokines had a 37 percent probabilityof a response, whereas those with multiple metastatic siteshad a 23 percent probability of a response.
Table 4. Multivariate Analysis of Factors Predicting Response and Rapid Progression.
Factors Predicting Rapid Progression
Multivariate analysis identified five independent predictorsof rapid progression (i.e., progression within 10 weeks): numberof metastatic sites (two or more vs. one), treatment group (1or 2 vs. 3), the time from the diagnosis of primary tumor tometastasis (1 year or less vs. more than 1 year), presence ofliver metastases, and presence of mediastinal lymph-node metastases(Table 4).
Patients who had more than one organ with metastasis, metastasisto the liver, and metastasis less than one year after the diagnosisof primary tumor had a probability of rapid progression of atleast 70 percent, even if they received both cytokines. Thisgroup represented 20 percent of the patients enrolled in thestudy. In this subpopulation, the response rate with the combinationof cytokines was 14 percent, and median survival was six months.
Discussion
There is no standard treatment for metastatic renal-cell carcinoma,4,22but many patients with this condition receive interleukin-2or interferon alfa outside the setting of a therapeutic trial.These cytokines are the only drugs that have been shown to inducetumor regression in some patients.4 There are, however, no datato indicate which patients are most likely to benefit from suchtreatment and which cytokine regimen is the most active.
Our results confirm that clinically relevant tumor regressionoccurs in a minority of cytokine-treated patients. Moreover,monotherapy with interferon alfa-2a or interleukin-2 gave verylow response rates (7.5 percent and 6.5 percent, respectively,at 10 weeks). The group treated with both cytokines had a responserate of 18.6 percent and significantly longer event-free survival.However, since there was no significant difference in overallsurvival among the three groups, we cannot conclude that thecombined treatment provided a significant advantage.
In our study, the toxicity of the regimens containing interleukin-2was, as expected, dramatically higher than the toxicity of interferonalfa-2a alone. Indeed, the severity of the toxic reactions tointerleukin-2 limits the use of regimens based on this cytokine.In patients who died from non–disease-related causes,we observed a correlation with unfavorable prognostic factorsrelated to the disease. Reducing the toxicity of regimens containinginterleukin-2 is therefore a high priority for future studies.Selecting patients with metastatic renal-cell carcinoma whoare most likely to respond to cytokine treatment could be onemeans of achieving this goal. Previous retrospective studiesidentified performance status, disease-free interval, presenceor absence of liver involvement, and number of metastatic sitesas predictors of overall survival.1,5,6,23
We found that the factors that predicted a response (metastasisto only one organ and combined treatment) could not be usedto select patients effectively. Indeed, patients with severalmetastatic sites had a 23 percent probability of response withthe combined treatment. For this reason, we have identifiedprognostic factors for rapid progression under treatment, whichcan be used to select patients with little chance of a response.Patients with more than one metastatic site, liver involvement,and an interval from diagnosis of the primary tumor to the appearanceof metastatic disease of less than one year have a 70 percentor higher probability of rapid progression and poor survival(median survival, six months).
In conclusion, significantly higher rates of response and event-freesurvival were seen with the combined cytokine therapy, but noneof the three regimens we tested had any advantage in terms ofoverall survival. The toxic effects frequently observed withcombined therapy emphasize the need for careful selection ofpatients. It is usually recommended that cytokine treatmentbe restricted to patients who are ambulatory and have no majororgan failure.4 Our study identifies a subgroup of patientswho have virtually no chance of benefiting from treatment.
Supported by grants from the Association pour la Recherche contrele Cancer.
* Other investigators are listed in the Appendix.
Source Information
From the Departments of Medical Oncology (S.N., T.P.) and Biostatistics (C.L., J.S.), Centre Léon Bérard, Lyons; Institut Gustave Roussy, Villejuif (B.E., T.T.); Centre René Gauducheau, Nantes (J.-Y.D.); Centre Claudius Régaud, Toulouse (C.C.); Institut Bergonié, Bordeaux (A.R.); Hôpital Edouard Herriot, Lyons (A.M.); Centre François Baclesse, Caen (J.P.); and Hôpital Michalon, Grenoble (M.M.) — all in France.
