|Year : 2016 | Volume
| Issue : 5 | Page : 109-115
A comparison of drug resistances of targeted drugs for advanced renal cell cancer approved by the Food and Drug Administration: A meta-analysis of randomized clinical trials
Ming Guo1, Yunsong Cao2, Jingzhe Yang3, Jingfeng Zhang2
1 Department of Hematology, 2nd Affiliated Hospital, Beijing University of Traditional Chinese Medicine, Beijing, 100078, China
2 Department of Nephrology, 2nd Affiliated Hospital, Beijing University of Traditional Chinese Medicine, Beijing, 100078, China
3 Department of Urology and Andragogy, 2nd Affiliated Hospital, Beijing University of Traditional Chinese Medicine, Beijing, 100078, China
|Date of Web Publication||7-Oct-2016|
Department of Hematology, Nephrology, 2nd Affiliated Hospital, Beijing University of Traditional Chinese Medicine, Beijing, 100078
Source of Support: None, Conflict of Interest: None
Purpose: The purpose of this study was to conduct network meta-analysis to assess drug resistances of the Food and Drug Administration-approved drugs for advanced renal cell carcinoma.
Materials and Methods: Database searches were conducted to identify randomized controlled trials reporting results for eligible treatments. After searching for PubMed, MEDLINE, EMBASE, and ISI Web of Science, 22 studies (n = 7854 patients) were included for the comparison of drug resistance in the present meta-analysis.
Results: For overall present, the mean 6-month progression-free survival rates were 65.4%, 49.3%, 60.6%, 70.3%, 62.6%, 41.6%, 38.2%, 66.1%, 43.1%, and 17.9% for sunitinib, sorafenib, pazopanib, axitinib, bevacizumab plus interferon (IFN)-a, everolimus, temsirolimus, temsirolimus plus bevacizumab, IFN-a, and placebo, respectively. For indirect comparison, two combined therapies (bevacizumab plus IFN-a and temsirolimus plus bevacizumab) and sunitinib were of less ability of drug resistance. The risk ratio of sunitinib therapy was 3.64 (95% confidence interval [CI] [3.12, 4.25]), the risk ratio of temsirolimus plus bevacizumab therapy was 3.68 (95% CI [3.14, 4.33]), and the risk ratio of bevacizumab plus IFN-a therapy was 3.49 (95% CI [2.99, 4.06]).
Conclusions: Our results support that combination of targeted therapies might be a novel strategy against advanced renal cell carcinomas.
Keywords: Drug resistance, meta-analysis, molecular targeted drugs, renal cell cancer
|How to cite this article:|
Guo M, Cao Y, Yang J, Zhang J. A comparison of drug resistances of targeted drugs for advanced renal cell cancer approved by the Food and Drug Administration: A meta-analysis of randomized clinical trials. J Can Res Ther 2016;12:109-15
|How to cite this URL:|
Guo M, Cao Y, Yang J, Zhang J. A comparison of drug resistances of targeted drugs for advanced renal cell cancer approved by the Food and Drug Administration: A meta-analysis of randomized clinical trials. J Can Res Ther [serial online] 2016 [cited 2018 Aug 16];12:109-15. Available from: http://www.cancerjournal.net/text.asp?2016/12/5/109/191617
| > Introduction|| |
Renal cell carcinoma (RCC) is the most common form of kidney cancer and accounts for ~2%–3% of adult cancers worldwide. In general, patients have a poor prognosis, and 12%–25% of patients with a new diagnosis of RCC will have metastatic disease at presentation. About 70% of patients were present with localized or locally advanced RCC (ARCC); unfortunately, 20%–40% of these patients would experience recurrence and metastasis. It affects mainly an elderly population with the peak incidence occurring between the ages of 60 and 70 years. Renal cancer cells are insensitive to chemotherapy and radiotherapy and of great ability of multidrug resistance.
Before 2005, the standard of care was limited to cytokine therapy with interleukin-2 and/or interferon (IFN)-a. These treatments are associated with limited efficacy and high toxicity. Several newer targeted treatments are now available, and survival rates have improved in recent years following the introduction of tyrosine kinase inhibitors (TKIs) and other targeted treatments. Targeted therapies have improved disease control rates and outcomes for patients with advanced conventional (clear cell) RCC. Four multitargeted TKIs: sorafenib, sunitinib, pazopanib, and axitinib; the humanized anti-vascular endothelial growth factor (VEGF) monoclonal antibody bevacizumab with IFN-a, and two mammalian target of rapamycin (mTOR) complex 1 kinase inhibitors (temsirolimus  and everolimus ). Sunitinib is currently the standard of care in the first-line treatment.
