INTRODUCTION
Metastatic renal cell carcinoma (mRCC) accounts for approximately 20%-30% of all kidney cancer cases; it has limited treatment options and is associated with a poor prognosis [1]. Surgical metastasectomy (i.e., the removal of metastatic lesions) has been considered a treatment option for carefully selected patients with limited metastases, aiming to prolong survival and improve the quality of life [2]. However, mRCC is characterized by a high rate of recurrence and metastasis, even after surgical intervention [3].
Tyrosine kinase inhibitors (TKIs) have transformed the treatment landscape for advanced RCC, demonstrating significant efficacy as both first-line and subsequent therapies [4]. Consequently, the use of TKIs following metastasectomy as an adjuvant therapy has been explored as a possible way to improve outcomes in patients with mRCC [5]. However, the optimal timing, duration, and patient selection for adjuvant TKI therapy after metastasectomy remain debatable.
Several clinical studies have investigated the role of TKIs after metastasectomy in mRCC patients, but the results are unclear. This systematic review and meta-analysis aimed to systematically evaluate the available evidence and quantify the impact of TKIs on relapse-free/disease-free survival (RFS/DFS), overall survival (OS), and adverse events of TKIs in mRCC patients.
MATERIALS AND METHODS
This systematic review and meta-analysis adhered to the Preferred Reporting Items for Systematic Review and Meta-Analysis (PRISMA) guidelines [6].
1. Literature Search
A comprehensive literature search was conducted using electronic databases, including MEDLINE (Ovid), Embase, Scopus, Web of Science, Cochrane Central Library, KoreaMed, and KMbase, to analyze relevant studies published up to October 6, 2021. The search strategy included keywords related to mRCC, metastasectomy, and TKIs (Supplementary Material). Clinical trial registries were also searched, including the United States National Institutes of Health Ongoing Trials Register Clinical Trials and the World Health Organization International Clinical Trials Registry Platform.
2. Study Selection and Outcomes
Two researchers (ECH and HMG) independently reviewed all studies that appeared to fit the inclusion criteria. All authors were involved in the final decision regarding the inclusion or exclusion of each study. Studies were considered eligible if they met the following criteria: (1) evaluated the use of TKIs after metastasectomy in patients with mRCC; (2) reported survival outcomes (OS and/or RFS/DFS); and (3) were randomized clinical trials (RCTs) published as original articles, abstracts, or brief communications. Prospective or retrospective cohort studies, case reports, and review articles were excluded. If patient data were reported more than once by the same institution, the most informative and recent article was included in the analysis. RFS/DFS was defined as the interval from metastasectomy date until the detection of tumor recurrence. OS extended from the metastasectomy date until death from any cause. Adverse events during TKI therapy were recorded.
3. Data Extraction and Risk of Bias Assessment
For studies that fulfilled the inclusion criteria, 2 review authors (ECH and HMG) independently extracted the following information: (1) study characteristics, including the names of the authors, study region, and sample size; (2) treatment regimens, including TKI agents and dosages; and (3) survival data, including OS and RFS/DFS. The risk of bias for RCTs was assessed using the Cochrane Risk of bias tool [7]. When the 2 authors disagreed, a final consensus was decided on by a third author (JHJ).
4. Statistical Analysis
Using a random-effects model, pooled hazard ratios (HRs), relative risk (RR), and 95% confidence intervals (CIs) were calculated for RFS/PFS, OS, and adverse events. The HRs, RR, and 95% CIs were extracted directly from the articles. Heterogeneity among the studies was evaluated using the Cochran chi-square test and the Higgins I2 statistic. A p-value less than 0.10 was considered statistically significant for the Cochran chi-square test, and an I2 greater than 50% indicated substantial heterogeneity among the studies. All statistical tests were 2-sided, and a p-value less than 0.05 indicated statistical significance. A meta-regression or subgroup analysis was not conducted and publication bias was not assessed since only 2 studies were available. All statistical tests were performed using Review Manager 5.4.1 software (Cochrane Collaboration, Copenhagen, Denmark).
5. Summary of Findings
The certainty of evidence (CoE) was rated on a per-outcome basis using the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) framework, which considers 5 criteria related to internal validity (risk of bias, inconsistency, imprecision, and publication bias) and external validity (generalizability of the results) [8]. For each comparison, 2 review authors (ECH and HMG) independently rated the CoE for each outcome as “high,” “moderate,” “low,” or “very low” using the GRADEpro software, and summary of findings tables were constructed. Discrepancies were resolved by consensus. For each comparison, these tables provided key information about the best estimate of relative and absolute effects for each outcome [9]. The GRADE guidance was used to describe the CoE and magnitude of the effect size [10].
RESULTS
1. Study Identification and Selection
The initial literature search found 2,117 potentially relevant studies. The systematic review process is shown in the PRISMA flowchart (Fig. 1). Seventeen studies did not meet the inclusion criteria or were irrelevant to the review question. Ultimately, 2 studies met the inclusion criteria and were included in the meta-analysis, comprising 197 RCC patients [11,12].
2. Study Characteristics
All randomized patients in the included studies underwent metastasectomy, with or without adjuvant therapy. The studies were performed in the United States [11] and Italy [12]. One study compared pazopanib after metastasectomy to no additional treatment after metastasectomy [11], and the other study compared sorafenib after metastasectomy with metastasectomy only [12]. In the former study, reported as an abstract, the demographic characteristics of the patients were not ascertainable [11]. In the latter study, there was a single site of metastasis in 81% (n=26) of the patients in the sorafenib arm and 80% (n=29) in the observation arm. The lung was the most common metastatic site (27%, n=15), followed by the adrenal gland (22%, n=12) in both arms. In patients with multiple metastatic sites, the lung with other sites were the most common sites, and all included participants had no residual lesions following metastasectomy [12]. Data on OS and RFS/DFS were available in the 2 studies [11,12], but adverse events were only available in 1 study [12]. Table 1 provides additional details of the included studies [11,12].