Address reprint requests to Dr. Negrier at the Centre Léon Bérard, 69373 Lyons CEDEX 08, France.
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Appendix
In addition to the authors, the following investigators andcenters from the Groupe Français d'Immunothérapie(which is part of the Fédération Nationale desCentres de Lutte contre le Cancer) participated in this study:B. Coronel (Hôpital E. Herriot, Lyons); J.-F. Rossi (CentreHospitalier Universitaire, Montpellier); M. Fabbro (Centre P.Lamarque, Montpellier); J.-P. Bergerat (Centre Hospitalier Universitaire,Strasbourg); A. Caty (Centre O. Lambret, Lille); D. Baume (InstitutP. Calmettes, Marseilles); J. Fleury (Centre J. Perrin, Clermont-Ferrand);J.-M. Ferrero, A. Thyss (Centre A. Lacassagne, Nice); R. Delva(Centre P. Papin, Angers); N. Tubiana-Mathieu (Hôpitalde la Timone, Marseilles); P. Fargeot (Centre G.F. Leclerc,Dijon); T. Lesimple (Centre E. Marquis, Rennes); T. Dorval (InstitutCurie, Paris); M.-B. Orgerie (Hôpital Minjoz, Besançon);T. Conroy (Centre A. Vautrin, Nancy); A. Goupil (Centre R. Huguenin,Saint-Cloud); E. Khenifar (Hôpital Saint-Jacques, Besançon);B. Audhuy (Centre Hospitalier, Colmar); J.-C. Eymard (InstitutJ. Godinot, Reims); Tumor Response Evaluation Committee: L.Ollivier (Institut Curie, Paris); D. Di Stefano-Louineau (InstitutP. Calmette, Marseilles); P. Thiesse (Centre L. Bérard,Lyons); Toxicity Review Committee: T. Vial (Hôpital E.Herriot, Lyons); G. Nitenberg (Institut G. Roussy, Villejuif);S. Robard (Centre R. Gauducheau, Nantes); Data Monitoring andStatistical Center: K. Pignard, M. Drevon, F. Chauvin (CentreL. Bérard, Lyons); N. Rodrigo, J. Maupas (APRET, Lyons);Methods Review Committee: H. Sancho-Garnier (Centre Val d'Aurelle,Montpellier); J.-P. Boissel (Hôpital Cardiologique, Lyons)— all in France; M. Buyse (International Institute forDrug Development, Brussels, Belgium).
Cytokine Therapy in Metastatic Renal Cancer
Stadler W. M., Vogelzang N. J., Jerian S., Keegan P., Siegel J., Davis I. D., Gleave M., Elhilali M., Negrier S., Lasset C., Escudier B., The Groupe Français d'Immunothérapie
Extract |
Full Text
N Engl J Med 1998;
339:849-851, Sep 17, 1998.
Correspondence
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Negrier, S., Perol, D., Ravaud, A., Bay, J. O., Oudard, S., Chabaud, S., Fargeot, P., Delva, R., Deplanque, G., Gravis, G., Escudier, B., for the French Immunotherapy Group,
(2008). Randomized Study of Intravenous versus Subcutaneous Interleukin-2, and IFN{alpha} in Patients with Good Prognosis Metastatic Renal Cancer. Clin. Cancer Res.
14: 5907-5912
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Remak, E., Charbonneau, C., Negrier, S., Kim, S. T., Motzer, R. J.
(2008). Economic Evaluation of Sunitinib Malate for the First-Line Treatment of Metastatic Renal Cell Carcinoma. JCO
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Coutinho, E. L., de Sousa Andrade, L. N., Chammas, R., Morganti, L., Schor, N., Bellini, M. H.
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Gollob, J. A., Rathmell, W. K., Richmond, T. M., Marino, C. B., Miller, E. K., Grigson, G., Watkins, C., Gu, L., Peterson, B. L., Wright, J. J.
