Survival outcome and treatment response of patients with late relapse from renal cell carcinoma in the era of targeted therapy

Nils Kroeger; Toni K. Choueiri; Jae Lyn Lee; Georg A. Bjarnason; Jennifer J. Knox; Mary J. Mackenzie; Lori Wood; Sandy Srinivas; Ulka N. Vaishamayan; Sun Young Rha; Sumanta K. Pal; Takeshi Yuasa; Frede Donskov; Neeraj Agarwal; Min Han Tan; Aristotelis Bamias; Christian K. Kollmannsberger; Scott A. North; Brian I. Rini; Daniel Y.C. Heng

doi:10.1016/j.eururo.2013.07.031

Survival outcome and treatment response of patients with late relapse from renal cell carcinoma in the era of targeted therapy

Nils Kroeger, Toni K. Choueiri, Jae Lyn Lee, Georg A. Bjarnason, Jennifer J. Knox, Mary J. Mackenzie, Lori Wood, Sandy Srinivas, Ulka N. Vaishamayan, Sun Young Rha, Sumanta K. Pal, Takeshi Yuasa, Frede Donskov, Neeraj Agarwal, Min Han Tan, Aristotelis Bamias, Christian K. Kollmannsberger, Scott A. North, Brian I. Rini, Daniel Y.C. Heng

Department of Internal Medicine

Research output: Contribution to journal › Article › peer-review

66 Citations (Scopus)

Abstract

Background A subset of primarily localized renal cell carcinoma (RCC) patients will experience disease recurrence ≤5 yr after initial nephrectomy. Objective To characterize the clinical outcome of patients with late recurrence beyond 5 yr. Design, setting, and participants Patients with metastatic RCC (mRCC) treated with targeted therapy were retrospectively characterized according to time to relapse. Relapse was defined as the diagnosis of recurrent metastatic disease >3 mo after initial curative-intent nephrectomy. Patients with synchronous metastatic disease at presentation were excluded. Patients were classified as early relapsers (ERs) if they recurred within 5 yr; late relapsers (LRs) recurred after 5 yr. Outcome measurements and statistical analysis Demographics were compared with the Student t test, the chi-square test, or the Fisher exact test. The survival time was estimated with the Kaplan-Meier method, and associations with survival outcome were assessed with univariable and multivariable Cox regression analyses. Results and limitations Among 1210 mRCC patients treated with targeted therapy after surgery for localized disease, 897 (74%) relapsed within the first 5 yr and 313 (26%) (range: 5-35 yr) after 5 yr. LRs presented with younger age (p < 0.0001), fewer with sarcomatoid features (p < 0.0001), more clear cell histology (p = 0.001), and lower Fuhrman grade (p < 0.0001). Overall objective response rates to targeted therapy were better in LRs versus ERs (31.8% vs 26.5%; p = 0.004). LRs had significantly longer progression-free survival (10.7 mo vs 8.5 mo; p = 0.005) and overall survival (OS; 34.0 mo vs 27.4 mo; p = 0.004). The study is limited by its retrospective design, noncentralized imaging and pathology review, missing information on metastatectomy, and nonstandardized follow-up protocols. Conclusions A quarter of patients who eventually developed metastatic disease and were treated with targeted therapy relapsed over 5 yr from initial nephrectomy. LRs have more favorable prognostic features and consequently better treatment response and OS.

Original language	English
Pages (from-to)	1086-1092
Number of pages	7
Journal	European Urology
Volume	65
Issue number	6
DOIs	https://doi.org/10.1016/j.eururo.2013.07.031
Publication status	Published - 2014 Jun