In this article, we conducted a network meta-analysis (NMA) to assess drug resistances of the Food and Drug Administration (FDA)-approved drugs for ARCC. We presented a pool of overall survival (OS), progression-free survival (PFS), and 6-month progression-free survival from all studies enrolled in the meta-analysis with corresponding data to show an impression on all seven drugs. Finally, we utilized 6-months PFS as an indicator of drug resistance, comparing the drug resistance of the FDA-approved seven drugs.
| > Materials and Methods|| |
We conducted a bibliographic search for original research articles, using multiple electronic databases, including PubMed, MEDLINE, EMBASE, and ISI Web of Science. We used the search terms “Sunitinib,” “Sorafenib,” “Pazopanib,” “Axitinib,” “Bevacizumab,” “Everolimus,” “Temsirolimus,” “advanced renal cell carcinomas,” and “advanced renal cancer” from 2007 onward. We also hand-searched the reference sections of all obtained publications to find out any study missed by the search strategies. For comparison, studies were retrieved from the same databases within the same publication period. To effectively identify relevant articles, a protocol for structured literature retrieval was followed, and retrieval result in each step is given in [Figure 1].
|Figure 1: Selection strategy of studies enrolled in the current meta-analysis|
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The following eligibility criteria were applied: (1) Original articles published in English between January 2007 and January 2016; (2) eligibility criteria included randomized controlled trials (RCTs) conducted in adult patients (>18 years old) undergoing any line of treatment for ARCC; (3) ARCC was strictly limited to Stage III/IV or metastatic disease with reference to the 7th edition of cancer staging by the American Joint Committee on Cancer; (4) primary outcomes of interest were 6-month PFS, PFS, and OS, which were reported or could be extrapolated based on published results; (5) relevant treatments included but were not restricted to sunitinib, sorafenib, pazopanib, axitinib, bevacizumab, temsirolimus, everolimus, and IFN-a (according to the European licensed indication). Some authors had more than one report meeting the inclusion criteria. To minimize data overlap, each report was analyzed to ensure that only the report with latest results and largest patient number was enrolled. If the patient population was from a different time period or different outcomes were reported, both reports were included in this study for analysis.
Two reviewers independently extracted data from all studies. Additional data obtained from the studies included the first author, publication year, research phase, treatment arms, patients per arm, median age (year range), number of males (percent), ECOG performance status, Memorial Sloan-Kettering Cancer Center (MSKCC) score, median OS, median PFS, and 6-month PFS. Disagreements were resolved by consensus between the two readers. Survival data (median OS, median PFS, and 6-month PFS), not available within the context, were extracted from the survival curve using Engauge Digitizer V4.1 (Slashdot Media, Torrance, California, USA). At the same time, the extracted data of survival were confirmed with the data available in the context in the same year. The acceptable error is ± 0.05. The risk of bias (RoB) assessment was performed using the standard Cochrane Collaboration RoB tool for RCTs.
All patients were filtrated in sunitinib, sorafenib, pazopanib, axitinib, bevacizumab, temsirolimus, everolimus, IFN-a, or combination treat group. The results of the study were considered statistically significant when the P < 0.05 in univariate analysis. Relative risk (RR) with 95% confidence interval (CI) synthesized was used to assess the strength of association. Considering the many sources of heterogeneity between studies and consequently between their individual RR estimates, we calculated the overall RR according to the DerSimonian and Laird method, with a random effect model when homogeneity was not fine (P > 0.10, I2 > 50%). An observed RR >1 indicated better outcomes for the targeted treatment to placebo group and would be considered statistically significant if the 95% CI did not overlap 1, with P < 0.05. Forest plots were used to estimate the relationship between the targeted treatment to placebo group, created by RevMan 5.3 (Cochrane Collaboration, Oxford, UK) in our NMA.
| > Results|| |
Literature search and characteristics
Our electronic search algorithm retrieved a total of 2781 references for sunitinib, sorafenib, pazopanib, axitinib, bevacizumab, temsirolimus, everolimus, and advanced renal cell cancer. After removal of duplicated articles, studies of tumors from other origins, animal and laboratory studies, and studies on other pathway, 137 candidate studies were retrieved for abstract reading. After further evaluation, 33 studies were retrieved for full-text assessment. Of all the 32 reports, 11 were excluded: one in Chinese, Three in German,,,, one is molecular biology study, and three are reviews ,,,, [Figure 1]. Finally, 22 studies (n = 7854 patients) were eligible for the present meta-analysis.
