Introduction
Renal cell carcinoma (RCC) is one of the most progressive urological cancers among men and women (1,2), and is considered as one of the most difficult cancers to diagnose and to treat (3). Advanced RCC is highly resistant to radiotherapy and chemotherapy. Approximately 25–30% of RCC patients suffer metastatic or advanced disease, with a 5-year survival rate <10% (4). Prior to recent advancements in understanding of the molecular mechanism of RCC and the development of angiogenesis inhibitors, cytokine-based therapy such as interleukin-2 (IL-2) and interferon (IFN) was the main therapy used to treat RCC (5). However, the therapeutic effect of these treatments is quite limited, as there is only a 4–6% combined response rate for most single agent or combination regimens (6).
Therapeutic options for patients have significantly expanded due to the successful development and adaptation of several targeting agents in the first-line treatment of advanced RCC, including multikinase inhibitors sorafenib (7), sunitinib (8), pazopanib (9) and axitinib (10); the combination of the anti-vascular endothelial growth factor (VEGF) agent bevacizumab with IFN-α (11); and mammalian target of rapamycin (mTOR) inhibitors temsirolimus (12) and everolimus (13). However, considering the poor physical condition, such as cachexia, that is common among patients with advanced RCC (14), selection of treatment should not only consider the therapeutic effect, but also adverse events. In order to make a more rational choice of treatment for individual patients with advanced RCC, it is necessary to identify the level of adverse effects of these options. In this scenario, a meta-analysis of randomized trials was performed to evaluate the therapeutic and adverse effects of the multikinase inhibitors sorafenib, sunitinib, pazopanib and axitinib.
Discussion
This meta-analysis aimed to identify the therapeutic effect and associated adverse events of the currently used multikinase inhibitors sorafenib, sunitinib, pazopanib and axitinib in advanced RCC. The results demonstrate that individual use of sorafenib, sunitinib, pazopanib and axitinib is more effective in terms of PDR and ORR. However, the results also show that multikinase inhibitors are associated with a higher risk of grade 3 or 4 adverse events for hypertension and gastrointestinal effects, including diarrhea, nausea and vomiting. Although much progress has been achieved in understanding the molecular mechanism of advanced RCC and in the development of targeting drugs, the overall efficiency of these therapies is far from satisfactory. Considering the poor physical condition of patients with advanced RCC, the appropriate selection of treatments and the proper management of adverse events are required to improve the quality of life of such patients.
Although the combination of bevacizumab and IFN may provide a higher ORR compared with either agent alone, the higher frequency or grade of adverse events may be unbearable for some patients (23). However, although the individual use of sorafenib, sunitinib or temsirolimus is less toxic, the efficiency of these drugs in improving the ORR is limited (23). In clinical practice, the balance between therapeutic effect and associated adverse events should be carefully evaluated prior to the final selection of a treatment. Previous studies observed that patients suffered hypertension as early as the first day of taking sorafenib (24) and axitinib (25). Rini et al (26) observed that the median time of all-grade hypertension onset was independent of baseline antihypertensive use. However, the onset of grade 3 or 4 hypertension occurred significantly earlier in patients that received antihypertensive medications than in those that did not at baseline. Thus, patients receiving antihypertensive medication might be more biologically susceptible to earlier axitinib-induced hypertension (26). Therefore, it is recommended that clinicians consider collaborating with patients and other practitioners to manage treatment-induced hypertension actively. Prior to treatment, it is necessary for practitioners to assess the blood pressure status, cardiovascular risk factors and previous antihypertensive medication use of the patients. Based on this assessment, patients may be divided into normotensive, uncontrolled hypertensive, sub-optimally medication-controlled hypertensive or medication-controlled hypertensive groups (25). For patients with uncontrolled hypertension, short-acting antihypertensive agents could be provided. Following the initiation of multikinase treatment, short-acting antihypertensive agents may be switched to long-acting agents. For patients with sub-optimally controlled hypertension, treatment-induced hypertension could be controlled through increasing the dose of current medication or adding new medication. Pretreatment evaluation of risk factors of cardiovascular diseases, such as peripheral vascular disease, diabetes mellitus, cardiac conditions and renal disease is essential since patients with these risk factors may require close monitoring and the aggressive management of cardiovascular events during treatment (27). In addition, clinicians should to check whether patients have received hypertension-inducing agents such as hormones or steroids, which may complicate the management of axitinib-induced hypertension (28). It is recommended that during treatment with multikinase inhibitors, blood pressure should be monitored regularly in-clinic and at home. In order to gain a higher level of compliance of the patient to treatment, blood pressure assessment prior to treatment, including an assessment of the likelihood of hypertension developing during therapy and home monitoring could be provided. The clinician could support patients by training them and their family members in the proper use of the blood pressure-monitoring device, calibration of the device and recording and the reporting of measurements.
Gastrointestinal adverse events, including diarrhea, nausea and vomiting were commonly reported for these multikinase inhibitors. Although these events might not lead to treatment discontinuation and can be properly managed by pharmacological intervention and dietary modifications, in elderly patients, these events might lead to serious dehydration if they are not well controlled (29). Previous studies also reported that treatment-related diarrhea can be persistent for the duration of multikinase therapy and mild-to-moderate diarrhea can reduce the mobility and independence of patients, impairing quality of life (30–32). Therefore, it is recommended that clinical guidelines for the management of cancer treatment-related gastrointestinal adverse events should be followed (33). The major limitation of this study is the small number of studies involved. This small selection of studies was not adequate to perform patient subgroup analyses.
In conclusion, multikinase inhibitors can significantly control disease progress and improve the ORR. However, they are also associated with a higher risk of grade 3 and 4 hypertension and gastrointestinal events. Proper management of these events is necessary to improve quality of life.