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      Validation of preoperative variables and stratification of patients to help predict benefit of cytoreductive nephrectomy in the targeted therapy ERA

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          ABSTRACT

          Objectives

          To further elucidate which patients with metastatic renal cell carcinoma (mRCC) may benefit from cytoreductive nephrectomy (CN) before targeted therapy (TT), and to assess the overall survival of patients undergoing CN and TT versus TT alone.

          Materials and Methods

          We identified 88 patients who underwent CN at our institution prior to planned TT and 35 patients who received TT without undergoing CN. Preoperative risk factors described in the literature were assessed in our patient population (serum albumin, liver metastasis, symptomatic metastasis, clinical ≥T3 disease, retroperitoneal and supradiaphragmatic lymphadenopathy). Patients were stratified by number of pretreatment risk factors and overall survival (OS) was compared.

          Results

          TT patients had significantly more risk factors compared to CN patients (3.06 vs. 2.11, p<0.01). Patients who received TT alone had median OS of 5.8 months. All but one patient receiving TT alone had two or more risk factors. A comparison of the CN and TT groups was performed by constructing Kaplan-Meier curves. There was no significant difference in median OS for those patients with exactly two risk factors (447 vs. 389 days, p=0.24), and those with three or more risk factors (184 vs. 155 days, p=0.87).

          Conclusions

          Using previously described pretreatment risk factors we found that patients with two or more risk factors derived no significant survival advantage from CN in the TT era. These risk factors should be incorporated in the assessment of patients for CN.

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          Most cited references17

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          Cytoreductive nephrectomy in patients with metastatic renal cancer: a combined analysis.

          Metastatic renal cancer is associated with a poor prognosis. Recent advances in immunotherapy for this problem have rekindled interest in cytoreductive nephrectomy. We report a combined analysis of 2 prospective randomized trials that used an identical study protocol. A total of 331 patients were randomized to 2 identical protocols comparing cytoreductive nephrectomy plus interferon alpha-2b vs interferon alpha-2b alone in patients with metastatic renal cancer, in whom the primary tumor was present and believed to be resectable. The primary end point for each trial was overall survival with a secondary end point of the response rate. Patients were stratified at pre-randomization by performance status (0 or 1), site of metastases (lung only vs other) and disease measurability. All results were analyzed by intent to treat criteria. Assuming a median survival of 1 year for interferon only, the Southwest Oncology Group trial was designed to detect a 50% improvement in median survival duration and a 15% improvement in response rate with a power of 0.85. The European Organization for the Research and Treatment of Cancer accrued an additional 80 patients in that study. The combined analysis of these 2 trials yielded a median survival of 13.6 months for nephrectomy plus interferon vs 7.8 months for interferon alone. This difference represents a 31% decrease in the risk of death (p = 0.002). There was no evidence of a difference in the size of the treatment effect according to pre-randomization stratification factors. Cytoreductive nephrectomy appears to improve significantly overall survival in patients with metastatic renal cancer treated with interferon immunotherapy independent of patient performance status, the site of metastases and the presence of measurable disease. Although it is highly statistically significant, the overall survival advantage is only 5.8 months for the entire group. These data emphasize the need to determine if this survival advantage can be further improved using more aggressive immunotherapy or other novel agents in the setting of cytoreductive nephrectomy.
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            Radical nephrectomy plus interferon-alfa-based immunotherapy compared with interferon alfa alone in metastatic renal-cell carcinoma: a randomised trial.

