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Published in: BMC Cancer 1/2016

Open Access 01-12-2016 | Research article

A retrospective study of predictive factors for unexpectedly prolonged or shortened progression-free survival and overall survival among patients with metastatic renal cell carcinoma who received first-line targeted therapy

Authors: Sung Han Kim, Sohee Kim, Jungnam Joo, Ho Kyung Seo, Jae Young Joung, Kang Hyun Lee, Jinsoo Chung

Published in: BMC Cancer | Issue 1/2016

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Abstract

Background

To identify predictors of prolonged or shortened progression-free survival (PFS) and overall survival (OS) among patients with metastatic renal cell carcinoma (mRCC) who received first-line targeted therapies.

Methods

This retrospective study included 146 patients with mRCC who were treated during 2007–2015. These patients were divided into a group with the worst response (WG), an expected group (EG), and a group with the best response (BG), based on their PFS (≤3 monthsnths, 3–18 monthsnths, and >18 monthsnths, respectively) and OS (<1 year, 1–3 years, and >3 years, respectively). To identify significant predictive factors, the BG and WG were compared to the EG using the Memorial Sloan Kettering Cancer Center and Heng risk models.

Results

The overall PFS and OS were 9.3 months and 16.4 months, respectively. The median PFS for the WG (41.8 %), EG (45.9 %), and BG (12.3 %) were 2.7 months, 9.3 months, and 56.6 months, respectively, and the median OS for the WG (45.9 %), EG (35.6 %), and BG (18.5 %) were 5.5 months, 21.6 months, and 63.1 months, respectively; these outcomes were significantly different (p < 0.001). Nephrectomy (odds ratio [OR]: 7.15) was a significant predictor of PFS in the BG, and the significant predictors of OS in the BG were MSKCC intermediate risk (OR: 0.12), poor risk (OR: 0.04), and a disease-free interval of <1 year (OR: 0.23) (all, p < 0.05). Anemia (OR: 3.25) was a significant predictor of PFS in the WG, and the significant predictors of OS were age (OR: 1.05), anemia (OR: 4.13), lymphocytopenia (OR: 4.76), disease-free interval of <1 year (OR: 4.8), and synchronous metastasis (OR: 3.52) (all, p < 0.05).

