Prognostic value of performance status in metastatic renal cell carcinoma patients receiving tyrosine kinase inhibitors: a systematic review and meta-analysis

Renal cell carcinoma (RCC) is the most common cancer of kidney in adults [1]. Nearly half of RCC patients eventually progress to metastatic RCC (mRCC), and the 5-year survival rate of these patients is poor [2, 3]. The molecular mechanisms of the pathogenesis have been widely investigated and has promoted the development of targeted agents in the past few decades [4]. Tyrosine kinase inhibitors (TKIs), which target the vascular endothelial growth factor pathway, have been approved for the first-line or later line of treatment for mRCC [5‐7]. The TKIs, such as sorafenib, sunitinib, axitinib and pazopanib, have been consistently demonstrated in clinical trials to prolong both overall survival (OS) and progression-free survival (PFS) in patients with mRCC [6‐8]. However, these targeted agents have provoked marked changes in the management of RCC, and new predictive and prognosis clinical markers are required.

Many previous studies have demonstrated that the prognosis of mRCC patients treated with TKIs varies greatly after treatment [7, 9], so it is important to assess which patients may benefit from TKIs before treatment. Performance status (PS) is used to quantify quickly the general well-being of people with illness and their ability to perform activities of daily living [10]. It is usually a proxy measure estimated by clinician and influences the decision to apply treatment regiments [11‐13]. PS has been identified as an independent prognostic factor in several cancers, such as bladder cancer [12], lung cancer [11] and liver cancer [13]. Previous reports have shown that a poor PS predicts poor survival of patients with metastatic RCC [14‐16]. However, the prognostic value of PS in patients with mRCC treated with TKIs is controversial. Bamias et al. found that PS was an independent prognostic factor (HR: 3.04, 95% CI: 1.46–6.33, p = 0.003) for mRCC patients receiving TKIs [17], and several other studies have drawn similar conclusions [18‐20]. But there were also studies have shown no significant relationship between PS and prognosis [21‐26], such as a retrospective study of 257 patients by Hwang et al. (HR: 1.71, 95% CI: 0.74–3.95, p = 0.21) [26].

Furthermore, the association between PS and survival outcomes in patients with mRCC receiving TKIs has not been previously reviewed. Therefore, we conducted a systematic review and meta-analysis to evaluate the prognostic value of pretreatment PS in mRCC patients receiving TKIs.

A total of 852 articles were identified from electronic databases (PubMed, Embase and the Cochrane Library) and 3 additional studies were identified from reference lists. Sixty duplicate articles were removed. After a careful review of titles and abstracts, 731 articles were excluded for not relevant, other urinary cancer, laboratory studies, reviews, letters and comments. After assessing the full text of the remaining 64 articles, 45 articles were excluded for some specific reasons, including not TKI treatment, not evaluate the association between PS and survival outcome, involving other targeted therapies, not available hazard ratio, duplicate data and not English articles. Finally, 19 retrospective cohort studies [17‐26, 34‐42] were included in the following meta-analysis. Figure 1 shows the full screening procedure.

Since applying TKIs to the management of mRCC patients, the prognosis of these patients has been significantly improved compared to that in the era of cytokine therapy [43, 44]. The introduction of these drugs has induced a dramatic paradigm shift in the treatment of mRCC. These molecular targeted agents need novel factors that precisely reflect susceptibility to TKIs, thereby providing individualized risk-directed treatment for patients with mRCC. To date, several model systems predicting the prognosis of patients with mRCC in the era of immunotherapy have been reported [14, 45, 46]; in particular, the Memorial Sloan-Kettering Cancer Center (MSKCC) scoring system is still applied to patients receiving TKIs era [17]. However, these models were based on traditional markers of risk, rather than molecular characteristics.

This meta-analysis based on currently available clinical evidence adjusted clinical and demographic variables that may have affected survival outcomes. We found that poor PS may significantly predict unfavorable prognostic outcomes in mRCC patients receiving TKIs and may play an important role in the management of mRCC patients. Although the International Metastatic Renal Cell Carcinoma Database Consortium (IMDC) [19] and MSKCC [17] risk models are being used to predict the prognosis of mRCC patients, PS is expected to be a simpler indictor for screening of mRCC patients who received TKIs in clinical practice.

PS was used to quickly quantify the general health status of the patient population and their ability to perform daily activities [11, 47]. It is usually a proxy measure estimated by the clinician or researcher and affects the decision to apply the management plan, especially in terms of conservative and non-conservative care and planning for self-care. PS has been reported to be associated with the survival outcomes of several malignancies, such as bladder cancer [12], hepatocellular carcinoma [13], and non-small-cell lung cancer [11]. PS has been regarded as a key determinant of the malignant tumor patients’ ability to undergo therapy.

Many previous studies have consistently identified that PS was a significant prognostic factor in patients with RCC [14‐16]. In a retrospective study of 670 patients with RCC [14], median survival time was 2.7 , 6.1 , 10.6 and 14.4 months for patients with Karnofsky PS (KPS) of 60, 70, 80 and 90%, respectively (P <  0.0001). As well, another study identified ECOG PS as an independent prognostic factor for survival in a multivariate analysis of 782 patients of mRCC [48]. However, the prognostic value of PS in patients with mRCC treated with TKIs was controversial.

There are some limitations in our meta-analysis. First, all the included studies in this meta-analysis were retrospective, which may lead to selection bias. High-quality prospective researches needed to further investigation in this field. Second, the simple size of partial eligible was relatively small. The large-scale studies are necessary to achieve more credible results in the future. Finally, the potential heterogeneity might still exist. Although heterogeneity was not significantly from the results of meta-analysis and subgroup analysis, but the cut-off values across the included studies were not completely consistent, which might lead to unknown heterogeneity. Therefore, more uniform standards should be established to increase homogeneity between the studies.

To conclude, the present meta-analysis demonstrates that poor PS may significantly predict unfavorable prognostic outcomes in mRCC patients receiving TKIs. Therefore, PS may play an important role in the management of mRCC patients. However, in order to better evaluate the prognostic value of PS in mRCC patients treated with TKIs, additional prospective, large-scale, and homogeneous clinical studies will be needed in the future.