Given that nearly 25% of all patients with kidney cancer present with locally advanced or metastatic renal cell carcinoma (RCC), kidney cancer is a malignancy with a poor prognosis (1). Conventional therapies, such as chemotherapy and radiation therapy are not effective and only 10 to 20% of patients benefit from immunotherapy (2–4). Recently enhanced understanding of the etiology of advanced RCC has led to the development of angiogenesis inhibitor agents.

In randomized clinical trials (RCTs), first generation angiogenesis inhibitors sunitinib, sorafenib and bevacizumab plus interferon α, have demonstrated efficacy in prolonging progression-free survival and/or overall survival as first-line treatment (4–6). The efficacy of sunitinib and sorafenib has also been established in expanded access programs (EAP) (7,8). Due to their strong efficacy profiles, these agents have become the new standard of treatment for advanced RCC. All these drugs were approved by corresponding regulatory agencies for use in the US, Europe and Asia (9–13).

However, RCTs and EAPs have also demonstrated that these angiogenesis inhibitors are associated with high rates of toxicity and treatment modifications, including discontinuations and dose changes. Since clinical trials may not be representative of real-life clinical practice due to treatment selection criteria, observational studies are necessary to understand the effects of treatment in the wider population of patients who actually receive these therapies. Small observational studies conducted in real-world clinical practice settings in US, Korea, Japan and Europe have provided further evidence of high toxicity profiles associated with these agents (14–21). Data from these varied care settings highlight that adverse events (AEs) in advanced RCC patients receiving angiogenesis therapies are common and often lead to treatment modifications, including treatment discontinuation.

As the use of angiogenesis inhibitors rises over time and treatment paradigms continue to evolve, there is a critical need to gain a thorough understanding of toxicity profiles and treatment patterns of these agents across various real-world clinical settings. Therefore, the goal of this study was to examine the toxicity profiles of sunitinib, sorafenib, and bevacizumab in advanced RCC among patients treated in US, Europe and Asia, and describe how clinicians in these settings modify treatment according to patient experiences.

Findings from the current study with data from 883 patients contribute to the growing body of knowledge on the use of sunitinib, sorafenib and bevacizumab as first-line agents among patients with advanced RCC treated in real-world clinical practice across different geographical regions. Tolerability and management of side-effects for patients receiving sunitinib, sorafenib and bevacizumab as first-line anti-angiogenesis treatment for advanced RCC are significant issues for patients and the physicians who care for them.

There were variations in treatment and outcomes across global regions. In the US and Europe, patients receiving sunitinib were almost twice as likely as those in Asia to initiate therapy at 50 mg QD 4/2. This observation raises the issue relative to the use of fixed doses of suntinib (and also of all molecularly targeted agents), irrespective of parameters like gender and body weight/body surface area. Indeed, a population pharmacokinetic analysis identified low body weight (and female gender) as covariates that significantly increase exposure to sunitinib, potentially leading to increased toxicity (23). Moreover, the most commonly experienced AEs also varied across region. In the US and Europe, fatigue was the most common AE among patients receiving sunitinib, sorafenib and bevacizumab while hand-foot syndrome was the most common AE in Asian patients receiving sunitinib or sorafenib. Notably, the AEs most commonly leading to treatment discontinuation also varied.

Despite these differences, there were some universal findings across settings. Notably, the median treatment duration was generally shorter in this observational study compared with that reported in RCTs and EAPs. The median treatment duration for sunitinib was 11 and 16.6 months in the RCT and EAP (4,7), respectively, whereas the median ranged from 6.1 to 10.7 months across regions in this study. Similarly, the median treatment duration for sorafenib was 12 months in the EAP (8) whereas it ranged from 5.1 to 8.5 months across regions in the current analysis. For bevacizumab the median treatment duration was 9.7 months in one RCT (24) and 8.2 months in another RCT (25) whereas it ranged from 7.5 to 9.8 months across regions in this study.