Conclusion

We identified several significant predictors of unexpectedly good and poor response to first-line targeted therapy among patients with mRCC.
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Literature
1.
go back to reference Choudhury AD, Eeles R, Freedland SJ, Isaacs WB, Pomerantz MM, Schalken JA, Tammela TL, Visakorpi T. The role of genetic markers in the management of prostate cancer. Eur Urol. 2012;62(4):577–87.CrossRefPubMed Choudhury AD, Eeles R, Freedland SJ, Isaacs WB, Pomerantz MM, Schalken JA, Tammela TL, Visakorpi T. The role of genetic markers in the management of prostate cancer. Eur Urol. 2012;62(4):577–87.CrossRefPubMed
2.
go back to reference Pecuchet N, Fournier LS, Oudard S. New insights into the management of renal cell cancer. Oncology. 2013;84(1):22–31.CrossRefPubMed Pecuchet N, Fournier LS, Oudard S. New insights into the management of renal cell cancer. Oncology. 2013;84(1):22–31.CrossRefPubMed
3.
go back to reference Heng DY, Xie W, Regan MM, Harshman LC, Bjarnason GA, Vaishampayan UN, Mackenzie M, Wood L, Donskov F, Tan MH, et al. External validation and comparison with other models of the International Metastatic Renal-Cell Carcinoma Database Consortium prognostic model: a population-based study. Lancet Oncol. 2013;14(2):141–8.CrossRefPubMedPubMedCentral Heng DY, Xie W, Regan MM, Harshman LC, Bjarnason GA, Vaishampayan UN, Mackenzie M, Wood L, Donskov F, Tan MH, et al. External validation and comparison with other models of the International Metastatic Renal-Cell Carcinoma Database Consortium prognostic model: a population-based study. Lancet Oncol. 2013;14(2):141–8.CrossRefPubMedPubMedCentral
4.
go back to reference Julka PK, Doval DC, Gupta S, Rath GK. Response assessment in solid tumours: a comparison of WHO, SWOG and RECIST guidelines. Br J Radiol. 2008;81(966):444–9.CrossRefPubMed Julka PK, Doval DC, Gupta S, Rath GK. Response assessment in solid tumours: a comparison of WHO, SWOG and RECIST guidelines. Br J Radiol. 2008;81(966):444–9.CrossRefPubMed
5.
go back to reference Eisenhauer EA, Therasse P, Bogaerts J, Schwartz LH, Sargent D, Ford R, Dancey J, Arbuck S, Gwyther S, Mooney M, et al. New response evaluation criteria in solid tumours: revised RECIST guideline (version 1.1). Eur J Cancer. 2009;45(2):228–47.CrossRefPubMed Eisenhauer EA, Therasse P, Bogaerts J, Schwartz LH, Sargent D, Ford R, Dancey J, Arbuck S, Gwyther S, Mooney M, et al. New response evaluation criteria in solid tumours: revised RECIST guideline (version 1.1). Eur J Cancer. 2009;45(2):228–47.CrossRefPubMed
6.
go back to reference Leon L, Garcia-Figueiras R, Suarez C, Arjonilla A, Puente J, Vargas B, Mendez Vidal MJ, Sebastia C. Recommendations for the clinical and radiological evaluation of response to treatment in metastatic renal cell cancer. Target Oncol. 2014;9(1):9–24.CrossRefPubMed Leon L, Garcia-Figueiras R, Suarez C, Arjonilla A, Puente J, Vargas B, Mendez Vidal MJ, Sebastia C. Recommendations for the clinical and radiological evaluation of response to treatment in metastatic renal cell cancer. Target Oncol. 2014;9(1):9–24.CrossRefPubMed
7.
go back to reference Motzer RJ, Bacik J, Murphy BA, Russo P, Mazumdar M. Interferon-alfa as a comparative treatment for clinical trials of new therapies against advanced renal cell carcinoma. J Clin Oncol Off J Am Soc Clin Oncol. 2002;20(1):289–96.CrossRef Motzer RJ, Bacik J, Murphy BA, Russo P, Mazumdar M. Interferon-alfa as a comparative treatment for clinical trials of new therapies against advanced renal cell carcinoma. J Clin Oncol Off J Am Soc Clin Oncol. 2002;20(1):289–96.CrossRef
8.