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Kato, Y., Yoshimura, K., Shin, T., Verheul, H., Hammers, H., Sanni, T. B., Salumbides, B. C., Van Erp, K., Schulick, R., Pili, R.
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Hudes, G., Carducci, M., Tomczak, P., Dutcher, J., Figlin, R., Kapoor, A., Staroslawska, E., Sosman, J., McDermott, D., Bodrogi, I., Kovacevic, Z., Lesovoy, V., Schmidt-Wolf, I. G.H., Barbarash, O., Gokmen, E., O'Toole, T., Lustgarten, S., Moore, L., Motzer, R. J., the Global ARCC Trial,
(2007). Temsirolimus, Interferon Alfa, or Both for Advanced Renal-Cell Carcinoma. NEJM
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Haferkamp, A., Hohenfellner, M.
(2007). Medical treatment options in patients with metastatic renal cell carcinoma. Nephrol Dial Transplant
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Chouhan, J. D, Zamarripa, D. E, Lai, P. H, Oramasionwu, C. U, Grabinski, J. L
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Garcia, J. A., Rini, B. I.
(2007). Recent Progress in the Management of Advanced Renal Cell Carcinoma. CA Cancer J Clin
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Goodman, V. L., Rock, E. P., Dagher, R., Ramchandani, R. P., Abraham, S., Gobburu, J. V.S., Booth, B. P., Verbois, S. L., Morse, D. E., Liang, C. Y., Chidambaram, N., Jiang, J. X., Tang, S., Mahjoob, K., Justice, R., Pazdur, R.
(2007). Approval Summary: Sunitinib for the Treatment of Imatinib Refractory or Intolerant Gastrointestinal Stromal Tumors and Advanced Renal Cell Carcinoma. Clin. Cancer Res.
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Choueiri, T., Rini, B., Garcia, J., Baz, R., Abou-Jawde, R., Thakkar, S., Elson, P, Mekhail, T., Zhou, M, Bukowski, R.
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Ernstoff, M. S., Crocenzi, T. S., Seigne, J. D., Crosby, N. A., Cole, B. F., Fisher, J. L., Uhlenhake, J. C., Mellinger, D., Foster, C., Farnham, C. J., Mackay, K., Szczepiorkowski, Z. M., Webber, S. M., Schned, A. R., Harris, R. D., Barth, R. J. Jr., Heaney, J. A., Noelle, R. J.
(2007). Developing a Rational Tumor Vaccine Therapy for Renal Cell Carcinoma: Immune Yin and Yang. Clin. Cancer Res.
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Motzer, R. J., Hutson, T. E., Tomczak, P., Michaelson, M. D., Bukowski, R. M., Rixe, O., Oudard, S., Negrier, S., Szczylik, C., Kim, S. T., Chen, I., Bycott, P. W., Baum, C. M., Figlin, R. A.
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Escudier, B., Eisen, T., Stadler, W. M., Szczylik, C., Oudard, S., Siebels, M., Negrier, S., Chevreau, C., Solska, E., Desai, A. A., Rolland, F., Demkow, T., Hutson, T. E., Gore, M., Freeman, S., Schwartz, B., Shan, M., Simantov, R., Bukowski, R. M., the TARGET Study Group,
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Tsai, K.-Y., Yang, C.-H., Kuo, T.-t., Hong, H.-S., Chang, J. W.C.
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Kausche, S., Wehler, T., Schnurer, E., Lennerz, V., Brenner, W., Melchior, S., Grone, M., Nonn, M., Strand, S., Meyer, R., Ranieri, E., Huber, C., Falk, C. S., Herr, W.
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Barkholt, L., Bregni, M., Remberger, M., Blaise, D., Peccatori, J., Massenkeil, G., Pedrazzoli, P., Zambelli, A., Bay, J.-O., Francois, S., Martino, R., Bengala, C., Brune, M., Lenhoff, S., Porcellini, A., Falda, M., Siena, S., Demirer, T., Niederwieser, D., Ringden, O., On behalf of the French ITAC group and the EBMT So,
(2006). Allogeneic haematopoietic stem cell transplantation for metastatic renal carcinoma in Europe. Ann Oncol
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Pan, J., Burdick, M. D., Belperio, J. A., Xue, Y. Y., Gerard, C., Sharma, S., Dubinett, S. M., Strieter, R. M.