Characteristics of the 22 eligible studies are listed in [Table 1]. All the eligible studies were clinical trials. Nine reports belong to Phase II study, and thirteen belong to Phase III study. All except two studies reported MSKCC score. According to the information, the clinical trials are reported ranged from the year 2005 to 2015; the percentage of male is nearly 70% [Table 1]. Twenty studies reported PFS and/or 6-month PFS [Table 2].
|Table 1: 22 studies on targeted drugs for advanced renal cancer included in the current meta-analysis|
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|Table 2: Final progression-free survival and/or 6-month progression-free survival data for included trials|
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Systematic review of included literature
A pooled presentation of OS, PFS, and 6-months PFS from all studies enrolled in this meta-analysis with corresponding data available is shown in [Figure 2]. The mean 6-month PFS rates were 65.4%, 49.3%, 60.6%, 70.3%, 62.6%, 41.6%, 38.2%, 66.1%, 43.1%, and 17.9% for sunitinib, sorafenib, pazopanib, axitinib, bevacizumab plus IFN-a, everolimus, temsirolimus, temsirolimus plus bevacizumab, IFN-a, and placebo, respectively.
|Figure 2: Mean overall survival, progression-free survival, and 6-month progression-free survival (6-month progression-free survival) comparison of the Food and Drug Administration-approved targeted drugs for advanced renal cell cancer. A pooled presentation of overall survival, progression-free survival, and 6-month progression-free survival from all studies enrolled in this meta-analysis with corresponding data available|
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[Figure 3] illustrates the network diagram used to compare treatments. The median PFS (with 95% CI) or 6-month PFS for the studies included in the meta-analysis (reported by independent and investigator assessment) is reported in [Table 2]. The RoB was generally low across most studies [Figure 4].
|Figure 3: Network diagram for studies that report progression-free survival and/or 6-month progression-free survival|
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|Figure 4: Risk of bias assessment of included studies. Green: low risk of bias; yellow: unclear risk of bias; red: high risk of bias|
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Indirect comparison of the treatment effects for 6-month progression-free survival by independent assessment
To compare the drug resistance, placebo was defined as a control for all other targeted treatments. The meta-analysis showed that two combined therapies (bevacizumab plus IFN-a and temsirolimus plus bevacizumab) and sunitinib were of less ability of drug resistance, which was contrast to the previous studies. The risk ratio of sunitinib therapy was 3.64 (95% CI [3.12, 4.25]), the risk ratio of temsirolimus plus bevacizumab therapy was 3.68 (95% CI [3.14, 4.33]), and the risk ratio of bevacizumab plus IFN-a therapy was 3.49 (95% CI [2.99, 4.06]) [Figure 5].
|Figure 5: Meta-analysis of 6-month progression-free survival for nine targeted therapies|
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| > Discussion|| |
The lack of suitable studies that evaluate the efficiency of target cell therapies (TCTs) for ARCC was noted during the systematic review and only a few were submitted to meta-analysis. It was also observed difficult to collect data from the studies since some presented neither clear nor objective results. Among the revised studies, there were several difficulties regarding the interpretation of results, such as randomization and 6-month PFS that impaired precision. Many selected works were excluded since they were not prospective, randomized, and with the necessary information for analysis. Subgroup analysis studies were also excluded as well as those with duplicated populations.
