Originally published as JCO Early Release 10.1200/JCO.2004.06.155 on February 23 2004

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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)

From the Medizinische Hochschule Hannover, Hämatologie und Onkologie Hannover; Klinikum Hannover Siloah Hämatologie/Onkologie, Hannover; Europäisches Institut für Tumor Immunologie und Prävention; Medizinische Einrichtungen der Universität Bonn, Urologische Universitätsklinik, Bonn; Fachklinik Hornheide an der Universität Münster Internistische Onkologie, Münster; Universitätsklinik Ulm, Innere Medizin 3, Ulm; Klinikum Ernst-von-Bergmann Urologische Klinik, Potsdam; Klinikum der Martin-Luther-Universität Urologische Klinik, Halle; Charité Berlin Urologische Klinik, Berlin; Klinikum Minden, Hämatologie/Onkologie, Minden; Universitätsklinikum Heidelberg, Urologische Klinik, Heidelberg; Städtische Kliniken Oldenburg Hämatologie/Onkologie, Oldenburg; Krankenhaus der Anhaltischen Diakonissenanstalten, Urologische Klinik, Dessau; Klinikum Planegg, Urologische Klinik, Planegg; Ludwig-Maximilians-Universität München; Urologische Klinik, München; and Universitätsklinik Frankfurt, Hämatologie und Onkologie, Frankfurt, Germany

Address reprint requests to Jens Atzpodien, MD, PhD, Fachklinik Hornheide an der Universität Münster, Dorbaumstraße, 300 D-48157 Münster, Germany; e-mail: Sekrprofatzpodien{at}yahoo.de

	ABSTRACT

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PURPOSE: We conducted a prospectively randomized clinical trial to compare the efficacy of three outpatient therapy regimens in 341 patients with progressive metastatic renal cell carcinoma.

PATIENTS AND METHODS: Patients were stratified according to known clinical predictors and were subsequently randomly assigned. Treatment arms were: arm A (n = 132), subcutaneous interferon alfa-2a (sc-IFN--2a), subcutaneous interleukin-2 (sc-IL-2), and intravenous (IV) fluorouracil; arm B (n = 146): arm A treatment combined with per oral 13-cis-retinoic acid; and arm C (n = 63), sc-IFN--2a and IV vinblastine.

RESULTS: Treatment (according to the standard 8-week Hannover Atzpodien regimen) arms A, B, and C yielded objective response rates of 31%, 26%, and 20%, respectively. Arm B, but not arm A, showed a significantly improved progression-free survival (PFS) compared with arm C (P = .0248). Both arm A (median overall survival, 25 months; P = .0440) and arm B (median overall survival, 27 months; P = .0227) led to significantly improved overall survival (OS) compared with arm C (median OS, 16 months). All three sc-IFN--2a–based therapies were moderately or well tolerated.

CONCLUSION: Our results established the safety and improved long-term therapeutic efficacy of sc-IL-2 plus sc-INF--2a–based outpatient immunochemotherapies, compared with sc-INF--2a/IV vinblastine.

	INTRODUCTION

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Renal cell carcinoma (RCC) accounts for 2% to 3% of all malignant tumors in adults.¹ Patients with untreated metastatic RCC have an overall median survival of no more than 12 months and a 5-year survival of less than 10%. Because conventional therapy regimens such as single-agent chemotherapy or hormonal therapy have shown unsatisfactory results, new strategies are needed.

Promising results were reported with the use of recombinant cytokines, notably interleukin-2 (IL-2), given intravenously,² subcutanously alone, or in combination in outpatient therapy regimens, with objective response rates between 6% and 31%.^3-6 Subcutaneous interferon--2a (sc-INF--2) was evaluated at single doses of 3MU or more, yielding objective response rates of approximately 17%.⁷ Cytokine outpatient therapy treatments were associated with overall moderate drug-related toxicities. The combination of cytokines with chemotherapeutic agents further enhanced antineoplastic activity. Although immunotherapies combined with intravenous (IV) fluorouracil (FU) achieved objective response rates between 12%⁸ and 39%,⁹ the widely used addition of IV vinblastine to immunotherapies reached objective response rates between 24%¹⁰ and 39%¹¹ in patients with advanced RCC.

Oral 13-cis-retinoic acid (po13cRA), which is known to regulate cell differentiation, enhanced antitumor efficacy in IFN-–or IFN- plus IL-2–treated RCC patients, with objective response rates between 17%¹² and 30%.¹³

Here we prospectively compared the long-term therapeutic efficacy of three outpatient combination regimens: (A) sc-IFN--2a, sc-IL-2, and IV-FU; (B) sc-IFN--2a, sc-IL-2, and IV-FU combined with po-13cRA; and (C) sc-IFN--2a and IV vinblastine.

