Impact of Bone and Liver Metastases on Patients with Renal Cell Carcinoma Treated with Targeted Therapy

doi:10.1016/j.eururo.2013.08.012

European Urology

Volume 65, Issue 3, March 2014, Pages 577-584

https://doi.org/10.1016/j.eururo.2013.08.012 Get rights and content

Abstract

Background

The skeleton and liver are frequently involved sites of metastasis in patients with metastatic renal cell carcinoma (RCC).

Objective

To analyze outcomes based on the presence of bone metastases (BMs) and/or liver metastases (LMs) in patients with RCC treated with targeted therapy.

Design, setting, and participants

We conducted a review from the International Metastatic Renal Cell Carcinoma Database Consortium (IMDC) of 2027 patients with metastatic RCC.

Outcome measurements and statistical analysis

We analyzed the impact of the site of metastasis on overall survival (OS) and time-to-treatment failure. Statistical analyses were performed using multivariable Cox regression.

Results and limitations

The presence of BMs was 34% overall, and when stratified by IMDC risk groups was 27%, 33%, and 43% in the favorable-, intermediate-, and poor-risk groups, respectively (p < 0.001). The presence of LMs was 19% overall and higher in the poor-risk patients (23%) compared with the favorable- or intermediate-risk groups (17%) (p = 0.003). When patients were classified into four groups based on the presence of BMs and/or LMs, the hazard ratio, adjusted for IMDC risk factors, was 1.4 (95% confidence interval [CI], 1.22–1.62) for BMs, 1.42 (95% CI, 1.17–1.73) for LMs, and 1.82 (95% CI, 1.47–2.26) for both BMs and LMs compared with other metastatic sites (p < 0.0001). The prediction model performance for OS was significantly improved when BMs and LMs were added to the IMDC prognostic model (likelihood ratio test p < 0.0001). Data in this analysis were collected retrospectively.

Conclusions

The presence of BMs and LMs in patients treated with targeted agents has a negative impact on survival. Patients with BMs and/or LMs may benefit from earlier inclusion on clinical trials of novel agents or combination-based therapies.

Introduction

The most common site of metastasis in patients with renal cell carcinoma (RCC) is the lung, affecting 45–50% of patients with metastatic disease [1]. Other frequent sites of involvement include the skeleton and liver, with estimates of involvement of 30% and 20%, respectively [1]. Bone metastases (BMs) from RCC cause significant morbidity and are associated with high rates of skeletal complications. Prior to the era of targeted therapy, the rate of skeletal-related events (SREs), defined as pathologic fracture, bone radiotherapy, bone surgery, spinal cord compression, and in some series hypercalcemia, was 74% to upward of 85% [2].

Recent advances in our understanding of the pathogenesis of RCC have led to a new treatment paradigm for patients with metastatic RCC. Although studies of patients treated in the cytokine era suggest that the presence of BMs and/or liver metastases (LMs) is associated with a poor prognosis, the impact of BMs and/or LMs on the outcomes of patients treated with agents targeting the vascular endothelial growth factor (VEGF) and mammalian target of rapamycin (mTOR) axis is largely unknown. We used the International Metastatic Renal Cell Carcinoma Database Consortium (IMDC) to determine whether baseline BMs and/or LMs are associated with worse overall survival (OS) and time-to-treatment failure (TTF) in patients with metastatic RCC treated with first-line targeted therapy.

Section snippets

Study design

The IMDC is a consecutive patient series from institutions in Canada, Denmark, South Korea, and the United States. We used the IMDC to identify 2370 patients from 20 centers treated for metastatic RCC. The database was locked for the current analysis on October 10, 2012. Patient inclusion criteria comprised a diagnosis of metastatic RCC of any histologic subtype treated with first-line targeted therapy. Patients who received prior immunotherapy were included in the analysis. Patients were

Patient and disease characteristics and clinical outcomes

Table 1 shows patient and disease characteristics at the initiation of targeted therapy. Most patients were men ≥60 yr of age with good performance status and clear cell histology. In total, 97.6% (n = 1978) received first-line VEGF targeted therapy, and 2.4% (n = 49) received first-line mTOR targeted therapy. Most of the patients had a previous nephrectomy, and less than one-third of patients had received previous immunotherapy.