Treatment discontinuation was high, reaching 63.1% among sunitinib patients in the US, 90.0% among sorafenib patients in Europe, and 81.8% of bevacizumab patients in US. For patients who discontinued sunitinib treatment due to AEs the average number of AEs per discontinuation was 2.3–2.5 across regions; for sorafenib it was 1.9–3.1. This illustrates that in real-world practice physicians manage multiple AEs per patient and may discontinue or modify treatment based on the observed effects of these AEs. The proportion of patients with any type of treatment modification due to an AE was also consistently high across all regions, reaching 59.2% among sunitinib patients in Asia, 64.1% among sorafenib patients in US and 53.3% of bevacizumab patients in Europe.

This study builds upon prior evidence from RCTs and EAPs on the toxicity and treatment patterns of angiogenesis inhibitors. Similar to results in this global chart review study, treatment discontinuation was high in RCTs and EAPs. In the RCT comparing sunitinib to interferon α, 86% of patients experienced a treatment discontinuation (versus 62.4 to 63.1% in the current study) (4). In the EAP for sorafenib, 100% of patients experienced a treatment discontinuation (versus 68.8 to 90.0% in the current study) (8). In the RCT comparing bevacizumab plus interferon to placebo, 72% of patients experienced a treatment discontinuation (versus 66.7 to 81.8% in the current study) (24). In RCTs, diarrhea was the most commonly reported AE for both sunitinib and sorafenib (versus fatigue in the US and Europe, and hand-foot syndrome in Asia in the current study) and anorexia was the most commonly reported AE for bevacizumab (versus fatigue in the current study for US and Europe) (4,8,24). In EAPs for sunitinib and sorafenib, the most commonly reported AEs were diarrhea and hand-foot syndrome.

Differences with RCT may arise due to differences in the underlying study populations as well as how data are collected. For example, the proportion of patients with brain metastasis in the current study were 7.0, 7.2 and 11.1%, for sunitinib, sorafenib and bevacizumab, respectively, while these patients were excluded in RCTs. Besides, RCTs have well-defined operational definitions for AE identification and gradation, as well as a rigorous protocol to capture them whereas in a retrospective setting such as in the current study, AEs are captured based on the treating physicians' reports and judgments. Sometimes physicians may record only those AEs that lead to a treatment modification or if the AEs are severe enough to warrant specific treatment; therefore, under-reporting of AEs in this study may have occurred.

Findings from this study were generally consistent with those from other observational studies (14–20). In the Korean study by Hong et al (14), 76% of sunitinib patients had a dose interruption or dose reduction due to AEs, and 11% overall discontinued due to toxicity. A high proportion of patients in that study (>75%) experienced fatigue, anorexia and hand-foot syndrome. In the Korean study by Hwang et al (15), 29% of sunitinib patients experienced a dose reduction. In the UK study by Ansari et al (16), 15% of sunitinib patients experienced a dose discontinuation in their first cycle of treatment, and 75% experienced at least one dose reduction. Notably, the number of patients in the current study was several fold higher than the aforementioned observational studies.

Some disparities in study results between this study and other observational studies reported above may have occurred due to differences in treatment durations, frequency of patient visits where AEs are reported, incomplete or inadequate recording of AEs, and differences in practice patterns relative to management of AEs across countries. Differences in drug approval dates, affecting drug availability, could have affected practice patterns as well. Differences in healthcare should also be kept in mind while making comparisons across studies.

There are some limitations associated with this study. Since data collection for this study preceded marketing authorization for pazopanib in Europe, this study does not include information on patients receiving pazopanib as first-line treatment. Further, due to the small sample sizes in certain groups for some regions, especially bevacizumab in all regions and sorafenib in Asia, the findings reported are descriptive in nature.

This multi-country study provides evidence that AEs are common in patients with advanced RCC treated with angiogenesis inhibitors, and that these AEs often lead to treatment modifications in the real-world clinical setting. This real-world practice study suggests that management of toxicities associated with anti-angiogenic agents for the treatment of advanced RCC presents significant issues for treating physicians and patients. The findings from this study further underscore the continued need for novel tolerable treatment options for advanced RCC. Additionally, the results of this study show the potential benefits of use of observational studies to further understand real-world treatment patterns and outcomes, beyond information that may be available from other data sources.