            Surgery is the main treatment for localised renal cell carcinoma, but use of radical nephrectomy for metastatic disease is highly controversial. We aimed to establish whether radical nephrectomy done before interferon-alfa-based immunotherapy improved time to progression and overall survival (primary endpoints) compared with interferon alfa alone. We included 85 patients from June, 1995, to July, 1998: two (one per group) were ineligible. 42 of the 83 participants were randomly assigned combined treatment (study group) and 43 immunotherapy alone (controls). All patients had metastatic renal-cell carcinoma that had been histologically confirmed and was progressive at entry. In study patients, surgery was done within 4 weeks of randomisation, and immunotherapy (5x10(6) IU/m(2) subcutaneously three times per week) started 2-4 weeks later. In controls, immunotherapy was started within 1 working day of randomisation. Follow-up visits were monthly. All analyses were by intention to treat. 40 (53%) of 75 patients received at least 16 weeks of interferon-alfa treatment, which was also the median duration of treatment. Time to progression (5 vs 3 months, hazard ratio 0.60, 95% CI 0.36-0.97) and median duration of survival were significantly better in study patients than in controls (17 vs 7 months, 0.54, 0.31-0.94). Five patients responded completely to combined treatment, and one to interferon alfa alone. Dose modification was necessary in 32% of patients, most commonly because of non-haematological side-effects. Radical nephrectomy before interferon-based immunotherapy might substantially delay time to progression and improve survival of patients with metastatic renal cell carcinoma who present with good performance status.
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              The impact of cytoreductive nephrectomy on survival of patients with metastatic renal cell carcinoma receiving vascular endothelial growth factor targeted therapy.

              Vascular endothelial growth factor targeted therapy is a standard of care in patients with metastatic renal cell carcinoma. The role of cytoreductive nephrectomy in the era of novel agents remains poorly defined. We retrospectively reviewed baseline characteristics and outcomes of 314 patients with anti-vascular endothelial growth factor therapy naïve, metastatic renal cell carcinoma from United States and Canadian cancer centers to study the impact of cytoreductive nephrectomy on overall survival. Patients who underwent cytoreductive nephrectomy (201) were younger (p < 0.01), and more likely to have a better Karnofsky performance status (p < 0.01), more than 1 site of metastasis (p = 0.04) and lower corrected calcium levels (p < 0.01) compared to those who did not undergo cytoreductive nephrectomy (113). On univariable analysis cytoreductive nephrectomy was associated with a median overall survival of 19.8 months compared to 9.4 months for patients who did not undergo cytoreductive nephrectomy (HR 0.44; 95% CI 0.32, 0.59; p < 0.01). On multivariable analysis and adjusting for established prognostic risk factors the overall survival difference persisted (adjusted HR 0.68; 95% CI 0.46, 0.99; p = 0.04) in favor of the cytoreductive nephrectomy group. In subgroup analyses stratified for favorable/intermediate/poor risk criteria, patients in the poor risk group had a marginal benefit (p = 0.06). Similarly patients with Karnofsky performance status less than 80% also had a marginal survival benefit (p = 0.08). In this retrospective study cytoreductive nephrectomy was independently associated with a prolonged overall survival of patients with metastatic renal cell carcinoma treated with vascular endothelial growth factor targeted agents, although the benefit is marginal in those patients with poor risk features. Copyright © 2011 American Urological Association Education and Research, Inc. Published by Elsevier Inc. All rights reserved.
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                Author and article information

                Journal
                Int Braz J Urol
                Int Braz J Urol
                ibju
                International Brazilian Journal of Urology : official journal of the Brazilian Society of Urology
                Sociedade Brasileira de Urologia
                1677-5538
                1677-6119
                May-Jun 2017
                May-Jun 2017
                : 43
                : 3
                : 432-439
                Affiliations
                [1 ]Washington University School of Medicine, Division of Urology, St. Louis, Missouri, USA
                Author notes
                Correspondence address: Seth A. Strope, MD. 4960 Children’s Place. Campus Box 8242. St. Louis, MO 63110, USA. Telephone: +1 314 454-8049. E-mail: stropes@ 123456wudosis.wustl.edu

                CONFLICT OF INTEREST

                None declared.

                Article
                S1677-5538.IBJU.2015.0118
                10.1590/S1677-5538.IBJU.2015.0118
                5462133
                28128914
                76910dfd-0f5a-4328-a8d5-4da9e7d6c0f9

                This is an Open Access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

                History
                : 06 March 2015
                : 18 December 2016
                : 19 January 2017
                Page count
                Figures: 3, Tables: 3, Equations: 0, References: 17, Pages: 8
                Categories
                Original Article

                carcinoma, renal cell,kidney neoplasms,nephrectomy,risk factors,comorbidity

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