Most patients had more than one site of metastasis. Stratified by the

Discussion

In our study, the presence of BMs and LMs was associated with a clinically significant negative impact on survival. Our series is currently the largest to date, with >2000 patients, evaluating the effect of not only BMs but also LMs on the outcomes of patients with RCC. In addition, in our series, we included RCC patients of all histologic subtypes. Because the treatment paradigm for patients with metastatic RCC is rapidly evolving, prognostic factors need to reflect changes in systemic

Conclusions

The presence of BMs and LMs in patients with metastatic RCC treated with targeted therapy has a negative impact on survival. The site of metastasis may possibly be used for the risk stratification of patients with metastatic RCC. In addition to providing prognostic information, data regarding site of metastasis may have therapeutic implications in guiding clinical decision making.

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The clinical data of consecutive RCC patients with bone-only metastasis at Peking University Cancer Hospital between 2006 and 2018 were retrospectively collected and analyzed.
Fifty-four eligible patients were screened from an RCC database of 1,878 metastatic patients. After a median follow-up of 43.6 m, 61.1% of the patients were presented with progression of prior BM or new BM. The progression-free survival (PFS) and overall survival (OS) was 16.2 m (95%CI: 11.4–21.0) and 65.2 m, respectively. For the 30 patients with oligo-metastasis ( $\leq$ 3 loci) and 24 ones with multiple-metastasis (>3 loci), the median OS was not reached and 42.0m (95%CI: 12.7–71.2) with statistical difference (P < 0.001). In the oligo-metastasis group, the median PFS of the 15 patients treated with local therapy and of the 13 patients treated with systemic therapy was 14.2 m (95%CI: 5.3–23.3) and 18.0 m (95%CI:15.4–20.6), respectively. In the multiple-metastasis group, the median PFS and OS of the 18 patients treated with systemic therapy was 16.6 m (95%CI: 7.5–25.7) and 63.9 m (95%CI: 21.8–106.0), respectively. Univariate analysis and multivariate analysis showed that the number of metastatic sites (oligo/multiple) and International Metastatic Renal Cell Carcinoma Database Consortium (IMDC) score, RCC pathological subtype were significantly associated with prognosis (P < 0.05).
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Although in metastatic renal cell carcinoma (mRCC) patients with intermediate and poor risk the benefit of combination strategies versus tyrosine kinase inhibitor (TKI) has been ascertained, in those with favorable risk data are ambiguous. Herein, we investigated the impact of number and type of metastatic site in patients with favorable risk to contribute to the best therapeutic choice.
Multicenter data regarding patients with favorable risk mRCC carcinoma receiving first-line TKIs, sunitinib or pazopanib, were retrospectively collected. We divided our population into 2 groups based on the number of metastatic sites and analyzed its impact on tumor response and efficacy outcome. The Kaplan-Meier method was used to estimate efficacy outcomes and the log-rank test to examine differences between subgroups.
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The prognostic significance of number and location of organ-specific metastatic sites in treated metastatic clear cell renal carcinoma (ccmRCC) patients is object of debate. The current study aimed to test the association between number and location of organ-specific metastatic sites and overall survival (OS) in ccmRCC.
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Platinum Priority – Kidney CancerEditorial by Guru Sonpavde, Sunil Sudarshan and Bernard Escudier on pp. 585–586 of this issueImpact of Bone and Liver Metastases on Patients with Renal Cell Carcinoma Treated with Targeted Therapy

Abstract

Background

Objective

Design, setting, and participants

Outcome measurements and statistical analysis

Results and limitations

Conclusions

Introduction

Section snippets

Study design

Patient and disease characteristics and clinical outcomes

Discussion

Conclusions

Ann Oncol

Bone

Ann Oncol

Ann Oncol

Eur J Cancer

Ann Oncol

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

Testing for improvement in prediction model performance

Stat Med

Impact of immune parameters on long-term survival in metastatic renal cell carcinoma

J Clin Oncol

Validation and extension of the Memorial Sloan-Kettering prognostic factors model for survival in patients with previously untreated metastatic renal cell carcinoma

J Clin Oncol

Platinum Priority – Kidney Cancer
Editorial by Guru Sonpavde, Sunil Sudarshan and Bernard Escudier on pp. 585–586 of this issue
Impact of Bone and Liver Metastases on Patients with Renal Cell Carcinoma Treated with Targeted Therapy