	PATIENTS AND METHODS

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Patients
Between January 1995 and October 1998, 398 patients with metastastic RCC were stratified: 57 high-risk patients received individual care outside the study, and 341 intermediate- and low-risk patients were treated in this multicenter randomized clinical trial (Table 1). Median follow-up of these patients was 22 months (range, 2 to 80 months). Fourteen patients were lost to follow-up, with a median follow-up of 11 months. Patient pretreatment included radical tumor nephrectomy (88%), radiotherapy (3%), hormonal therapy (4%), chemotherapy (1%), immunotherapy (5%), chemoimmunotherapy (2%), and naturopathic therapy (7%; Table 1).

This study was approved by the Institutional Review Board of the Medizinische Hochschule Hannover; written informed consent was obtained from all patients before their entry onto the study. There was a central registration, with Medizinische Hochschule Hannover as the coordinating center. The 33 participating centers (listed on the first page) entered a total of 341 eligible patients onto this trial.

Study Design
Patients were stratified according to a validated model of known clinical predictors¹⁴ to allow for equal risk distribution in all treatment arms (Tables 2 and 3). Given that all treatment regimens were designed to be administered in the outpatient setting, this required selection of patients with good or fair performance status. Thus, patients who were stratified for high risk were not randomly assigned, because of their poor prognosis, and we offered individual and supportive care outside the present study. Only patients stratified for low risk (median overall survival, 28 months) and intermediate risk (median overall survival, 21 months) were randomly assigned according to a per-center 2:2:1 (arm A:arm B:arm C) randomization to receive sc-IFN--2a, sc-IL-2, and IV-FU (arm A); sc-IFN--2a, sc-IL-2, and IV-FU combined with po-13cRA (arm B); or sc-IFN--2a and IV vinblastine (arm C; Fig 1). On written receipt of patient prestudy evaluation, per-center block randomization was performed to rule out center-related statistical bias. There was no statistically significant imbalance of risk factors and risk scores when comparing all three treatment arms (Table 3).

View larger version (44K): [in this window] [in a new window]   Fig 1. Trial profile. *Initial risk stratification was performed to allow for equal risk distribution in all treatment arms. Patients in the high-risk group were treated optionally outside this study. sc IL-2, subcutaneous interleukin-2; sc IFN-, subcutaneous interferon alfa; IV, intravenous; po 13-cRA, oral 13-cis-retinoic acid; CR, complete response, PR, partial response; SD, stable disease.

Eight-week treatment cycles were repeated for up to three courses unless progression of disease occurred. If patients achieved a complete remission in the third cycle, a fourth cycle was added. After the first 8 weeks of therapy, on disease progression, patients primarily treated with arm C (sc-IFN--2a/IV vinblastine) subsequently crossed over to arm B (sc-IFN--2a/sc-IL-2/IV-FU/po-13cRA), wherever performance status allowed further systemic therapy. Patients with progressive disease on arm A or B left study to receive subsequent individual care. Reevaluation of the patient's tumor status was performed between treatment cycles. Patients on arms A, B, and C received a mean of 1.8, 1.9, and 1.7 (without crossover) 8-week cycles, respectively (range, 1 to 6 cycles). Concomitant medication was given as needed to control adverse effects of immunochemotherapy. Twenty-eight percent of patients (arm A: 20%; arm B: 32%; arm C: 34%) did not complete cycle 1, because of early progression before the first response evaluation (11%), intolerance (14%), or both early disease progression and intolerance (3%). Less than 2% of patients required inpatient care throughout treatment. All patients were seen at regular weekly or biweekly intervals by oncologic specialists; additional care was provided whenever needed.

Assessment of Response, Survival and Toxicity
Response to therapy was evaluated according to WHO criteria on an intent-to-treat basis. All responses were reviewed by board-certified expert radiologists; however, a second external review of responses was not performed. In the case of progression on first re-evaluation after 8 weeks of treatment, progression-free survival was calculated at 0 months. Survival was measured from start of therapy to date of death or to the last date the patient was known to be alive. All patients had to be followed up for survival for at least 3 years as cutoff. Systemic maximum toxicity was evaluated at weekly intervals using a grading system adapted from the WHO.