go back to reference Motzer RJ, Bacik J, Schwartz LH, Reuter V, Russo P, Marion S, Mazumdar M. Prognostic factors for survival in previously treated patients with metastatic renal cell carcinoma. J Clin Oncol Off J Am Soc Clin Oncol. 2004;22(3):454–63.CrossRef Motzer RJ, Bacik J, Schwartz LH, Reuter V, Russo P, Marion S, Mazumdar M. Prognostic factors for survival in previously treated patients with metastatic renal cell carcinoma. J Clin Oncol Off J Am Soc Clin Oncol. 2004;22(3):454–63.CrossRef
9.
go back to reference Heng DY, Xie W, Regan MM, Warren MA, Golshayan AR, Sahi C, Eigl BJ, Ruether JD, Cheng T, North S, et al. Prognostic factors for overall survival in patients with metastatic renal cell carcinoma treated with vascular endothelial growth factor-targeted agents: results from a large, multicenter study. J Clin Oncol Off J Am Soc Clin Oncol. 2009;27(34):5794–9.CrossRef Heng DY, Xie W, Regan MM, Warren MA, Golshayan AR, Sahi C, Eigl BJ, Ruether JD, Cheng T, North S, et al. Prognostic factors for overall survival in patients with metastatic renal cell carcinoma treated with vascular endothelial growth factor-targeted agents: results from a large, multicenter study. J Clin Oncol Off J Am Soc Clin Oncol. 2009;27(34):5794–9.CrossRef
10.
go back to reference Cho IC, Chung J. Current status of targeted therapy for advanced renal cell carcinoma. Korean J Urology. 2012;53(4):217–28.CrossRef Cho IC, Chung J. Current status of targeted therapy for advanced renal cell carcinoma. Korean J Urology. 2012;53(4):217–28.CrossRef
11.
go back to reference Park SJ, Lee JL, Park I, Park K, Ahn Y, Ahn JH, Lee DH, Ahn S, Song C, Hong JH, et al. Comparative efficacy of sunitinib versus sorafenib as first-line treatment for patients with metastatic renal cell carcinoma. Chemotherapy. 2012;58(6):468–74.CrossRefPubMed Park SJ, Lee JL, Park I, Park K, Ahn Y, Ahn JH, Lee DH, Ahn S, Song C, Hong JH, et al. Comparative efficacy of sunitinib versus sorafenib as first-line treatment for patients with metastatic renal cell carcinoma. Chemotherapy. 2012;58(6):468–74.CrossRefPubMed
12.
go back to reference Ye D, Eto M, Chung JS, Kimura G, Chang WC, Chang YH, Pang ST, Lee JL, Niu Y, Gurney H, et al. Use of targeted therapies for advanced renal cell carcinoma in the Asia-Pacific region: opinion statement from China, Japan, Taiwan, Korea, and Australia. Clin Genitourin Cancer. 2014;12(4):225–33.CrossRefPubMed Ye D, Eto M, Chung JS, Kimura G, Chang WC, Chang YH, Pang ST, Lee JL, Niu Y, Gurney H, et al. Use of targeted therapies for advanced renal cell carcinoma in the Asia-Pacific region: opinion statement from China, Japan, Taiwan, Korea, and Australia. Clin Genitourin Cancer. 2014;12(4):225–33.CrossRefPubMed
13.
go back to reference Porta C, Tortora G, Linassier C, Papazisis K, Awada A, Berthold D, Maroto JP, Powles T, De Santis M. Maximising the duration of disease control in metastatic renal cell carcinoma with targeted agents: an expert agreement. Med Oncol. 2012;29(3):1896–907.CrossRefPubMed Porta C, Tortora G, Linassier C, Papazisis K, Awada A, Berthold D, Maroto JP, Powles T, De Santis M. Maximising the duration of disease control in metastatic renal cell carcinoma with targeted agents: an expert agreement. Med Oncol. 2012;29(3):1896–907.CrossRefPubMed
14.
go back to reference Choueiri TK, Rini B, Garcia JA, Baz RC, Abou-Jawde RM, Thakkar SG, Elson P, Mekhail TM, Zhou M, Bukowski RM. Prognostic factors associated with long-term survival in previously untreated metastatic renal cell carcinoma. Annals Oncol. 2007;18(2):249–55.CrossRef Choueiri TK, Rini B, Garcia JA, Baz RC, Abou-Jawde RM, Thakkar SG, Elson P, Mekhail TM, Zhou M, Bukowski RM. Prognostic factors associated with long-term survival in previously untreated metastatic renal cell carcinoma. Annals Oncol. 2007;18(2):249–55.CrossRef