Bibliographical note

Funding Information:
A substantial number of mRCC patients relapse >5 yr after initial nephrectomy, and these patients have more favorable prognostic characteristics. LRs have better treatment response, PFS, and OS when treated with targeted therapy because of more favorable prognostic features. This knowledge is important when informing patients about their prognosis after they have developed a late disease relapse from RCC and may warrant longer term surveillance beyond 5 yr in patients with localized disease. Author contributions: Daniel Y.C. Heng had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis. Study concept and design: Kroeger, Heng, Choueiri. Acquisition of data: Kroeger, Choueiri, Lee, Bjarnason, Knox, MacKenzie, Wood, Srinivas, Vaishamayan, Rha, Pal, Yuasa, Donskov, Agarwal, Tan, Bamias, Kollmannsberger, North, Rini, Heng. Analysis and interpretation of data: Kroeger, Heng, Choueiri, Rini. Drafting of the manuscript: Kroeger, Heng, Choueiri. Critical revision of the manuscript for important intellectual content: Kroeger, Choueiri, Lee, Bjarnason, Knox, MacKenzie, Wood, Srinivas, Vaishamayan, Rha, Pal, Yuasa, Donskov, Agarwal, Tan, Bamias, Kollmannsberger, North, Rini, Heng. Statistical analysis: Kroeger, Heng. Obtaining funding: None. Administrative, technical, or material support: Kroeger, Choueiri, Lee, Bjarnason, Knox, MacKenzie, Wood, Srinivas, Vaishamayan, Rha, Pal, Yuasa, Donskov, Agarwal, Tan, Bamias, Kollmannsberger, North, Rini, Heng. Supervision: Heng, Choueiri. Other (specify): None. Financial disclosures: Daniel Y.C. Heng certifies that all conflicts of interest, including specific financial interests and relationships and affiliations relevant to the subject matter or materials discussed in the manuscript (eg, employment/affiliation, grants or funding, consultancies, honoraria, stock ownership or options, expert testimony, royalties, or patents filed, received, or pending), are the following: Jae-Lyn Lee receives honoraria from Novartis, Bayer, and Pfizer, and research funding from Bayer. Mary J. MacKenzie is an adviser at Novartis and Pfizer and has received research funding from both. Georg A. Bjarnason is a consultant and adviser for Pfizer. He receives honoraria and research funding from Pfizer. Jennifer J. Knox is a consultant and adviser for AVEO and has received research funding from Pfizer. Lori Wood is an adviser for Pfizer and Novartis and has received research funding from Pfizer, Novartis, and GlaxoSmithKline. Ulka N. Vaishamayan has received honoraria and research funding from Pfizer, Novartis, and GlaxoSmithKline. Sun-Young Rha is an adviser for Novartis, Pfizer, and GlaxoSmithKline and has received research funding from Novartis and Bayer Korea. Frede Donskov has received research funding from Novartis. Christian K. Kollmannsberger is an adviser for Pfizer, Novartis, and GlaxoSmithKline. Scott A North is a consultant and adviser for Novartis, Bayer, GlaxoSmithKline, and Pfizer. Brian I. Rini is an adviser for Pfizer, GlaxoSmithKline, Bayer, and Onyx, and he has received research funding from GlaxoSmithKline and Pfizer. Toni K. Choueiri has received research funding from Pfizer and is an adviser for AVEO, Pfizer, Novartis, GlaxoSmithKline, Genentech, Bayer, and Onyx. Daniel Y.C. Heng is an adviser for AVEO, Pfizer, Novartis, and Bayer. Nils Kroeger, Sandy Srinivas, Sumanta K. Pal, Takeshi Yuasa, Neeraj Agarwal, and Min-Han Tan have nothing to disclose. Funding/Support and role of the sponsor: None.

All Science Journal Classification (ASJC) codes

Urology

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10.1016/j.eururo.2013.07.031

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Kroeger, N., Choueiri, T. K., Lee, J. L., Bjarnason, G. A., Knox, J. J., Mackenzie, M. J., Wood, L., Srinivas, S., Vaishamayan, U. N., Rha, S. Y., Pal, S. K., Yuasa, T., Donskov, F., Agarwal, N., Tan, M. H., Bamias, A., Kollmannsberger, C. K., North, S. A., Rini, B. I., & Heng, D. Y. C. (2014). Survival outcome and treatment response of patients with late relapse from renal cell carcinoma in the era of targeted therapy. European Urology, 65(6), 1086-1092. https://doi.org/10.1016/j.eururo.2013.07.031