Statistical Analysis
The statistical end points in our analysis were (1) objective response (the primary end point), (2) progression-free survival, and (3) overall survival of patients. The probability of overall survival and progression-free survival was plotted over time according to the method of Kaplan and Meier.¹⁵ Statistical significance was assessed using the Breslow test. P values were not adjusted for multiple comparisons. The potential objective response rates were hypothized to show a 15% advantage of arm B over arm A (45% v 30%) and a 30% advantage of arm B over arm C (45% v 15%). Using an of 0.05 (one-sided) a sample size of 128 patients (arm A and B) and 28 patients (arm C), respectively, was needed to have 80% power to statistically establish the assumed difference in response rates. To detect a 0.20 difference in 3-year-survival rates between IL-2–based treatments regimens (arms A and B) and arm C, 64 patients per treatment arm were needed to have 80% power using an of 0.05 (one-sided). To meet these statistical end points, randomization was performed 2:2:1, with cohort sizes of 128 patients (arm A), 128 patients (arm B), and 64 patients (arm C), respectively.

	RESULTS

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Three hundred forty-one stratified low or intermediate risk metastatic RCC patients were prospectively randomly assigned to receive sc-IFN--2a, sc-IL-2 and IV-FU (arm A, n = 132); sc-IFN--2a, sc-IL-2, and IV-FU combined with po-13cRA (arm B, n = 146); or sc-IFN--2a and IV vinblastine (arm C; n = 63).

Treatment Response
Seven arm A (sc-IFN--2a/sc-IL-2/IV-FU)–treated patients (5%) achieved a complete response, and 34 patients (26%) had a partial remission (Table 4). The overall objective response rate was 31% (95% CI, 22 to 38). Thirty-six patients (27%) showed disease stabilization, and 55 patients (42%) exhibited continuous disease progression despite therapy.

In arm C (IFN--2a/IV vinblastine), four patients (6%) achieved a complete response, and nine patients (14%) had a partial remission. The overall objective response rate was 20% (95% CI, 10 to 31). Twenty-one patients (34%) showed disease stabilization, and 29 patients (46%) exhibited continuous disease progression despite therapy. There were no statistically significant differences in objective response rates comparing all three arms.

Progression-Free Survival
One hundred thirteen patients (86%) in arm A (IFN--2a/sc-IL-2/IV-FU), 122 patients (84%) in arm B (IFN--2a/sc-IL-2/IV-FU/po-13cRA), and 58 patients (92%) in arm C (IFN--2a/IV vinblastine) exhibited tumor progression. The median progression-free survival was significantly prolonged (P = .0248) in arm B (IFN--2a/sc-IL-2/IV-FU/po-13cRA; 7 months; range, 0 to 77 months) when compared with arm C (IFN--2a/IV vinblastine; 5 months; range, 0 to 69 months), but not when compared with arm A (IFN--2a/sc-IL-2/IV-FU; 6 months; range, 0 to 69 months; Fig 2).

View larger version (16K): [in this window] [in a new window]   Fig 2. Progression-free survival (PFS): Kaplan-Meier estimates. Arm A, interleukin-2, interferon alfa-2a, and fluorouracil; n = 132; median PFS, 6 months; 3-year PFS,15.58%. Arm B, interleukin-2, interferon alfa-2a, fluorouracil, and per oral 13-cis-retinoic acid; n = 146; median PFS, 7 months; 3-year PFS, 17.73%. Arm C, interferon alfa-2a and vinblastine; n = 63; median PFS, 5 months; 3-year PFS, 8.35%.

Overall Survival
Thirty-three patients (25%) in arm A (IFN--2a/sc-IL-2/IV-FU), 39 patients (27%) in arm B (IFN--2a/sc-IL-2/IV-FU/po-13cRA), and 12 patients (19%) in arm C (IFN--2a/IV vinblastine) continued to be alive at last follow-up. Both arm A (IFN--2a/sc-IL-2/IV-FU; median survival, 25 months; range, 2 to 73 months; P = .0440) and arm B (IFN--2a/sc-IL-2/IV-FU/po-13cRA; median survival, 27 months; range, 2 to 80 months; P = .0227) patients exhibited a significantly improved overall survival when compared with arm C (IFN--2a/IV vinblastine; median survival, 16 months; range, 2 to 69 months; Fig 3).

View larger version (17K): [in this window] [in a new window]   Fig 3. Overall survival (OS): Kaplan-Meier estimates. Arm A, interleukin 2, interferon alfa-2a, and fluorouracil; n = 132; median OS, 25 months; 3-year overall survival, 37.24%. Arm B, interleukin-2, interferon alfa-2a, fluorouracil, and per oral 13-cis-retinoic acid; n = 146; median OS, 27 months; 3-year OS, 41.02%. Arm C, interferon alfa-2a and vinblastine; n = 63; median OS, 16 months; 3-year OS, 21.40%.

