Hypertension as a prognostic factor in metastatic renal cell carcinoma treated with tyrosine kinase inhibitors: a systematic review and meta-analysis

Renal cell carcinoma (RCC) is the 9th most common cancer in men and 14th most common cancer in women worldwide [1]. Its incidence (3–6/100,000) and mortality (1.2–2.5/100,000) are increasing rapidly, which has a great negative effect on our society [2, 3]. In addition, about 25–30% of patients have evidence of metastasis upon its diagnosis [4]. Now, vascular endothelial growth factor receptor tyrosine kinase inhibitors (TKIs), like sunitinib, pazopanib, sorafenib or axitinib, are the favored medicine for metastatic RCC (mRCC). Several clinical trials showed that response to TKIs was uncertain (objective response rate was 31–67.4%) [5‐8], which indicated the existence of wide inter-individual variation and the lack of reliable factors for predicting the outcomes of mRCC patients. Therefore, a big challenge faced by urologists is how to predict the prognosis of mRCC patients receiving TKIs more precisely.

The occurrence of several adverse events (AEs) during TKIs therapy, such as hypertension, hand-foot syndrome or hypothyroidism, were shown to be correlated with the longer median progression-free survival (PFS) and overall survival (OS) of mRCC patients [9]. Hypertension during TKIs therapy was very common, with incidence ranging from 22 to 81% [9, 10]. Recently, a study found that RCC patients with longer median PFS (>5.3 months) demonstrated a significantly higher incidence of high-grade hypertension (a treatment-associated adverse event) than those with shorter PFS [11]. It indicated that TKIs-induced hypertension may be associated with improved prognosis [12, 13]. However, others reported insignificant results [14, 15]. In 2014, a systematic review and meta-analysis reported that the occurrence of hypertension due to sorafenib therapy may be associated with improved prognosis of patients with cancer. However, this study did not specifically focus on the mRCC patients. Thus, the association between TKIs-induced hypertension and prognosis of mRCC is still controversial. In the present study, we attempt to conduct a systematic review and meta-analysis to assess the predictive value of the TKIs-induced hypertension for PFS and OS in patients with mRCC during TKIs therapy.

This meta-analysis and systematic review investigated whether TKIs-induced hypertension can predict the prognosis of patients suffering from mRCC. AEs, like hypothyroidism, though shown to be a good predictor of PFS or OS, was usually diagnosed later than hypertension [17, 36]. Thus, it would be better if we can predict the prognosis of mRCC patients based on the TKIs-induced hypertension. It will help urologists decide whether patients should continue this TKIs therapy or not, which may help patients get more suitable treatments as soon as possible. Based on 22 original studies, our results showed that the occurrence of hypertension during treatment may predict better survival for mRCC, with longer PFS and OS. Additionally, when it comes to different TKIs, sunitinib or pazopanib therapy were both associated with longer PFS and OS.

The mechanisms of hypertension induced by TKIs are complicated. First, activation of VEGF receptor-2 via phosphoinositide 3-kinase and its downstream serine protein kinase Akt can stimulate endothelium-derived nitric oxide synthase, leading to the production of nitric oxide (NO). Therefore, the inhibition of VEGF receptor might lead to a decrease in NO bioavailability, followed by vasoconstriction and increased blood pressure (BP) [17, 37‐39]. Second, plasma vasoconstrictor endothelin-1, a vasoconstrictor produced by the endothelium, also increased in patients or rats receiving sunitinib [40‐42]. Third, NO is also involved in the control of renal and glomerular hemodynamics, tubuloglomerular feedback response, release of renin and sympathetic transmitters, tubular ion transport. As a result, reduction of NO can also result in renal water and sodium retention, leading to hypertension [43]. TKIs may also directly cause renal injury and proteinuria, which could play a role in long-lasting hypertension [44]. Finally, hypertension may also result from structural or functional vascular rarefaction [45‐47]. VEGF is also crucial in the maintenance of endothelial viability [48, 49]. Therefore, the inhibition of VEGF and PDGF receptors can induce endothelial cell apoptosis, reduction in capillary density, vascular diameter and microvascular flow, and thus increase the blood pressure.

The reason why TKIs-induced hypertension might be a prognostic factor in patients with mRCC is still not quite clear. The anticarcinogenic effect of TKIs relies on the block of VEGF receptor, which may also lead to hypertension as above mentioned. Thus, when TKIs inhibit the progress of mRCC and prolong the PFS or OS of patients, hypertension may occur at the same time. It may be the reason why the rise of blood pressure could indicate a better prognosis in mRCC patients.

Of note, the intention of therapy is not to drive all patients into a hypertensive state. On the contrary, when hypertension occurs, patients should receive antihypertensive therapy as soon as possible. Additionally, despite the PFS and OS of mRCC patients have prolonged because of TKIs therapy, few comparable benefits have been described in terms of the quality of life [50, 51]. An innovative study that compared sunitinib with pazopanib to evaluate patient preferences suggested that the toxicity profile may have an impact on quality of life and the choice of treatment when two comparable options are on offer [52]. In addition, sunitinib-induced hypertension may be associated with cardiotoxicity or reversible posterior leukoencephalopathy [53‐55]. Thus, the panel of National Cancer Institute of the USA had several recommendations for mRCC patients received TKIs [56]. First, urologists should recognize the preexisting hypertension prior to therapy or actively monitor BP throughout treatment. Early use of antihypertensive medication is necessary when high blood pressure occurs, and it is critical for maintaining dose intensity and improving a patient’s quality of life simultaneously [56]. If possible, the goal of management is to reduce BP below 140/90 mmHg. It was also suggested that there was no need to reduce the dose of antihypertensive medication because it did not compromise efficacy of TKIs [57]. Some evidence indicated that using Angiotensin receptor blockers (ARBs) or angiotensin-I-converting enzyme inhibitors may even protect against cancer [58‐60]. ARBs were shown to induce apoptosis and inhibit the proliferation of RCC cells in vitro [28]. Thus, some randomized prospective studies could be carried out to see if it is better to use more than one drugs with different antihypertensive mechanisms, which may improve the prognosis [12]. Second, doctors should assess the risk of potential cardiovascular complications.

Several underlying limitations of the study should be presented. First, most eligible studies were retrospective, though with high NOS scores. Second, the reciprocal correlation between the hypertension and other AEs should be noted. Patients with more than one adverse event of any grade had longer PFS and OS [61]. Thus, further studies are needed to analyze the relationship between several adverse events and mRCC. Third, obvious inter-study heterogeneity was observed in this meta analysis, which may be due to different therapies mRCC patients had received before, such as cytokine immunotherapy. In addition, a publication bias was detected in this study. The potential reason may be that studies with non-significant results were not published. High heterogeneity and publication bias weakened the quality of evidence, which may be improved by more randomized prospective trials.

However, our analysis also has some advantages. First, we conducted this review with enough data available for extraction by a comprehensive and robust search strategy. Second, we applied a rigorous inclusion/exclusion criterion. Additionally, most of the studies operated multivariable analysis, which could eliminate the co-factors affecting the PFS and OS of mRCC patients.

In summary, our analysis of currently available clinical evidence suggests that TKIs-induced hypertension may predict longer PFS and OS in patients with mRCC during TKIs therapy, especially using sunitinib or pazopanib.