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(2006). Activity of SU11248, a Multitargeted Inhibitor of Vascular Endothelial Growth Factor Receptor and Platelet-Derived Growth Factor Receptor, in Patients With Metastatic Renal Cell Carcinoma. JCO
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Hainsworth, J. D., Sosman, J. A., Spigel, D. R., Edwards, D. L., Baughman, C., Greco, A.
(2005). Treatment of Metastatic Renal Cell Carcinoma With a Combination of Bevacizumab and Erlotinib. JCO
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Brouwers, A. H., Buijs, W. C.A.M., Mulders, P. F.A., de Mulder, P. H.M., van den Broek, W. J.M., Mala, C., Oosterwijk, E., Boerman, O. C., Corstens, F. H.M., Oyen, W. J.G.
(2005). Radioimmunotherapy with [131I]cG250 in Patients with Metastasized Renal Cell Cancer: Dosimetric Analysis and Immunologic Response. Clin. Cancer Res.
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Brouwers, A. H., Mulders, P. F.A., de Mulder, P. H.M., van den Broek, W. J.M., Buijs, W. C.A.M., Mala, C., Joosten, F. B.M., Oosterwijk, E., Boerman, O. C., Corstens, F. H.M., Oyen, W. J.G.
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Aass, N., De Mulder, P. H.M., Mickisch, G. H.J., Mulders, P., van Oosterom, A. T., van Poppel, H., Fossa, S. D., de Prijck, L., Sylvester, R. J.
(2005). Randomized Phase II/III Trial of Interferon Alfa-2a With and Without 13-cis-Retinoic Acid in Patients With Progressive Metastatic Renal Cell Carcinoma: The European Organisation for Research and Treatment of Cancer Genito-Urinary Tract Cancer Group (EORTC 30951). JCO
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Hoving, S., Brunstein, F., aan de Wiel-Ambagtsheer, G., van Tiel, S. T., de Boeck, G., de Bruijn, E. A., Eggermont, A. M.M., ten Hagen, T. L.M.
(2005). Synergistic Antitumor Response of Interleukin 2 with Melphalan in Isolated Limb Perfusion in Soft Tissue Sarcoma-Bearing Rats. Cancer Res.
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McDermott, D. F., Regan, M. M., Clark, J. I., Flaherty, L. E., Weiss, G. R., Logan, T. F., Kirkwood, J. M., Gordon, M. S., Sosman, J. A., Ernstoff, M. S., Tretter, C. P.G., Urba, W. J., Smith, J. W., Margolin, K. A., Mier, J. W., Gollob, J. A., Dutcher, J. P., Atkins, M. B.
(2005). Randomized Phase III Trial of High-Dose Interleukin-2 Versus Subcutaneous Interleukin-2 and Interferon in Patients With Metastatic Renal Cell Carcinoma. JCO
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Kami, M., Makimoto, A., Heike, Y., Takaue, Y.
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Takemoto, Y., Yano, H., Momosaki, S., Ogasawara, S., Nishida, N., Kojiro, S., Kamura, T., Kojiro, M.
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Dorrschuck, A., Schmidt, A., Schnurer, E., Gluckmann, M., Albrecht, C., Wolfel, C., Lennerz, V., Lifke, A., Di Natale, C., Ranieri, E., Gesualdo, L., Huber, C., Karas, M., Wolfel, T., Herr, W.
(2004). CD8+ cytotoxic T lymphocytes isolated from allogeneic healthy donors recognize HLA class Ia/Ib-associated renal carcinoma antigens with ubiquitous or restricted tissue expression. Blood
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Alatrash, G., Hutson, T. E., Molto, L., Richmond, A., Nemec, C., Mekhail, T., Elson, P., Tannenbaum, C., Olencki, T., Finke, J., Bukowski, R. M.