3. Risk of Bias of the Included Studies
One RCT was only an abstract; therefore, all domains were rated as having an unclear risk of bias [11]. The study by Mennitto et al. [12] had a high risk of performance bias and an unclear risk of detection bias since this study was openlabel. The risk of bias summary of the included studies is summarized in Fig. 2.
DISCUSSION
This meta-analysis provides evidence against the use of TKIs as an adjuvant therapy after metastasectomy in patients with mRCC. These findings show no significant improvement in RFS/DFS with the addition of TKIs to surgery. To some extent, these results align with previous studies demonstrating the efficacy of upfront cytonephrectomy in selected patients with advanced mRCC [13].
Like other cancers, RCC is a heterogeneous disease with various histopathological subtypes, molecular phenotypes, and clinical features. Tumor biology determines the response to targeted therapies (TTs), and a remission period after the beginning of a TT is often followed by disease progression as tumors adapt and utilize alternative molecular pathways. This clinical pattern of tumor behavior may be explained by the significant genetic heterogeneity that exists between regions of the same primary tumor or between the primary tumor and metastatic lesion [14]. Alterations in the mammalian target of rapamycin pathway (SETD2, PTEN, and KDM5C) have been identified in different metastatic lesions within the same patient. In addition, Callea et al. [15] showed discordance in programmed cell death protein 1 expression between primary clear cell RCCs and metastatic sites in approximately 20% of patients. Various characteristics of the tumor phenotype and microenvironment play an important role in the progression and development of metastasis. In RCC, tumor progression and metastasis have been linked to the upregulation of VEGRF, MET, and AXL [14]. Therefore, developing a precision oncological approach deriving from molecular profiling of an individual’s tumor may allow for personalized therapeutic targets. This approach may also identify patients more likely to benefit from metastasectomy.
TKIs targeting angiogenesis through the inhibition of vascular endothelial growth factor receptor (VEGFR) were associated with substantial response rates and improved survival, thus transforming the prognosis of mRCC [16]. However, most patients eventually developed drug resistance and disease progression while on therapy, including in the adjuvant setting after nephrectomy [17-19]. The biological rationale related to the failure of adjuvant TKI treatment remains unclear. It is possible that the differential TKI inhibitor activity of these drugs, as well as discrepancies in trial inclusion criteria, might have influenced the conflicting results observed in the S-TRAC [20] and ASSURE trials [21].
In the light of the failure of the ASSURE trial, we could speculate on the possible mechanisms of action of sunitinib or sorafenib in the biological scenario of micrometastatic residual disease; hypothetical possibilities could include a limited weight of angiogenesis-driven tumor growth, decreasing the sensitivity to VEGF/VEGFR inhibition, or a limited or even bad impact on immune response of sunitinib or sorafenib [12,22,23]. However, further studies are needed to clarify the biological pathways underlying these results.
The European Association of Urology (EAU) guidelines on managing mRCC strongly recommend not offering TKI treatment to mRCC patients with no evidence of disease (NED) after metastasectomy [24]. This recommendation is driven by the same trial results [11,12] that we meta-analyzed. Based on the recommendation of the EAU guidelines and the results of our meta-analysis, we conclude that TKI therapy provides no survival benefit to mRCC patients with NED after metastasectomy.
Recently, immune checkpoint inhibitors (ICIs), which target tumor or immune cell surface receptors triggering immune tolerance, have been shown to be effective in both pretreated and treatment-naïve patients with mRCC [19]. The randomized, phase 3 KEYNOTE-564 study was designed to investigate adjuvant pembrolizumab monotherapy (novel ICI) versus placebo after nephrectomy for participants with high-risk localized RCC or complete metastasectomy for mRCC patients [25]. In an updated analysis after 30 months of follow-up, subgroup analyses showed the benefit of adjuvant pembrolizumab irrespective of the disease risk category, in particular, metastatic patients after metastasectomy (DFS: HR, 0.28; 95% CI, 0.12-0.66). However, only 6% of patients were included in the experimental and placebo arm, and the results should be interpreted cautiously [26]. Another adjuvant ICI study with the PD-L1 inhibitor atezolizumab (IMmotion010) also included a complete metastasectomy subgroup, but showed no DFS advantage [27], contradicting the KEYNOTE-564 study. Patients who have undergone a successful nephrectomy or complete metastasectomy are considered to be disease-free but remain at a high risk of recurrence or mortality within 5 years after surgery in the absence of suitable adjuvant options [26,27]. Therefore, an optimal biomarker study to find suitable patients who respond to adjuvant therapy is needed.
This study has several limitations. First, the enrolled studies and sample sizes are too small to draw definitive conclusions. Second, the follow-up durations varied, and the TKIs differed (pazopanib and sorafenib) among the studies. Despite these limitations, to our knowledge, this is the first systematic review conducted with a rigorous methodology using the GRADE approach.
CONCLUSIONS
TKIs following metastasectomy did not improve RFS/DFS, but slightly improved OS. Furthermore, TKIs following metastasectomy increased adverse events compared with surgery only. The CoE ranged from moderate (signaling confidence that the reported effect size is likely close to the true effect) to low (indicating that the true effect may differ substantially from the estimated effect). The findings of this study should help to inform future guidelines and clinical decision-making at the point of care.
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