Among all urological malignant tumors, renal cell carcinoma (RCC) is the third most common, after prostate cancer and urothelial cancer (1). As a serious and potentially lethal disease, it presents a challenge in multidisciplinary treatment. Approximately 30% of patients with clear cell RCC are initially diagnosed in the metastatic stage of disease, and 1/3 of patients will relapse with metastases up to 3 years after being surgically treated for initially localized clear cell RCC (2). Systemic targeted therapy and immunotherapy are the mainstays of treatment for metastatic clear cell RCC (mRCC). Owing to emerging evidence from clinical trials demonstrating improved overall survival with both dual immunotherapy and a combination of immunotherapy with targeted therapy compared to single-agent Tyrosine kinase inhibitor (TKI) therapy, international treatment guidelines and recommendations for first-line treatment of mRCC have been dramatically changed in recent years (3, 4). Moreover, real world data published so far on this topic appear to be similar to results found in recently reported clinical trials (5). Second-line therapy is a necessary part of treatment and options are based on the treatment received in the first-line setting. However, following treatment recommendations for mRCC becomes a challenge when access to new drugs is limited. In Serbia, sunitinib and pazopanib are the only available first-line targeted therapies. The second-line treatment for mRCC has never been and is still not available. Limited evidence exists on treatment outcomes of first-line targeted therapy when access to second-line treatment for mRCC is not available. Other studies which explored treatment outcomes of first-line targeted therapy focused more on choosing the appropriate options in second-line treatment rather than on maintaining first-line treatment for as long as possible.

This study is the first retrospective observational study conducted in Serbia with the aim of describing treatment characteristics and survival outcomes in patients with mRCC who received first-line sunitinib or pazopanib in a real-world setting when access to second-line treatment is not available.

For the most part, when access to a subsequent line of treatment for treating patients with clear cell mRCC is still lacking, clinicians in Serbia are challenged with how to maximize clinical effectiveness and how to maintain first-line TKI treatment for as long as possible.

In this observational study, we analyzed data collected retrospectively from the medical records of 759 patients with clear cell mRCC who received sunitinib or pazopanib in first-line treatment. Our goal was to present the characteristics and survival outcomes of treatment in everyday clinical practice when second-line therapy is not available.

The general characteristics of our patients are in accordance with published data from the literature (6–9). At the time of initial diagnosis, around 30% of patients in our study population had metastatic RCC, which is in line with previously reported data (2). The role of cytoreductive nephrectomy and metastasectomy in patients with mRCC has been controversial to date. According to data published so far from two randomized and a number of retrospective studies, the use of surgical treatment before and/or during systemic therapy in patients with mRCC should be carefully considered in accordance with patient characteristics and disease (10). Therefore, it is not surprising that in 79% of our patients primarily diagnosed with mRCC, cytoreductive nephrectomy was performed before the start of targeted therapy. However, even with the goal of maintaining first-line TKI as long as possible, the addition of metastasectomy and stereotactic radiosurgery was less used before and/or during systemic therapy in our patient population, mainly due to a lack of evidence-based data. It is known that in clinical practice, optimizing the dosing regimen provides an improvement in the efficacy and safety of the therapy. Keeping in mind that first-line TKI is the only available treatment for patients with mRCC in Serbia, it was decided to avoid unnecessary treatment discontinuation due to adverse events. All patients in our study started treatment with the standard dose of sunitinib or pazopanib, which differs from the reported 75–87% in observational studies (11–19). In our cohort, 23% of patients started with a 2/1 sunitinib schedule, and 30% of patients who started with a 4/2 regimen were switched to a 2/1 dosing schedule. Only 13% of patients in both treatment groups had a dose reduction during treatment, which is significantly less compared to data reported in the COMPARZ study (pazopanib 44% and sunitinib 51%) (8), but is also less in comparison with studies from everyday practice (21–67%) (11–19). Findings published so far have shown that sunitinib was better tolerated in patients who received a 2/1 regimen compared with those on a standard 4/2 regimen (20), with similar treatment outcomes (21).

During the treatment, grade 3 and 4 AEs occurred in 28% of patients in our study, which is lower compared to data from the literature. To date, a very wide range of reported grade 3 and 4 AEs can be found in published phase 3 studies. Moreover, in comparing different phase 3 clinical studies, great variability in the occurrence of grade 3 and 4 AEs becomes obvious even with the same drug. Namely, in the phase 3 registration study for pazopanib, 33% of grade 3 and 4 AEs were reported (7), while 74% of patients in the COMPARZ study had grade 3 and 4 toxicities with pazopanib and sunitinib (8). However, data collected retrospectively together with less strict reporting of AE in everyday practice contributes to the variable results reported in observational studies. Namely, the significantly lower rate of grade 3 and 4 AEs reported in everyday practice may indicate that their actual occurrence is underestimated (11–19). However, it should also be noted that most TKI-related AE can be prevented and successfully treated when recognized in time (22). In our study, only 7% of patients permanently discontinued treatment because of significant TKI toxicity.