@article{9b1edfd8576b414b81191d1d36ba4069,

title = "Survival outcome and treatment response of patients with late relapse from renal cell carcinoma in the era of targeted therapy",

abstract = "Background A subset of primarily localized renal cell carcinoma (RCC) patients will experience disease recurrence ≤5 yr after initial nephrectomy. Objective To characterize the clinical outcome of patients with late recurrence beyond 5 yr. Design, setting, and participants Patients with metastatic RCC (mRCC) treated with targeted therapy were retrospectively characterized according to time to relapse. Relapse was defined as the diagnosis of recurrent metastatic disease >3 mo after initial curative-intent nephrectomy. Patients with synchronous metastatic disease at presentation were excluded. Patients were classified as early relapsers (ERs) if they recurred within 5 yr; late relapsers (LRs) recurred after 5 yr. Outcome measurements and statistical analysis Demographics were compared with the Student t test, the chi-square test, or the Fisher exact test. The survival time was estimated with the Kaplan-Meier method, and associations with survival outcome were assessed with univariable and multivariable Cox regression analyses. Results and limitations Among 1210 mRCC patients treated with targeted therapy after surgery for localized disease, 897 (74%) relapsed within the first 5 yr and 313 (26%) (range: 5-35 yr) after 5 yr. LRs presented with younger age (p < 0.0001), fewer with sarcomatoid features (p < 0.0001), more clear cell histology (p = 0.001), and lower Fuhrman grade (p < 0.0001). Overall objective response rates to targeted therapy were better in LRs versus ERs (31.8% vs 26.5%; p = 0.004). LRs had significantly longer progression-free survival (10.7 mo vs 8.5 mo; p = 0.005) and overall survival (OS; 34.0 mo vs 27.4 mo; p = 0.004). The study is limited by its retrospective design, noncentralized imaging and pathology review, missing information on metastatectomy, and nonstandardized follow-up protocols. Conclusions A quarter of patients who eventually developed metastatic disease and were treated with targeted therapy relapsed over 5 yr from initial nephrectomy. LRs have more favorable prognostic features and consequently better treatment response and OS.",

author = "Nils Kroeger and Choueiri, {Toni K.} and Lee, {Jae Lyn} and Bjarnason, {Georg A.} and Knox, {Jennifer J.} and Mackenzie, {Mary J.} and Lori Wood and Sandy Srinivas and Vaishamayan, {Ulka N.} and Rha, {Sun Young} and Pal, {Sumanta K.} and Takeshi Yuasa and Frede Donskov and Neeraj Agarwal and Tan, {Min Han} and Aristotelis Bamias and Kollmannsberger, {Christian K.} and North, {Scott A.} and Rini, {Brian I.} and Heng, {Daniel Y.C.}",

