Abstract
Background/Aim: According to the European Society for Medical Oncology (ESMO) and National Comprehensive Cancer Network (NCCN) recommendations, sunitinib is one of the recommended regimens for favorable and intermediate-risk metastatic renal cell carcinoma (mRCC) patients. The objective of this study was to evaluate sunitinib efficacy as a first-line treatment for mRCC patients with favorable/intermediate prognostic risk in a real-world setting. Patients and Methods: Patients diagnosed with mRCC and confirmed as appropriate candidates for the first-line systemic treatment were included in this retrospective study. The prognostic risk was evaluated according to the model of the International Metastatic RCC Database Consortium (IMDC). Results: Patients received sunitinib as a first-line treatment. A total of 94 patients were enrolled from 2019 to the 2020and 67 of them were included in the detailed analysis. Median progression-free survival (PFS) was 23.4 (95%CI=17.3-29.5), and median overall survival (OS) was 66 months (95%CI=44.9-87.1). The age over 60 years was a significant negative predictor for PFS and OS. Regarding the IMDC model for disease risk prediction, the number of two risk factors in the intermediate risk group was a significant predictor for a shorter response to the first-line therapy. Conclusion: Sunitinib is an effective tyrosine kinase inhibitor, which can be used as a first-line treatment in favorable/intermediate-risk groups of patients with mRCC, especially in countries where novel systemic treatment modalities are not yet available.
Kidney cancer is one of the most aggressive tumors of the urogenital system (1, 2). Most renal cell carcinoma (RCC) cases are asymptomatic and discovered incidentally, especially in the early stages (3). Unfortunately, up to 30% of patients still present with metastatic RCC (mRCC) disease (4). The prognosis for patients with mRCC has been historically poor; 5 years survival rate is less than 10% (5). Systemic therapy is the primary treatment strategy for mRCC. Previously, before the introduction of targeted therapies, cytokine-based therapy with interferon-alfa (IFN-α) and/or interleukin-2 (IL-2) was considered a standard first-line treatment for patients with mRCC. However, the response rates were low (approximately 15%), OS was limited to a median of 13 months, and treatment-related toxicities restricted their wider usage (6). In addition, previous studies of other therapies for cytokine-refractory patients with RCC were unable to show benefits (7). Nowadays, first-line treatment agents for mRCC include multitargeted tyrosine kinase inhibitors (TKIs), such as sunitinib (8) and pazopanib (9, 10). They can be used alone or in combination with immunotherapy. In the past four years, six new immunotherapy (IO) drug combinations, such as IO-TKI and IO-IO regimens, have demonstrated significant clinical efficacy compared to the standard of care of vascular endothelial growth factor (VEGF)-TKI sunitinib monotherapy (11).
Sunitinib is a TKI of platelet-derived growth factor (PDGF) receptors alfa and beta, VEGF receptors 1-3, and other tyrosine kinases that stimulate angiogenesis. This orally available, small molecule has been successfully used worldwide for the management of mRCC for over 14 years (8). It is presently the recommended first-line treatment modality for mRCC patients of favorable and intermediate risk groups according to the European Society for Medical Oncology (ESMO) and the National Comprehensive Cancer Network (NCCN) guidelines (7, 12).
The International Metastatic Renal Cell Carcinoma Database Consortium (IMDC) prognostic model for survival prediction of patients with mRCC is widely used in clinical practice and was used in our study for sunitinib efficacy assessment (13).
Based on the fact that Lithuania has one of the highest morbidity and mortality rates of kidney cancer in Europe (14) the main objective, of this retrospective study, was to evaluate sunitinib as a first-line treatment for patients with mRCC corresponding to favorable or intermediate prognostic groups.
Patients and Methods
Study design and patients. Between January 1, 2019, and December 31, 2020, 94 patients with mRCC were treated at the National Cancer Institute (NCI), Vilnius, Lithuania. A retrospective study was performed on 67 patients with metastatic disease treated in the first-line with sunitinib. 27 patients were excluded from the study due to other treatment modalities mainly pazopanib, lack of data related to IMDC, missing blood tests, or lost patient monitoring (Consort diagram, Figure 1). Approval from the Lithuanian Bioethics Committee was obtained.
Selection, treatment, and follow-up of the patients. A retrospective descriptive study was performed with patients treated for metastatic kidney cancer at the National Cancer Institute, Department of Urology in the period from 2019 to 2020. Prognostic risk was evaluated according to the International Metastatic RCC Database Consortium. Overall survival and progression-free survival were analyzed.
The study population comprised patients aged 18 years and over with morphologically confirmed diagnoses of mRCC (mainly clear cell carcinoma) having at least one measurable target according to Response Evaluation Criteria in Solid Tumours (RECIST) v1.1. According to IMDC, the patients were divided into favorable and intermediate-risk groups. The intermediate risk group was formed according to the number of risk factors (1 or 2), while the favorable risk group had no IMDC risk factors. According to metastasis number, the patients were divided into two groups: high disease burden (≥ metastases) and low disease burden (<3 metastases).