(2004). Clinical and Immunologic Effects of Subcutaneously Administered Interleukin-12 and Interferon Alfa-2b: Phase I Trial of Patients With Metastatic Renal Cell Carcinoma or Malignant Melanoma. JCO
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Negrier, S., Perol, D., Menetrier-Caux, C., Escudier, B., Pallardy, M., Ravaud, A., Douillard, J.-Y., Chevreau, C., Lasset, C., Blay, J.-Y.
(2004). Interleukin-6, Interleukin-10, and Vascular Endothelial Growth Factor in Metastatic Renal Cell Carcinoma: Prognostic Value of Interleukin-6--From the Groupe Francais d'Immunotherapie. JCO
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Chen, H. X.
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Rini, B. I., Halabi, S., Taylor, J., Small, E. J., Schilsky, R. L.
(2004). Cancer and Leukemia Group B 90206: A Randomized Phase III Trial of Interferon-{alpha} or Interferon-{alpha} Plus Anti-Vascular Endothelial Growth Factor Antibody (Bevacizumab) in Metastatic Renal Cell Carcinoma. Clin. Cancer Res.
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Negrier, S.
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Atzpodien, J., Kirchner, H., Jonas, U., Bergmann, L., Schott, H., Heynemann, H., Fornara, P., Loening, S.A., Roigas, J., Muller, S.C., Bodenstein, H., Pomer, S., Metzner, B., Rebmann, U., Oberneder, R., Siebels, M., Wandert, T., Puchberger, T., Reitz, M.
(2004). Interleukin-2- and Interferon Alfa-2a-Based Immunochemotherapy in Advanced Renal Cell Carcinoma: A Prospectively Randomized Trial of the German Cooperative Renal Carcinoma Chemoimmunotherapy Group (DGCIN). JCO
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Pandha, H.
(2004). Integrative Tumor Board: Metastatic Renal Cell Carcinoma. Integr Cancer Ther
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Atkins, M. B., Hidalgo, M., Stadler, W. M., Logan, T. F., Dutcher, J. P., Hudes, G. R., Park, Y., Liou, S.-H., Marshall, B., Boni, J. P., Dukart, G., Sherman, M. L.
(2004). Randomized Phase II Study of Multiple Dose Levels of CCI-779, a Novel Mammalian Target of Rapamycin Kinase Inhibitor, in Patients With Advanced Refractory Renal Cell Carcinoma. JCO
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Blaise, D., Bay, J. O., Faucher, C., Michallet, M., Boiron, J.-M., Choufi, B., Cahn, J.-Y., Gratecos, N., Sotto, J.-J., Francois, S., Fleury, J., Mohty, M., Chabannon, C., Bilger, K., Gravis, G., Viret, F., Braud, A. C., Bardou, V. J., Maraninchi, D., Viens, P.
(2004). Reduced-intensity preparative regimen and allogeneic stem cell transplantation for advanced solid tumors. Blood
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Tourani, J.-M., Pfister, C., Tubiana, N., Ouldkaci, M., Prevot, G., Lucas, V., Oudard, S., Malet, M., Cottu, P., Ferrero, J.-M., Mayeur, D., Rixe, O., Sun, X.-S., Bernard, O., Andre, T., Tournigand, C., Muracciole, X., Guilhot, J.
(2003). 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. JCO
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Hernberg, M., Virkkunen, P., Bono, P., Ahtinen, H., Maenpaa, H., Joensuu, H.
(2003). Interferon Alfa-2b Three Times Daily and Thalidomide in the Treatment of Metastatic Renal Cell Carcinoma. JCO
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Lara, P. N. Jr., Quinn, D. I., Margolin, K., Meyers, F. J., Longmate, J., Frankel, P., Mack, P. C., Turrell, C., Valk, P., Rao, J., Buckley, P., Wun, T., Gosselin, R., Galvin, I., Gumerlock, P. H., Lenz, H. J., Doroshow, J. H., Gandara, D. R.
(2003). SU5416 Plus Interferon {alpha} in Advanced Renal Cell Carcinoma: A Phase II California Cancer Consortium Study with Biological and Imaging Correlates of Angiogenesis Inhibition. Clin. Cancer Res.