note = "Funding Information: A substantial number of mRCC patients relapse >5 yr after initial nephrectomy, and these patients have more favorable prognostic characteristics. LRs have better treatment response, PFS, and OS when treated with targeted therapy because of more favorable prognostic features. This knowledge is important when informing patients about their prognosis after they have developed a late disease relapse from RCC and may warrant longer term surveillance beyond 5 yr in patients with localized disease. Author contributions: Daniel Y.C. Heng had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis. Study concept and design: Kroeger, Heng, Choueiri. Acquisition of data: Kroeger, Choueiri, Lee, Bjarnason, Knox, MacKenzie, Wood, Srinivas, Vaishamayan, Rha, Pal, Yuasa, Donskov, Agarwal, Tan, Bamias, Kollmannsberger, North, Rini, Heng. Analysis and interpretation of data: Kroeger, Heng, Choueiri, Rini. Drafting of the manuscript: Kroeger, Heng, Choueiri. Critical revision of the manuscript for important intellectual content: Kroeger, Choueiri, Lee, Bjarnason, Knox, MacKenzie, Wood, Srinivas, Vaishamayan, Rha, Pal, Yuasa, Donskov, Agarwal, Tan, Bamias, Kollmannsberger, North, Rini, Heng. Statistical analysis: Kroeger, Heng. Obtaining funding: None. Administrative, technical, or material support: Kroeger, Choueiri, Lee, Bjarnason, Knox, MacKenzie, Wood, Srinivas, Vaishamayan, Rha, Pal, Yuasa, Donskov, Agarwal, Tan, Bamias, Kollmannsberger, North, Rini, Heng. Supervision: Heng, Choueiri. Other (specify): None. Financial disclosures: Daniel Y.C. Heng certifies that all conflicts of interest, including specific financial interests and relationships and affiliations relevant to the subject matter or materials discussed in the manuscript (eg, employment/affiliation, grants or funding, consultancies, honoraria, stock ownership or options, expert testimony, royalties, or patents filed, received, or pending), are the following: Jae-Lyn Lee receives honoraria from Novartis, Bayer, and Pfizer, and research funding from Bayer. Mary J. MacKenzie is an adviser at Novartis and Pfizer and has received research funding from both. Georg A. Bjarnason is a consultant and adviser for Pfizer. He receives honoraria and research funding from Pfizer. Jennifer J. Knox is a consultant and adviser for AVEO and has received research funding from Pfizer. Lori Wood is an adviser for Pfizer and Novartis and has received research funding from Pfizer, Novartis, and GlaxoSmithKline. Ulka N. Vaishamayan has received honoraria and research funding from Pfizer, Novartis, and GlaxoSmithKline. Sun-Young Rha is an adviser for Novartis, Pfizer, and GlaxoSmithKline and has received research funding from Novartis and Bayer Korea. Frede Donskov has received research funding from Novartis. Christian K. Kollmannsberger is an adviser for Pfizer, Novartis, and GlaxoSmithKline. Scott A North is a consultant and adviser for Novartis, Bayer, GlaxoSmithKline, and Pfizer. Brian I. Rini is an adviser for Pfizer, GlaxoSmithKline, Bayer, and Onyx, and he has received research funding from GlaxoSmithKline and Pfizer. Toni K. Choueiri has received research funding from Pfizer and is an adviser for AVEO, Pfizer, Novartis, GlaxoSmithKline, Genentech, Bayer, and Onyx. Daniel Y.C. Heng is an adviser for AVEO, Pfizer, Novartis, and Bayer. Nils Kroeger, Sandy Srinivas, Sumanta K. Pal, Takeshi Yuasa, Neeraj Agarwal, and Min-Han Tan have nothing to disclose. Funding/Support and role of the sponsor: None. ",

year = "2014",

month = jun,

doi = "10.1016/j.eururo.2013.07.031",

language = "English",

volume = "65",

pages = "1086--1092",

journal = "European Urology",

issn = "0302-2838",

publisher = "Elsevier",

number = "6",

}

Kroeger, N, Choueiri, TK, Lee, JL, Bjarnason, GA, Knox, JJ, Mackenzie, MJ, Wood, L, Srinivas, S, Vaishamayan, UN, Rha, SY, Pal, SK, Yuasa, T, Donskov, F, Agarwal, N, Tan, MH, Bamias, A, Kollmannsberger, CK, North, SA, Rini, BI & Heng, DYC 2014, 'Survival outcome and treatment response of patients with late relapse from renal cell carcinoma in the era of targeted therapy', European Urology, vol. 65, no. 6, pp. 1086-1092. https://doi.org/10.1016/j.eururo.2013.07.031

TY - JOUR

T1 - Survival outcome and treatment response of patients with late relapse from renal cell carcinoma in the era of targeted therapy

AU - Kroeger, Nils

AU - Choueiri, Toni K.

AU - Lee, Jae Lyn

AU - Bjarnason, Georg A.

AU - Knox, Jennifer J.

AU - Mackenzie, Mary J.

AU - Wood, Lori

AU - Srinivas, Sandy

AU - Vaishamayan, Ulka N.

AU - Rha, Sun Young

AU - Pal, Sumanta K.