Sunitinib in the first-line treatment was administered at a dose of 50 mg daily in cycles of 14 days on and 7 days off or 28 days on and 14 days off every 6 weeks. Second-line treatment with axitinib, cabozantinib, or nivolumab was administered in case of progression upon first-line treatment. OS was defined as the time from treatment with sunitinib initiation until death or loss on follow-up. Progression-free survival (PFS) was defined as the time from treatment with sunitinib beginning until disease progression or the start date of a second-line treatment. The first patient included in the prospective evaluation started treatment with sunitinib on December 14, 2012. The data cut-off for the final evaluation was May 1, 2022.
Statistical analysis. The treatment efficacy measures, including PFS and OS, were determined. Survival outcomes were described using median time for PFS and OS with 95% confidence interval (CI). The statistical difference between the survival outcomes was determined using Cox regression analysis and 95%CI was applied for hazard ratio (HR) calculations. Also, Kaplan–Meier curves were used for the visualization of data, and trends or statistically significant changes in outcomes are represented as graphs. Differences were considered statistically significant when the p-value was <0.05. The data were analyzed using software: IBM® SPSS® Statistics 21 (IBM, Armonk, NY, USA), R version 4.0.3 (R Foundation, Vienna, Austria), and RStudio 2022.07.1 (Posit, Boston, MA, USA).
Results
Patients. In this retrospective single-center study, 67 patients with mRCC on first-line sunitinib therapy were analyzed. The median age of patients with mRCC was 62 years (interquartile range=56-67 years). The majority of patients were male (52 out of 67; 78%). At the beginning of treatment, all patients had an Eastern Cooperative Oncology Group (ECOG) score ≤2. Most patients with mRCC included in the analysis started treatment with sunitinib 50 mg/d orally once a day on schedule 2/1 (two weeks on/one week off) or 4/2 (four weeks on/two weeks off). In terms of clinical characteristics, the cohort consisted of patients diagnosed as follows: 60% with stage T3/T4, 33% with advanced metastases (M1), and 71% with high cell differentiation scores (G2-G4). The majority of patients had clear cell renal carcinoma (94%) with prior nephrectomy (94%). Regarding disease volume, 48% of patients had more than 3 metastatic sites (Table I). The main metastatic sites were lungs (70%)/and lymph nodes (27%) or/and bones (31%). Metastasectomy was performed in one-third of the patients.
Clinico-pathological and demographical characteristics of the study cohort.
Treatment efficacy. Overall, the median response time to sunitinib therapy was 23.4 months (95%CI=17.3-29.5 months) and the median OS was 66.0 months (95%CI=44.9-87.1 months). PFS and OS according to clinico-pathological and demographic characteristics are presented in Table II and the Kaplan–Meier curves are presented in Figure 2A, C, and D. Regarding IMDC risk prognostic groups and related risk factors, PFS and OS are presented in Table II, and the Kaplan–Meier curves in Figure 2B.
Survival time and Cox regression analysis to assess significant factors associated with survival outcomes.
Progression-free survival (PFS) and overall survival (OS) for sunitinib therapy in patients with metastatic renal cell carcinoma. Graphs are shown to disclose significant changes in PFS and OS by age (A, B) and International Metastatic RCC Database Consortium (IMDC) risk factors (C, D).
The age of over 60 years and the number of IMDC risk factors in the prognostic risk group were the main predictors for significantly shorter response to therapy with sunitinib. In agreement, patients classified in the IMDC intermediate-risk group had shorter PFS and HR=1.6 in comparison with the patient group lacking IMDC risk factors. The age over 60 years was a significant predictor not only for the shorter response to therapy but also for the worse OS. As was expected, patients with a high disease burden had a trend for shorter OS relative to patients with a low disease burden. It should be noted that the patients with two IMDC risk factors in the intermediate risk prognostic group had 1.7 times higher HR for OS in comparison with the patients lacking these negative factors in the favorable risk prognostic group. However, the length of OS in the intermediate risk prognostic group with one IMDC risk factor was comparable to that of the favorable risk prognostic group.
Discussion
Despite new treatment possibilities included in the latest ESMO and NCCN guidelines, sunitinib along with the TKI pazopanib are recommended as first-line treatment modality for patients with mRCC with favorable or intermediate risk prognostic factors (6, 7). Sunitinib demonstrated sufficient efficacy and safety in patients with mRCC and although it is not the newest treatment modality for mRCC patients, it still can be considered for patients with mRCC if newer treatment combinations are not accessible, or patients are not good candidates for immuno-oncology treatment due to their comorbidities.