Treatment Toxicity
All three sc-IFN--2a–based therapies were moderately or well tolerated and could be administered in the outpatient setting. Most side effects were limited to WHO grades 1 and 2; no toxic deaths occurred. All toxicities reversed spontaneously following completion of immunochemotherapy.

More than 5% of patients experienced grade 3 or 4 treatment-related anorexia (21% in arm B and 26% in arm C), malaise (18% in arm B and 11% in arm C), CNS toxicity or disorientation (11% in arm C), chills (6% in arm B), nausea or vomiting (6% in arm B), and hypotension (6% in arm B). Four percent of arm A (IFN--2a/sc-IL-2/IV-FU), 6% of arm B (IFN--2a/sc-IL-2/IV-FU/po-13cRA), and 8% of arm C (IFN--2a/IV vinblastine) patients discontinued treatment due to toxicity. Table 5 summarizes all treatment-related adverse effects by grade.

	DISCUSSION

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Patients with advanced renal cell carcinoma reached objective response rates of 31% (arm A), 26% (arm B), and 20% (arm C), respectively, which did not statistically differ, and which were comparable to results of other authors reporting objective response rates of 12% to 39% (sc-IFN-/IV IL-2/IV-FU),^8,9,16 17% (sc-IFN-/sc-IL-2/po-13cRA),¹² 24% (IFN--2a/IV vinblastine),¹⁰ 39% (sc-IFN-/sc-IL-2/IV vinblastine),¹¹ and 42% (sc-IFN-/sc-IL-2/IV-FU/IV vinblastine/po-13cRA).¹⁷ Thus, the primary response end point of the current trial was not reached. It should be noted that because no central review of responses was mandatory, there might have been considerable variability as to assessment of treatment response.

Our present results demonstrated a significantly prolonged progression-free survival (P = .0248) when comparing arm B with arm C. In a previous randomized phase III trial, patients treated with po-13cRA plus sc-IFN--2a achieved an improved progression-free survival when compared with single agent sc-IFN--2a therapy.¹⁸

Here we could also demonstrate significant improvements in overall survival when comparing both arm B therapy (sc-IFN--2a/sc-IL-2/IV-FU/po-13cRA; median, 27 months; P = .0440) and arm A therapy (sc-IFN--2a/sc-IL-2/IV-FU; median, 25 months; P = .0227) against arm C therapy (sc-IFN--2a/IV vinblastine; median, 16 months). Overall, arm C (sc-IFN--2a/IV vinblastine) patients seemed to display a more aggressive malignancy with less frequent nephrectomies and more patients with bone metastases and CNS involvement, whereas there was no significant difference in risk scores comparing arm C (sc-IFN--2a/IV vinblastine) with arm B (sc-IFN--2a/sc-IL-2/IV-FU/po-13cRA) and arm A (sc-IFN--2a/sc-IL-2/IV-FU) patients; the survival impact of nephrectomy and CNS metastasis was previously assessed and rendered insignificant on multivariate analysis.^14,19

Notably, the addition of 13cRA (arm B) did not significantly contribute to a prolonged overall survival when compared with the 13cRA-free arm A, a result established in prior observations of other authors.¹⁸

Previous randomized clinical trials in advanced renal cancer gave evidence of a significantly increased progression-free survival when using the IV IL-2 plus sc IFN--2a combination in comparison with either agent alone²⁰ and of a statistical equality in objective response rates comparing high-dose IV IL-2 with outpatient sc-IL-2 as single agents.²¹

Although arm A (sc-IFN--2a/sc-IL-2/IV-FU) and arm B (sc-IFN--2a/sc-IL-2/IV-FU/po-13cRA) were similar with respect to response and overall survival, our data suggest that grade 3 and 4 constitutional symptoms, such as chills, malaise, and anorexia, may have been more prevalent in arm B compared with the 13cRA-free arm A; however, no statistical significance was reached. Potentially, the limited toxicity in all three treatment arms was also due to positive selection of patients who were capable of receiving outpatient therapy. This was mainly achieved by patient risk stratification and subsequent exclusion of patients at highest risk.

In summary, this present prospectively randomized clinical trial established the safety and the improved long-term therapeutic efficacy of sc-IL-2 plus sc-INF--2a–based outpatient immunochemotherapies following the standard Atzpodien regimen in comparison with sc-INF-a-2a/IV vinblastine on a large controlled multicenter basis; it also demonstrated that addition of 13cRA is of no substantial benefit to the present immunochemotherapy regimen.