AU - Yuasa, Takeshi

AU - Donskov, Frede

AU - Agarwal, Neeraj

AU - Tan, Min Han

AU - Bamias, Aristotelis

AU - Kollmannsberger, Christian K.

AU - North, Scott A.

AU - Rini, Brian I.

AU - Heng, Daniel Y.C.

N1 - Funding Information: A substantial number of mRCC patients relapse >5 yr after initial nephrectomy, and these patients have more favorable prognostic characteristics. LRs have better treatment response, PFS, and OS when treated with targeted therapy because of more favorable prognostic features. This knowledge is important when informing patients about their prognosis after they have developed a late disease relapse from RCC and may warrant longer term surveillance beyond 5 yr in patients with localized disease. Author contributions: Daniel Y.C. Heng had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis. Study concept and design: Kroeger, Heng, Choueiri. Acquisition of data: Kroeger, Choueiri, Lee, Bjarnason, Knox, MacKenzie, Wood, Srinivas, Vaishamayan, Rha, Pal, Yuasa, Donskov, Agarwal, Tan, Bamias, Kollmannsberger, North, Rini, Heng. Analysis and interpretation of data: Kroeger, Heng, Choueiri, Rini. Drafting of the manuscript: Kroeger, Heng, Choueiri. Critical revision of the manuscript for important intellectual content: Kroeger, Choueiri, Lee, Bjarnason, Knox, MacKenzie, Wood, Srinivas, Vaishamayan, Rha, Pal, Yuasa, Donskov, Agarwal, Tan, Bamias, Kollmannsberger, North, Rini, Heng. Statistical analysis: Kroeger, Heng. Obtaining funding: None. Administrative, technical, or material support: Kroeger, Choueiri, Lee, Bjarnason, Knox, MacKenzie, Wood, Srinivas, Vaishamayan, Rha, Pal, Yuasa, Donskov, Agarwal, Tan, Bamias, Kollmannsberger, North, Rini, Heng. Supervision: Heng, Choueiri. Other (specify): None. Financial disclosures: Daniel Y.C. Heng certifies that all conflicts of interest, including specific financial interests and relationships and affiliations relevant to the subject matter or materials discussed in the manuscript (eg, employment/affiliation, grants or funding, consultancies, honoraria, stock ownership or options, expert testimony, royalties, or patents filed, received, or pending), are the following: Jae-Lyn Lee receives honoraria from Novartis, Bayer, and Pfizer, and research funding from Bayer. Mary J. MacKenzie is an adviser at Novartis and Pfizer and has received research funding from both. Georg A. Bjarnason is a consultant and adviser for Pfizer. He receives honoraria and research funding from Pfizer. Jennifer J. Knox is a consultant and adviser for AVEO and has received research funding from Pfizer. Lori Wood is an adviser for Pfizer and Novartis and has received research funding from Pfizer, Novartis, and GlaxoSmithKline. Ulka N. Vaishamayan has received honoraria and research funding from Pfizer, Novartis, and GlaxoSmithKline. Sun-Young Rha is an adviser for Novartis, Pfizer, and GlaxoSmithKline and has received research funding from Novartis and Bayer Korea. Frede Donskov has received research funding from Novartis. Christian K. Kollmannsberger is an adviser for Pfizer, Novartis, and GlaxoSmithKline. Scott A North is a consultant and adviser for Novartis, Bayer, GlaxoSmithKline, and Pfizer. Brian I. Rini is an adviser for Pfizer, GlaxoSmithKline, Bayer, and Onyx, and he has received research funding from GlaxoSmithKline and Pfizer. Toni K. Choueiri has received research funding from Pfizer and is an adviser for AVEO, Pfizer, Novartis, GlaxoSmithKline, Genentech, Bayer, and Onyx. Daniel Y.C. Heng is an adviser for AVEO, Pfizer, Novartis, and Bayer. Nils Kroeger, Sandy Srinivas, Sumanta K. Pal, Takeshi Yuasa, Neeraj Agarwal, and Min-Han Tan have nothing to disclose. Funding/Support and role of the sponsor: None.