At present, there are several available treatments with TCT: four multitargeted TKIs: sorafenib, sunitinib, pazopanib, and axitinib; the humanized anti-VEGF monoclonal antibody bevacizumab with IFN-a  and two mTOR complex 1 kinase inhibitors (temsirolimus  and everolimus ). Targeted therapies have improved disease control rates and outcomes for patients with advanced conventional (clear cell) RCC  although the drug resistances exist. Recently, a combination of multitarget drugs was highlighted for its outstanding effects on advanced renal cell cancer. After conducting an NMA, we support this strategy. In this meta-analysis, we have to use 6-month PFS as a substitution of drug resistance for the complexity in the generalization of renal cancer cell drug resistance.
| > Conclusion|| |
Our results support that combination of targeted therapies might be a novel strategy against advanced renal cell carcinomas. Specially, temsirolimus plus bavacizumab and bavacizumab plus IFN-a therapies are suitable for the treatment of advanced renal cell cancer.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
| > References|| |
Larkin J, Paine A, Foley G, Mitchell S, Chen C. First-line treatment in the management of advanced renal cell carcinoma: Systematic review and network meta-analysis. Expert Opin Pharmacother 2015;16:1915-27.
Gunduz S, Mutlu H, Tural D, Yildiz Ö, Uysal M, Coskun HS, et al.
Platelet to lymphocyte ratio as a new prognostic for patients with metastatic renal cell cancer. Asia Pac J Clin Oncol 2015;11:288-92.
Jin L, Xu X, Ye B, Pan M, Shi Z, Hu Y. Elevated serum interleukin-35 levels correlate with poor prognosis in patients with clear cell renal cell carcinoma. Int J Clin Exp Med 2015;8:18861-6.
Lindblad P. Epidemiology of renal cell carcinoma. Scand J Surg 2004;93:88-96.
Huguenin PU, Kieser S, Glanzmann C, Capaul R, Lütolf UM. Radiotherapy for metastatic carcinomas of the kidney or melanomas: An analysis using palliative end points. Int J Radiat Oncol Biol Phys 1998;41:401-5.
Atkins MB, Regan M, McDermott D. Update on the role of interleukin 2 and other cytokines in the treatment of patients with stage IV renal carcinoma. Clin Cancer Res 2004;10 (18 Pt 2):6342S-6S.
Wahlgren T, Harmenberg U, Sandström P, Lundstam S, Kowalski J, Jakobsson M, et al.
Treatment and overall survival in renal cell carcinoma: A Swedish population-based study (2000-2008). Br J Cancer 2013;108:1541-9.
Jonasch E, Futreal PA, Davis IJ, Bailey ST, Kim WY, Brugarolas J, et al.
State of the science: An update on renal cell carcinoma. Mol Cancer Res 2012;10:859-80.
Escudier B, Eisen T, Stadler WM, Szczylik C, Oudard S, Siebels M, et al.
Sorafenib in advanced clear-cell renal-cell carcinoma. N Engl J Med 2007;356:125-34.
Shi HZ, Tian J, Li CL. Safety and efficacy of sunitinib for advanced non-clear cell renal cell carcinoma. Asia Pac J Clin Oncol 2015;11:328-33.
Sternberg CN, Davis ID, Mardiak J, Szczylik C, Lee E, Wagstaff J, et al.
Pazopanib in locally advanced or metastatic renal cell carcinoma: Results of a randomized phase III trial. J Clin Oncol 2010;28:1061-8.
Rini BI, Escudier B, Tomczak P, Kaprin A, Szczylik C, Hutson TE, et al.
Comparative effectiveness of axitinib versus sorafenib in advanced renal cell carcinoma (AXIS): A randomised phase 3 trial. Lancet 2011;378:1931-9.
Escudier B, Pluzanska A, Koralewski P, Ravaud A, Bracarda S, Szczylik C, et al.
Bevacizumab plus interferon alfa-2a for treatment of metastatic renal cell carcinoma: A randomised, double-blind phase III trial. Lancet 2007;370:2103-11.
Motzer RJ, Hudes GR, Curti BD, McDermott DF, Escudier BJ, Negrier S, et al.
Phase I/II trial of temsirolimus combined with interferon alfa for advanced renal cell carcinoma. J Clin Oncol 2007;25:3958-64.
Motzer RJ, Escudier B, Oudard S, Hutson TE, Porta C, Bracarda S, et al.
Efficacy of everolimus in advanced renal cell carcinoma: A double-blind, randomised, placebo-controlled phase III trial. Lancet 2008;372:449-56.
DerSimonian R, Laird N. Meta-analysis in clinical trials. Control Clin Trials 1986;7:177-88.
Yang SY, Cui CL, Chi ZH, Si L, Sheng XN, Mao LL, et al.