15.
go back to reference De Lichtenberg TH, Hermann GG, Rorth M, Hojer Larsen MJ, Mansourvar Z, Holm ML, Scheike T. Overall survival after immunotherapy, tyrosine kinase inhibitors and surgery in treatment of metastatic renal cell cancer: outcome of 143 consecutive patients from a single centre. Scand J Urol Nephrol. 2014;48(4):379–86. De Lichtenberg TH, Hermann GG, Rorth M, Hojer Larsen MJ, Mansourvar Z, Holm ML, Scheike T. Overall survival after immunotherapy, tyrosine kinase inhibitors and surgery in treatment of metastatic renal cell cancer: outcome of 143 consecutive patients from a single centre. Scand J Urol Nephrol. 2014;48(4):379–86.
16.
go back to reference Buchler T, Klapka R, Melichar B, Brabec P, Dusek L, Vyzula R, Abrahamova J. Sunitinib followed by sorafenib or vice versa for metastatic renal cell carcinoma--data from the Czech registry. Annals Oncol. 2012;23(2):395–401.CrossRef Buchler T, Klapka R, Melichar B, Brabec P, Dusek L, Vyzula R, Abrahamova J. Sunitinib followed by sorafenib or vice versa for metastatic renal cell carcinoma--data from the Czech registry. Annals Oncol. 2012;23(2):395–401.CrossRef
17.
go back to reference Eichelberg C, Vervenne WL, De Santis M, Fischer Von Weikersthal L, Goebell PJ, Lerchenmuller C, Zimmermann U, Bos MM, Freier W, Schirrmacher-Memmel S, et al. SWITCH: A Randomised, Sequential, Open-label Study to Evaluate the Efficacy and Safety of Sorafenib-sunitinib Versus Sunitinib-sorafenib in the Treatment of Metastatic Renal Cell Cancer. Eur Urol. 2015;68(5):837–47.CrossRefPubMed Eichelberg C, Vervenne WL, De Santis M, Fischer Von Weikersthal L, Goebell PJ, Lerchenmuller C, Zimmermann U, Bos MM, Freier W, Schirrmacher-Memmel S, et al. SWITCH: A Randomised, Sequential, Open-label Study to Evaluate the Efficacy and Safety of Sorafenib-sunitinib Versus Sunitinib-sorafenib in the Treatment of Metastatic Renal Cell Cancer. Eur Urol. 2015;68(5):837–47.CrossRefPubMed
18.
go back to reference Motzer RJ, Hutson TE, Tomczak P, Michaelson MD, Bukowski RM, Oudard S, Negrier S, Szczylik C, Pili R, Bjarnason GA, et al. Overall survival and updated results for sunitinib compared with interferon alfa in patients with metastatic renal cell carcinoma. J Clin Oncol Off J Am Soc Clin Oncol. 2009;27(22):3584–90.CrossRef Motzer RJ, Hutson TE, Tomczak P, Michaelson MD, Bukowski RM, Oudard S, Negrier S, Szczylik C, Pili R, Bjarnason GA, et al. Overall survival and updated results for sunitinib compared with interferon alfa in patients with metastatic renal cell carcinoma. J Clin Oncol Off J Am Soc Clin Oncol. 2009;27(22):3584–90.CrossRef
19.
go back to reference Escudier B, Eisen T, Stadler WM, Szczylik C, Oudard S, Siebels M, Negrier S, Chevreau C, Solska E, Desai AA, et al. Sorafenib in advanced clear-cell renal-cell carcinoma. N Engl J Med. 2007;356(2):125–34.CrossRefPubMed Escudier B, Eisen T, Stadler WM, Szczylik C, Oudard S, Siebels M, Negrier S, Chevreau C, Solska E, Desai AA, et al. Sorafenib in advanced clear-cell renal-cell carcinoma. N Engl J Med. 2007;356(2):125–34.CrossRefPubMed
20.
go back to reference Escudier B, Szczylik C, Hutson TE, Demkow T, Staehler M, Rolland F, Negrier S, Laferriere N, Scheuring UJ, Cella D, 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 Off J Am Soc Clin Oncol. 2009;27(8):1280–9.CrossRef Escudier B, Szczylik C, Hutson TE, Demkow T, Staehler M, Rolland F, Negrier S, Laferriere N, Scheuring UJ, Cella D, 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 Off J Am Soc Clin Oncol. 2009;27(8):1280–9.CrossRef
21.