PY - 2014/6

Y1 - 2014/6

N2 - Background A subset of primarily localized renal cell carcinoma (RCC) patients will experience disease recurrence ≤5 yr after initial nephrectomy. Objective To characterize the clinical outcome of patients with late recurrence beyond 5 yr. Design, setting, and participants Patients with metastatic RCC (mRCC) treated with targeted therapy were retrospectively characterized according to time to relapse. Relapse was defined as the diagnosis of recurrent metastatic disease >3 mo after initial curative-intent nephrectomy. Patients with synchronous metastatic disease at presentation were excluded. Patients were classified as early relapsers (ERs) if they recurred within 5 yr; late relapsers (LRs) recurred after 5 yr. Outcome measurements and statistical analysis Demographics were compared with the Student t test, the chi-square test, or the Fisher exact test. The survival time was estimated with the Kaplan-Meier method, and associations with survival outcome were assessed with univariable and multivariable Cox regression analyses. Results and limitations Among 1210 mRCC patients treated with targeted therapy after surgery for localized disease, 897 (74%) relapsed within the first 5 yr and 313 (26%) (range: 5-35 yr) after 5 yr. LRs presented with younger age (p < 0.0001), fewer with sarcomatoid features (p < 0.0001), more clear cell histology (p = 0.001), and lower Fuhrman grade (p < 0.0001). Overall objective response rates to targeted therapy were better in LRs versus ERs (31.8% vs 26.5%; p = 0.004). LRs had significantly longer progression-free survival (10.7 mo vs 8.5 mo; p = 0.005) and overall survival (OS; 34.0 mo vs 27.4 mo; p = 0.004). The study is limited by its retrospective design, noncentralized imaging and pathology review, missing information on metastatectomy, and nonstandardized follow-up protocols. Conclusions A quarter of patients who eventually developed metastatic disease and were treated with targeted therapy relapsed over 5 yr from initial nephrectomy. LRs have more favorable prognostic features and consequently better treatment response and OS.

AB - Background A subset of primarily localized renal cell carcinoma (RCC) patients will experience disease recurrence ≤5 yr after initial nephrectomy. Objective To characterize the clinical outcome of patients with late recurrence beyond 5 yr. Design, setting, and participants Patients with metastatic RCC (mRCC) treated with targeted therapy were retrospectively characterized according to time to relapse. Relapse was defined as the diagnosis of recurrent metastatic disease >3 mo after initial curative-intent nephrectomy. Patients with synchronous metastatic disease at presentation were excluded. Patients were classified as early relapsers (ERs) if they recurred within 5 yr; late relapsers (LRs) recurred after 5 yr. Outcome measurements and statistical analysis Demographics were compared with the Student t test, the chi-square test, or the Fisher exact test. The survival time was estimated with the Kaplan-Meier method, and associations with survival outcome were assessed with univariable and multivariable Cox regression analyses. Results and limitations Among 1210 mRCC patients treated with targeted therapy after surgery for localized disease, 897 (74%) relapsed within the first 5 yr and 313 (26%) (range: 5-35 yr) after 5 yr. LRs presented with younger age (p < 0.0001), fewer with sarcomatoid features (p < 0.0001), more clear cell histology (p = 0.001), and lower Fuhrman grade (p < 0.0001). Overall objective response rates to targeted therapy were better in LRs versus ERs (31.8% vs 26.5%; p = 0.004). LRs had significantly longer progression-free survival (10.7 mo vs 8.5 mo; p = 0.005) and overall survival (OS; 34.0 mo vs 27.4 mo; p = 0.004). The study is limited by its retrospective design, noncentralized imaging and pathology review, missing information on metastatectomy, and nonstandardized follow-up protocols. Conclusions A quarter of patients who eventually developed metastatic disease and were treated with targeted therapy relapsed over 5 yr from initial nephrectomy. LRs have more favorable prognostic features and consequently better treatment response and OS.

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Survival outcome and treatment response of patients with late relapse from renal cell carcinoma in the era of targeted therapy

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