	Authors' Disclosures of Potential Conflicts of Interest

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The authors indicated no potential conflicts of interest.

	NOTES

 
Supported by grants from Deutsche Krebshilfe, Wilhelm-Sander-Stiftung, and Deutsche Gesellschaft zur Förderung immunologischer Krebstherapien eingetragener Verein (J.A.).

Authors’ disclosures of potential conflicts of interest are found at the end of this article.

	REFERENCES

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1. Elson PJ, Witte RS, Trump DL: Prognostic factors for survival in patients with recurrent or metastatic renal cell carcinoma. Cancer Res 48:7310, 1988[Abstract/Free Full Text]

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3. 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[CrossRef][Medline]

4. Sleijfer DT, Janssen RA, Buter J, et al: Phase II study of subcutaneous interleukin-2 in unselected patients with advanced renal cell cancer on an outpatient basis. J Clin Oncol 10:1119-1123, 1992[Abstract]

5. 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]

6. Lissoni P, Barni S, Ardizzoia A, et al: Second line therapy with low-dose subcutaneous interleukin-2 alone in advanced renal cancer patients resistant to interferon-alpha. Eur J Cancer 28:92-96, 1992

7. Savage PD, Muss HB: Renal Cell Cancer, in Devita VT, Hellman S, and Rosenberg SA (eds): Biologic Therapy of Cancer. Philadelphia, PA, Lippincott Williams and Wilkins, 1995, pp 373-387

8. van Herpen CM, Jansen RL, Kruit WH, et al: Immunochemotherapy with interleukin-2, interferon-alpha and 5-fluorouracil for progressive metastatic renal cell carcinoma: A multicenter phase II study—Dutch Immunotherapy Working Party. Br J Cancer 82:772-776, 2000[CrossRef][Medline]

9. Atzpodien J, Kirchner H, Illiger HJ, et al: IL-2 in combination with IFN- and FU versus tamoxifen in metastatic renal cell carcinoma: Long-term results of a controlled randomized clinical trial. Br J Cancer 85:1130-1136, 2001[CrossRef][Medline]

10. Fossa SD, Martinelli G, Otto U, et al: Recombinant interferon alfa-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]

11. Pectasides D, Varthalitis J, Kostopoulou M, et al: An outpatient phase II study of subcutaneous interleukin-2 and interferon-alpha-2b in combination with intravenous vinblastine in metastatic renal cell cancer. Oncology 55:10-15, 1998[CrossRef][Medline]

12. Stadler WM, Kuzel T, Dumas M, et al: Multicenter phase II trial of interleukin-2, interferon-alpha, and 13-cis-retinoic acid in patients with metastatic renal-cell carcinoma. J Clin Oncol 16:1820-1825, 1998[Abstract]

13. Motzer RJ, Schwartz L, Law TM, et al: Interferon alfa-2a and 13-cis-retinoic acid in renal cell carcinoma: Antitumor activity in a phase II trial and interactions in vitro. J Clin Oncol 13:1950-1957, 1995[Abstract/Free Full Text]

14. Lopez-Hänninen EH, 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[CrossRef][Medline]

15. Kaplan EL, Meier P: Nonparametric estimation from incomplete observations. J Am Stat Assoc 53:457, 1958[CrossRef]

16. Joffe JK, Patel PM, Banks RE, et al: Cytokines in combination with chemotherapy for advanced renal carcinoma: The importance of patient selection. Cancer Biother Radiopharm 11:309-313, 1996[Medline]

17. Atzpodien J, Kirchner H, Duensing S, et al: Biochemotherapy of advanced metastatic renal-cell carcinoma: Results of the combination of interleukin-2, alpha-interferon, 5-fluorouracil, vinblastine, and 13-cis-retinoic acid. World J Urol 13:174-177, 1995[Medline]

18. Motzer RJ, Murphy BA, Bacik J, et al: Phase III trial of interferon alfa-2a with or without 13-cis-retinoic acid for patients with advanced renal cell carcinoma. J Clin Oncol 18:2972-2980, 2000[Abstract/Free Full Text]

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

21. Yang JC, Rosenberg SA: An ongoing prospective randomized comparison of interleukin-2 regimens for the treatment of metastatic renal cell cancer. Cancer J Sci Am 1:S79-S84, 1997 (suppl 3)

Submitted June 26, 2002; accepted September 26, 2003.

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