Elsevier

European Urology

Volume 65, Issue 6, June 2014, Pages 1086-1092
European Urology

Platinum Priority – Kidney Cancer
Editorial by Matthew D. Galsky on pp. 1093–1094 of this issue
Survival Outcome and Treatment Response of Patients with Late Relapse from Renal Cell Carcinoma in the Era of Targeted Therapy

https://doi.org/10.1016/j.eururo.2013.07.031Get rights and content

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.

Introduction

More than two-thirds of renal cell carcinoma (RCC) patients are diagnosed with localized disease [1]. However, up to 30% of these patients will ultimately develop metastatic RCC (mRCC) [2], [3]. Using the criteria of adjuvant clinical trials in RCC, a recent retrospective study of primary localized RCC patients who were at high risk for disease recurrence found the median time to disease recurrence between 1.0 and 1.3 yr [3]. Consequently, it is common clinical practice to stop follow-up visits for patients at low risk and extend the periods for follow-up visits for patients with intermediate and high risk after a disease-free interval of approximately 5 yr [2], [4]. However, disease relapse can virtually take place at any time even after periods >5 yr.

Disease recurrence after a disease-free interval of numerous years is commonly characterized by uncertainty for both physicians and patients. Although risk features generally associated with the risk of disease recurrence and late recurrence in particular have been intensively studied [2], [3], [5], there is currently no robust characterization of treatment response and survival outcome after late recurrence. The International Metastatic Renal Cell Carcinoma Database Consortium (IMDC) risk model provides information to stratify patients for clinical trials and for patient counseling to prognosticate overall survival (OS) [6], [7]. Nonetheless, risk models like the IMDC are not sufficient to take every circumstance into consideration that may be of additional importance for patients’ individual outcome.

The aim of the current study was to characterize the treatment response and survival of patients who were diagnosed with metastatic disease from RCC after a disease-free interval >5 yr. The current study did not aim to develop a new prognostication tool. It was the ultimate goal to provide clinical information on this unique subset of mRCC patients. The current study is a project of the IMDC, a collaboration of 20 academic centers.

Section snippets

Study populations

The IMDC database includes centers from North America (Canada, United States), Europe (Denmark, Greece), and Asia (Singapore, Japan, South Korea). Data were collected from August 15, 2008, until February 1, 2013. At the time of analysis, the database contained data on 2754 patients who had received first-line targeted therapy between 2003 and 2013. Relapse from RCC was defined as a diagnosis of recurrent metastatic disease >3 mo after nephrectomy for localized disease based on criteria that

Patient and tumor characteristics

The study cohort was composed of 1210 patients who developed metastatic disease after a disease-free interval > 3 mo. Disease relapse was observed in 897 patients (74%) before 5 yr and in 315 patients (26%) after 5 yr. Overall, 692 patients (56.9%) had died after a median follow-up of 18.5 mo (25th–75th percentile: 9.5–33.1 mo); 1010 (84.0%) had discontinued their initial targeted therapy. The median time to recurrence was 15.3 mo (25th–75th percentile: 7.4–31.9) in ERs and 102.1 mo (25th–75th

Discussion

The current study shows that a quarter of patients treated with targeted therapies and metachronous RCC metastases have disease recurrence after a period >5 yr. The proportion of patients with late recurrence is substantial among the patients treated with targeted therapies, and consequently, physicians should be informed about treatment response and survival outcome of these patients. The current study shows a better response to first-line targeted therapies, a longer PFS, and better OS in LRs

Conclusions

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.

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