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Thompson, J. A., Figlin, R. A., Sifri-Steele, C., Berenson, R. J., Frohlich, M. W.
(2003). 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.
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Clark, J. I., Atkins, M. B., Urba, W. J., Creech, S., Figlin, R. A., Dutcher, J. P., Flaherty, L., Sosman, J. A., Logan, T. F., White, R., Weiss, G. R., Redman, B. G., Tretter, C. P.G., McDermott, D., Smith, J. W., Gordon, M. S., Margolin, K. A.
(2003). Adjuvant High-Dose Bolus Interleukin-2 for Patients With High-Risk Renal Cell Carcinoma: A Cytokine Working Group Randomized Trial. JCO
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Kemp, T. J., Elzey, B. D., Griffith, T. S.
(2003). Plasmacytoid Dendritic Cell-Derived IFN-{alpha} Induces TNF-Related Apoptosis-Inducing Ligand/Apo-2L-Mediated Antitumor Activity by Human Monocytes Following CpG Oligodeoxynucleotide Stimulation. J. Immunol.
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Caorsi, C., Quintana, E., Valdes, S., Munoz, C.
(2003). Continuous cardiac output and hemodynamic monitoring: high temporal correlation between plasma TNF-{alpha} and hemodynamic changes during a sepsis-like state in cancer immunotherapy. Innate Immunity
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Hutson, T. E., Molto, L., Mekhail, T., Elson, P., Finke, J., Tannenbaum, C., Borden, E., Dreicer, R., Olencki, T., Bukowski, R. M.
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Haas, N. B., Smith, M., Lewis, N., Littman, L., Yeslow, G., Joshi, I. D., Murgo, A., Bradley, J., Gordon, R., Wang, H., Rogatko, A., Hudes, G. R.
(2003). Weekly Bryostatin-1 in Metastatic Renal Cell Carcinoma: A Phase II Study. Clin. Cancer Res.
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Bukowski, R., Ernstoff, M. S., Gore, M. E., Nemunaitis, J. J., Amato, R., Gupta, S. K., Tendler, C. L.
(2002). Pegylated Interferon Alfa-2b Treatment for Patients With Solid Tumors: A Phase I/II Study. JCO
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(2002). 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 Oncol
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Escudier, B., Lassau, N., Couanet, D., Angevin, E., Mesrati, F., Leborgne, S., Garofano, A., Leboulaire, C., Dupouy, N., Laplanche, A.
(2002). Phase II trial of thalidomide in renal-cell carcinoma. Ann Oncol
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Griffith, T. S., Fialkov, J. M., Scott, D. L., Azuhata, T., Williams, R. D., Wall, N. R., Altieri, D. C., Sandler, A. D.
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Clark, J. I., Kuzel, T. M., Lestingi, T. M., Fisher, S. G., Sorokin, P., Martone, B., Viola, M., Sosman, J. A.
(2002). 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 Oncol
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Donskov, F., von der Maase, H., Henriksson, R., Stierner, U., Wersall, P., Nellemann, H., Hellstrand, K., Engman, K., Naredi, P.
(2002). 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 Oncol
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Tannock, I. F.
(2001). Removing the Primary Tumor after the Cancer Has Spread. NEJM
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Ibrahim, E. C., Guerra, N., Lacombe, M.-J. T., Angevin, E., Chouaib, S., Carosella, E. D., Caignard, A., Paul, P.
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(2001). Treatment with Low-Dose Interferon-{alpha} Restores the Balance between Matrix Metalloproteinase-9 and E-Cadherin Expression in Human Transitional Cell Carcinoma of the Bladder. Clin. Cancer Res.
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Nakano, O., Sato, M., Naito, Y., Suzuki, K., Orikasa, S., Aizawa, M., Suzuki, Y., Shintaku, I., Nagura, H., Ohtani, H.
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Izawa, J. I., Dinney, C. P.N.
(2001). The role of angiogenesis in prostate and other urologic cancers: a review. CMAJ
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set at 5 percent and 
at 10 percent. 
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