Phase II clinical trial of sorafenib plus local chemotherapy in the treatment of metastatic renal cell carcinoma with pleural effusion. Zhonghua Yi Xue Za Zhi 2012;92:2998-3000.
Okamura R, Sugitani I. Current progress and management in molecular targeted therapy for advanced thyroid cancer. Gan To Kagaku Ryoho 2014;41:148-52.
Rexer H. First-line therapy of advanced or metastasized renal cell cancer: Open randomized phase III sequence study to examine the effectiveness and tolerance of sorafenib followed by pazopanib versus pazopanib followed by sorafenib in the first-line treatment of patients with advanced or metastasized renal cell cancer (SWITCH-2 – AN 33/11). Urologe A 2012;51:724-6.
Rexer H. AUO (Working Group on Urological Oncology) study of metastasized renal cell carcinoma: Prospective randomized multicenter phase II study on resection of pulmonary metastases in clear cell renal cell carcinoma with or without adjuvant sunitinib therapy over 1 year (SMAT – AN 20/04 AUO)]. Urologe A 2011;50:83-4.
Rexer H. Adjuvant AUO study of renal cell carcinoma after nephrectomy: Randomized, double-blind, placebo-controlled phase III study (PROTECT – AN 30/10) to investigate the effectiveness and safety of pazopanib as adjuvant therapy in patients with localized or local advanced renal cell carcinoma after nephrectomy. Urologe A 2011;50:489-92.
Tsavachidou-Fenner D, Tannir N, Tamboli P, Liu W, Petillo D, Teh B, et al.
Gene and protein expression markers of response to combined antiangiogenic and epidermal growth factor targeted therapy in renal cell carcinoma. Ann Oncol 2010;21:1599-606.
Adjei AA, Blumenschein GR Jr., Mandrekar S, Hillman S, Gatzemeier U, Heigener D. Long-term safety and tolerability of sorafenib in patients with advanced non-small-cell lung cancer: A case-based review. Clin Lung Cancer 2011;12:212-7.
Blagoev KB, Wilkerson J, Stein WD, Motzer RJ, Bates SE, Fojo AT. Sunitinib does not accelerate tumor growth in patients with metastatic renal cell carcinoma. Cell Rep 2013;3:277-81.
Rizzo M, Cartenì G, Pappagallo G, Hollander L, Floriani I. The Orchidee study: Gathering new evidence on the use of everolimus in clinical practice. Tumori 2014;100:e290-2.
Durán M, Matheus W, Ferreira U, Clark O. Systematic review and meta-analysis of target terapies for the treatment of metastatic renal cancer. Int Braz J Urol 2013;39:768-78.
Albiges L, Choueiri T, Escudier B, Galsky M, George D, Hofmann F, et al.
A systematic review of sequencing and combinations of systemic therapy in metastatic renal cancer. Eur Urol 2015;67:100-10.
Merchan JR, Qin R, Pitot H, Picus J, Liu G, Fitch T, et al.
Safety and activity of temsirolimus and bevacizumab in patients with advanced renal cell carcinoma previously treated with tyrosine kinase inhibitors: A phase 2 consortium study. Cancer Chemother Pharmacol 2015;75:485-93.
Kondo T, Nakazawa H, Oya M, Kimura G, Fujii Y, Hatano T, et al.
Clinical efficacy and prognostic factors of tumor progression in Japanese patients with advanced renal cell carcinoma treated with sorafenib. Jpn J Clin Oncol 2015;45:274-80.
Xie M, He CS, Huang JK, Lin QZ. Phase II study of pazopanib as second-line treatment after sunitinib in patients with metastatic renal cell carcinoma: A Southern China urology cancer consortium trial. Eur J Cancer 2015;51:595-603.
Choueiri TK, Figueroa DJ, Fay AP, Signoretti S, Liu Y, Gagnon R, et al.
Correlation of PD-L1 tumor expression and treatment outcomes in patients with renal cell carcinoma receiving sunitinib or pazopanib: Results from COMPARZ, a randomized controlled trial. Clin Cancer Res 2015;21:1071-7.
Eisen T, Loembé AB, Shparyk Y, MacLeod N, Jones RJ, Mazurkiewicz M, et al.
A randomised, phase II study of nintedanib or sunitinib in previously untreated patients with advanced renal cell cancer: 3-year results. Br J Cancer 2015;113:1140-7.