go back to reference Sternberg CN, Hawkins RE, Wagstaff J, Salman P, Mardiak J, Barrios CH, Zarba JJ, Gladkov OA, Lee E, Szczylik C, et al. A randomised, double-blind phase III study of pazopanib in patients with advanced and/or metastatic renal cell carcinoma: final overall survival results and safety update. Eur J Cancer. 2013;49(6):1287–96.CrossRefPubMed Sternberg CN, Hawkins RE, Wagstaff J, Salman P, Mardiak J, Barrios CH, Zarba JJ, Gladkov OA, Lee E, Szczylik C, et al. A randomised, double-blind phase III study of pazopanib in patients with advanced and/or metastatic renal cell carcinoma: final overall survival results and safety update. Eur J Cancer. 2013;49(6):1287–96.CrossRefPubMed
22.
go back to reference Mathieu R, Pignot G, Ingles A, Crepel M, Bigot P, Bernhard JC, Joly F, Guy L, Ravaud A, Azzouzi AR, et al. Nephrectomy improves overall survival in patients with metastatic renal cell carcinoma in cases of favorable MSKCC or ECOG prognostic features. Urol Oncol. 2015;33(8):339. e339-339 e315.CrossRefPubMed Mathieu R, Pignot G, Ingles A, Crepel M, Bigot P, Bernhard JC, Joly F, Guy L, Ravaud A, Azzouzi AR, et al. Nephrectomy improves overall survival in patients with metastatic renal cell carcinoma in cases of favorable MSKCC or ECOG prognostic features. Urol Oncol. 2015;33(8):339. e339-339 e315.CrossRefPubMed
23.
go back to reference Shinohara N, Abe T. Prognostic factors and risk classifications for patients with metastatic renal cell carcinoma. Int J Urol. 2015;22(10):888–97.CrossRefPubMed Shinohara N, Abe T. Prognostic factors and risk classifications for patients with metastatic renal cell carcinoma. Int J Urol. 2015;22(10):888–97.CrossRefPubMed
24.
go back to reference Procopio G, Testa I, Verzoni E, Iacovelli R, Grassi P, Galli G, De Braud F, Saravia D, Salvioni R. Time from nephrectomy as a prognostic factor in metastatic renal cell carcinoma patients receiving targeted therapies: overall results from a large cohort of patients. Oncology. 2015;88(3):133–8.CrossRefPubMed Procopio G, Testa I, Verzoni E, Iacovelli R, Grassi P, Galli G, De Braud F, Saravia D, Salvioni R. Time from nephrectomy as a prognostic factor in metastatic renal cell carcinoma patients receiving targeted therapies: overall results from a large cohort of patients. Oncology. 2015;88(3):133–8.CrossRefPubMed
25.
go back to reference Santoni M, Buti S, Conti A, Porta C, Procopio G, Sternberg CN, Bracarda S, Basso U, De Giorgi U, Rizzo M, et al. Prognostic significance of host immune status in patients with late relapsing renal cell carcinoma treated with targeted therapy. Target Oncol. 2015;10(4):517–22.CrossRefPubMed Santoni M, Buti S, Conti A, Porta C, Procopio G, Sternberg CN, Bracarda S, Basso U, De Giorgi U, Rizzo M, et al. Prognostic significance of host immune status in patients with late relapsing renal cell carcinoma treated with targeted therapy. Target Oncol. 2015;10(4):517–22.CrossRefPubMed
26.
go back to reference Ueda T, Uemura H, Tomita Y, Tsukamoto T, Kanayama H, Shinohara N, Tarazi J, Chen C, Kim S, Ozono S, et al. Efficacy and safety of axitinib versus sorafenib in metastatic renal cell carcinoma: subgroup analysis of Japanese patients from the global randomized Phase 3 AXIS trial. Jpn J Clin Oncol. 2013;43(6):616–28.CrossRefPubMedPubMedCentral Ueda T, Uemura H, Tomita Y, Tsukamoto T, Kanayama H, Shinohara N, Tarazi J, Chen C, Kim S, Ozono S, et al. Efficacy and safety of axitinib versus sorafenib in metastatic renal cell carcinoma: subgroup analysis of Japanese patients from the global randomized Phase 3 AXIS trial. Jpn J Clin Oncol. 2013;43(6):616–28.CrossRefPubMedPubMedCentral
27.
go back to reference Hutson TE, Escudier B, Esteban E, Bjarnason GA, Lim HY, Pittman KB, Senico P, Niethammer A, Lu DR, Hariharan S, 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 Off J Am Soc Clin Oncol. 2014;32(8):760–7.CrossRef Hutson TE, Escudier B, Esteban E, Bjarnason GA, Lim HY, Pittman KB, Senico P, Niethammer A, Lu DR, Hariharan S, 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 Off J Am Soc Clin Oncol. 2014;32(8):760–7.CrossRef