Our retrospective data proved the efficacy and safety of sunitinib in favorable and intermediate risk groups of patients with mRCC according to IMDC classification. The median PFS in our patient population with IMDC favorable and intermediate risk was 26.0 months (95%CI=16.6-35.4 months) and 20.5 months (95%CI=11.8-29.2 months), respectively. Similar results were shown in the ADONIS observational trial (15). In this trial patients with mRCC were treated with first-line sunitinib and efficacy was evaluated according to IMDC and MSKCC criteria. The median PFS in the ADONIS trial for patients with favorable and intermediate risk were 23.8 months (95%CI=13.5-28.5 months) and 12.2 months (95%CI=8.7-19.8 months), respectively. The higher efficacy observed in our retrospective analysis among patients with intermediate risk could be attributed to variances in study design, patient population, and the inherent heterogeneity within the intermediate-risk group itself. This highlights the necessity of developing novel approaches for prognosis stratification (16, 17).
In our real-world mRCC patient population, the median OS for patients with favorable risk was 68.0 months (95%CI=29.7-106.3 months). OS results for the same patient population in the ADONIS trial (15) were similar (67.4 months, 95%CI=46.3-102 months) and comparable to OS data presented by Schwab et al. (72.0 months); however, in the retrospective analysis done by Schwab et al. patients with mRCC were treated not only with sunitinib but also with other TKIs and mTOR inhibitors (18).
The majority of patients (94%) in our study had prior cytoreductive nephrectomy (CN) and it is well-known that CN may provide an OS benefit in selected mRCC patient populations (19, 20). Metastasis volume, count, and site are important in assessing response to the treatment (21). Our data shows that patients diagnosed with more than 3 metastases had lower OS compared to patients with 3 or fewer metastases (44.0 months versus 70.0 months). It should be mentioned that metastasectomy is associated with improved oncologic outcomes and plays an important role in patient survival. Six studies reported a significantly longer median OS or cancer-specific survival (CSS) following complete metastasectomy (the median value for OS or CSS was 40.75 months, range=23–122 months) compared with incomplete and/or no metastasectomy (the median value for OS or CSS was 14.8 months, range=8.4–55.5 months) (22-27). Three studies reported the complex treatment of RCC metastases in the lung (28), liver (29), and pancreas (30). The lung metastases study reported a significantly higher median OS for metastasectomy vs. medical therapy (for both targeted therapy and immunotherapy) (28). Similarly, the liver and pancreas metastases study reported a significantly higher median OS and five-year OS for metastasectomy vs. no metastasectomy (29, 30). In our cohort, 30% of patients underwent metastasectomy and this factor possibly had a positive impact on OS.
Undoubtedly, an appropriate systemic treatment strategy results in prolonged patient survival (31, 32). According to our retrospective data, second-line therapy after sunitinib was mainly axitinib (48%) and other treatment modalities (cabozantinib, nivolumab). One of the explanations for the prolonged OS in our patient population in both risk groups in comparison with the pivotal phase III sunitinib trial (33), might be the benefit obtained from the second-line treatment with the newer systemic therapies, such as axitinib, cabozantinib, nivolumab.
Nowadays, immunotherapy-based drug combinations, such as IO-TKI and IO-IO regimens, are widely used and have proven their benefit and significant clinical efficacy (34). The phase III trials, such as CheckMate 214 (nivolumab plus ipilimumab), CheckMate 9ER (Nivolumab plus cabozantinib), KEYNOTE-426 (Pembrolizumab plus axitinib), IMmotion151 (Atezolizumab plus bevacizumab) showed superiority over sunitinib with OS up to 47 months for the IMDC intermediate- and poor-risk populations (35). The median OS with nivolumab plus ipilimumab was 74 months for favorable-risk patients (36). Combinations of immunotherapies and antiangiogenetic agents have improved patient outcomes, but sunitinib still shows sufficient efficacy and can be used especially in countries where novel combinations are not reimbursed yet. Furthermore, cost-effectiveness studies confirm that sunitinib is a significantly less expensive treatment option than nivolumab and ipilumab (37).
Study limitations. Limitations of our study include the retrospective data analysis, relatively small patient cohort, not presenting treatment-related adverse events, comorbidities, and dose modification of sunitinib during the treatment. However, such everyday clinical practice-based data provide further rationale for the use of sunitinib for mRCC with low to intermediate risk criteria.
Conclusion
Everyday clinical practice-based data shows sufficient efficacy of sunitinib in patients with mRCC and favorable and intermediate risk according to IMDC. Favorable clinical responses can be achieved using sunitinib as a first-line treatment, especially in countries where novel combinations, such as nivolumab/cabozantinib, pembrolizumab/axitinib, nivolumab/ipilimumab are not reimbursed yet.
Acknowledgements
The Authors gratefully acknowledge the contributions of all the oncologists and urologists of the National Cancer Institute, for the care and treatment of patients included in our study cohort.
Footnotes
Authors’ Contributions
AZ: Data collection, literature review, and manuscript preparation; Others: statistical analysis, revising manuscript critically for important intellectual content, substantial contributions to conception and design. All Authors read and approved the final manuscript.
Conflicts of Interest
The Authors have no conflicts of interest to declare in relation to this study.
- Received October 22, 2023.
- Revision received November 20, 2023.
- Accepted November 23, 2023.
- Copyright © 2024 International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.