Eto M, Uemura H, Tomita Y, Kanayama H, Shinohara N, Kamei Y, et al.
Overall survival and final efficacy and safety results from a Japanese phase II study of axitinib in cytokine-refractory metastatic renal cell carcinoma. Cancer Sci 2014;105:1576-83.
Motzer RJ, Barrios CH, Kim TM, Falcon S, Cosgriff T, Harker WG, et al.
Phase II randomized trial comparing sequential first-line everolimus and second-line sunitinib versus first-line sunitinib and second-line everolimus in patients with metastatic renal cell carcinoma. J Clin Oncol 2014;32:2765-72.
Hutson TE, Escudier B, Esteban E, Bjarnason GA, Lim HY, Pittman KB, et al.
Randomized phase III trial of temsirolimus versus sorafenib as second-line therapy after sunitinib in patients with metastatic renal cell carcinoma. J Clin Oncol 2014;32:760-7.
Rini BI, Bellmunt J, Clancy J, Wang K, Niethammer AG, Hariharan S, et al.
Randomized phase III trial of temsirolimus and bevacizumab versus interferon alfa and bevacizumab in metastatic renal cell carcinoma: INTORACT trial. J Clin Oncol 2014;32:752-9.
Procopio G, Verzoni E, Bracarda S, Ricci S, Sacco C, Ridolfi L, et al.
Overall survival for sorafenib plus interleukin-2 compared with sorafenib alone in metastatic renal cell carcinoma (mRCC): Final results of the ROSORC trial. Ann Oncol 2013;24:2967-71.
Hutson TE, Lesovoy V, Al-Shukri S, Stus VP, Lipatov ON, Bair AH, et al.
Axitinib versus sorafenib as first-line therapy in patients with metastatic renal-cell carcinoma: A randomised open-label phase 3 trial. Lancet Oncol 2013;14:1287-94.
Motzer RJ, Nosov D, Eisen T, Bondarenko I, Lesovoy V, Lipatov O, et al.
Tivozanib versus sorafenib as initial targeted therapy for patients with metastatic renal cell carcinoma: Results from a phase III trial. J Clin Oncol 2013;31:3791-9.
Motzer RJ, Hutson TE, Cella D, Reeves J, Hawkins R, Guo J, et al.
Pazopanib versus sunitinib in metastatic renal-cell carcinoma. N Engl J Med 2013;369:722-31.
Negrier S, Jäger E, Porta C, McDermott D, Moore M, Bellmunt J, et al.
Efficacy and safety of sorafenib in patients with advanced renal cell carcinoma with and without prior cytokine therapy, a subanalysis of TARGET. Med Oncol 2010;27:899-906.
Bellmunt J, Maroto-Rey P, Trigo JM, Carles J, Guillem V, López-Martín JA, et al.
A phase II trial of first-line sorafenib in patients with metastatic renal cell carcinoma unwilling to receive or with early intolerance to immunotherapy: SOGUG study 06-01. Clin Transl Oncol 2010;12:503-8.
Escudier B, Szczylik C, Hutson TE, Demkow T, Staehler M, Rolland F, et al.
Randomized phase II trial of first-line treatment with sorafenib versus interferon alfa-2a in patients with metastatic renal cell carcinoma. J Clin Oncol 2009;27:1280-9.
Motzer RJ, Hutson TE, Tomczak P, Michaelson MD, Bukowski RM, Oudard S, et al.
Overall survival and updated results for sunitinib compared with interferon alfa in patients with metastatic renal cell carcinoma. J Clin Oncol 2009;27:3584-90.
Melichar B, Koralewski P, Ravaud A, Pluzanska A, Bracarda S, Szczylik C, et al.
First-line bevacizumab combined with reduced dose interferon-alpha2a is active in patients with metastatic renal cell carcinoma. Ann Oncol 2008;19:1470-6.
Rini BI, Halabi S, Rosenberg JE, Stadler WM, Vaena DA, Ou SS, et al.
Bevacizumab plus interferon alfa compared with interferon alfa monotherapy in patients with metastatic renal cell carcinoma: CALGB 90206. J Clin Oncol 2008;26:5422-8.
[Figure 1], [Figure 2], [Figure 3], [Figure 4], [Figure 5]
[Table 1], [Table 2]