28.
go back to reference Kroeger N, Choueiri TK, Lee JL, Bjarnason GA, Knox JJ, MacKenzie MJ, Wood L, Srinivas S, Vaishamayan UN, Rha SY, et al. Survival outcome and treatment response of patients with late relapse from renal cell carcinoma in the era of targeted therapy. Eur Urol. 2014;65(6):1086–92.CrossRefPubMed Kroeger N, Choueiri TK, Lee JL, Bjarnason GA, Knox JJ, MacKenzie MJ, Wood L, Srinivas S, Vaishamayan UN, Rha SY, et al. Survival outcome and treatment response of patients with late relapse from renal cell carcinoma in the era of targeted therapy. Eur Urol. 2014;65(6):1086–92.CrossRefPubMed
29.
go back to reference Kwak C, Park YH, Jeong CW, Jeong H, Lee SE, Ku JH. Characteristics of metastasis as a prognostic factor for immunotherapy in metastatic renal cell carcinoma. Tumori. 2007;93(1):68–74.PubMed Kwak C, Park YH, Jeong CW, Jeong H, Lee SE, Ku JH. Characteristics of metastasis as a prognostic factor for immunotherapy in metastatic renal cell carcinoma. Tumori. 2007;93(1):68–74.PubMed
30.
go back to reference Keizman D, Ish-Shalom M, Huang P, Eisenberger MA, Pili R, Hammers H, Carducci MA. The association of pre-treatment neutrophil to lymphocyte ratio with response rate, progression free survival and overall survival of patients treated with sunitinib for metastatic renal cell carcinoma. Eur J Cancer. 2012;48(2):202–8.CrossRefPubMed Keizman D, Ish-Shalom M, Huang P, Eisenberger MA, Pili R, Hammers H, Carducci MA. The association of pre-treatment neutrophil to lymphocyte ratio with response rate, progression free survival and overall survival of patients treated with sunitinib for metastatic renal cell carcinoma. Eur J Cancer. 2012;48(2):202–8.CrossRefPubMed
31.
go back to reference Santoni M, De Giorgi U, Iacovelli R, Conti A, Burattini L, Rossi L, Luca Burgio S, Berardi R, Muzzonigro G, Cortesi E, et al. Pre-treatment neutrophil-to-lymphocyte ratio may be associated with the outcome in patients treated with everolimus for metastatic renal cell carcinoma. Br J Cancer. 2013;109(7):1755–9.CrossRefPubMedPubMedCentral Santoni M, De Giorgi U, Iacovelli R, Conti A, Burattini L, Rossi L, Luca Burgio S, Berardi R, Muzzonigro G, Cortesi E, et al. Pre-treatment neutrophil-to-lymphocyte ratio may be associated with the outcome in patients treated with everolimus for metastatic renal cell carcinoma. Br J Cancer. 2013;109(7):1755–9.CrossRefPubMedPubMedCentral
32.
go back to reference Kwon WA, Cho IC, Yu A, Nam BH, Joung JY, Seo HK, Lee KH, Chung J. Validation of the MSKCC and Heng risk criteria models for predicting survival in patients with metastatic renal cell carcinoma treated with sunitinib. Ann Surg Oncol. 2013;20(13):4397–40.CrossRefPubMed Kwon WA, Cho IC, Yu A, Nam BH, Joung JY, Seo HK, Lee KH, Chung J. Validation of the MSKCC and Heng risk criteria models for predicting survival in patients with metastatic renal cell carcinoma treated with sunitinib. Ann Surg Oncol. 2013;20(13):4397–40.CrossRefPubMed
Metadata
Title
A retrospective study of predictive factors for unexpectedly prolonged or shortened progression-free survival and overall survival among patients with metastatic renal cell carcinoma who received first-line targeted therapy
Authors
Sung Han Kim
Sohee Kim
Jungnam Joo
Ho Kyung Seo
Jae Young Joung
Kang Hyun Lee
Jinsoo Chung
Publication date
01-12-2016
Publisher
BioMed Central
Published in
BMC Cancer / Issue 1/2016
Electronic ISSN: 1471-2407
DOI
https://doi.org/10.1186/s12885-016-2615-4

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