This study aimed to assess the survival outcomes of patients with mRCC who received sunitinib or pazopanib as first-line treatment in everyday practice when subsequent therapy was not available. According to data published so far in the literature, both in phase 3 studies (6–8) and observational studies (11–19), the most common reason for permanent discontinuation of first-line TKI was disease progression. The median PFS in our patients was 14 months, which is very similar to the results of registration studies both for sunitinib and pazopanib (11 months) in the first-line of mRCC treatment (6, 7). However, in retrospective studies from everyday practice, the median PFS for first-line TKI ranged from 8.4 to 23.8 months (11–19). Huge variations in mPFS observed in retrospective studies can be explained partly by differences in radiographic assessment intervals in routine clinical practice. Moreover, note that PFS is mostly based on the subjective assessment of researchers. This is notably evident in real-world evidence, where most of the criteria for disease assessment are not clearly defined. Nevertheless, in Serbia, where patients cannot continue with the subsequent line of treatment, radiographic progression is assessed more carefully to avoid mistakes and unnecessary treatment cessation. The primary endpoint of this study was the evaluation of OS in patients treated for mRCC with the only available sunitinib or pazopanib in a first-line setting.

Our study showed that patients with clear cell mRCC treated with sunitinib or pazopanib in first line had worse OS (17 months; CI 95% 14.6–19.4) compared with the results of phase 3 studies in the same population. A comparative study (COMPARZ) showed that pazopanib and sunitinib had similar OS (28.4 vs. 29.3 months; HR 0.91; CI 95% 0.79–1.06; p = 0.275) (8). Given the relatively similar demographic and clinical characteristics of the patient population in our study and the phase 3 studies, the estimated OS should be expected to be comparable. However, OS reported in clinical practice studies varies widely between 16.7 and 44 months (11–19), which reflects the presence of significant heterogeneity in clinical characteristics of patients and differences in managing therapy compared to the strict protocol used in phase 3 studies. In addition, our findings are consistent with observational studies examining the OS in patients receiving sunitinib or pazopanib in first line, according to the MSKCC or IMDC risk score (23, 24). Namely, patients with intermediate prognosis were divided into those who have one, and those who have two risk factors in MSKCC or IMDC risk score. The results of these studies showed that OS in patients who had intermediate-1 risk was more similar to OS in patients who had favorable prognosis according to MSKCC or IMDC criteria. In contrast, OS in patients who had intermediate-2 risk was more similar to OS in patients who had poor prognosis according to MSKCC or IMDC criteria. Rini et al. (23) showed that for first-line sunitinib, the median OS for patients with MSKCC intermediate-1 risk was 23.1 months and 16.7 months for patients with intermediate-2 risk. Similar results were reported for first-line sunitinib by Schmidinger et al. (24) with a median OS of 20.5 months and 15.1 months in patients with intermediate IMDC prognosis who had one or two risk factors, respectively. In our study, according to MSKCC criteria, 504 (66%) patients had an intermediate prognosis, with two risk factors found in 351 (70%). It is likely that the population of patients at intermediate risk has the greatest impact on OS in our cohort.

In Serbia, the second-line therapy for mRCC has never been and is still unavailable. The number of patients who are candidates for continuing treatment in Serbia is 35–40%. According to available data from the literature, the number of patients who continue treatment after the failure of the first-line TKI ranges between 26 and 63% in everyday practice (25).

In this representative national cohort study, with only available sunitinib and pazopanib as first-line treatments, modest improvements are seen in the overall survival of patients with mRCC in real-world clinical practice. When access to a subsequent line of treatment and new cancer medicines is limited, common sense and clinical experience become more obvious than strictly following the treatment guidelines that cannot be followed. Considering the emerging new standard of care for clear cell mRCC, our results can accelerate patient access to novel cancer therapies shown to prolong survival in mRCC.

The original contributions presented in the study are included in the article/supplementary material. Further inquiries can be directed to the corresponding author.

The study was approved by the Ethical Committee of Institute of Oncology and Radiology of Serbia, Belgrade under the number 3134/01 issued on 25 August 2020. Written informed consent for participation was not required for this study in accordance with the national legislation and the institutional requirements.

PN and NB contributed to conception and design of the study. PN, NB, ZD, SS, VS, SM, ZP, KJ, and IS contributed to the acquisition, analysis, or interpretation of data. PN and SM wrote first draft of the manuscript. PN and IS performed statistical analysis. All authors listed have made a substantial, direct, and intellectual contribution to the work and approved it for publication.

Financial support for open access publication fees will be received by the Serbian Society of Medical Oncology (UMOS) with Independent General Research Grant Number 57567877 provided by Pfizer SRB d.o.o.

PN, NB, ZD, SS, VS, and SM received honoraria for lectures and travel grants from Pfizer and Novartis outside the submitted work. No other disclosures were reported.

The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

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