Stesura Seveso Archivio Italiano di Urologia e Andrologia 2023; 95(3):11672 1 SYSTEMATIC REVIEW nephrectomy techniques according to the staging of the disease (2, 3). Despite the fact that surgical resection of tumors in localized disease can be curative, disease pro- gression and mortality could be up to 20% of patients after primary treatment, and therefore any intervention to improve the oncological outcomes would be considered a significant benefit (4). Several variables including age, race, gender, stage, grade, tumor size, performance status, and blood type, have been found as independent predictors of mortality after nephrectomy for locoregional RCC. Although these risk variables may provide useful prognos- tic information, they typically offer limited opportunity for intervention to modify the disease's trajectory (5, 6).Unlike in metastatic RCC, targeted therapy and immunotherapy such as Vascular Endothelial Growth Factor (VEGF) or mam- malian-target of rapamycin (mTOR) inhibitor are shown to have minimal benefits in an adjuvant treatment scenario for localized RCC after surgery and a high-risk profile for disease recurrence (7-9). Given the high costs and limited availability of pharmacological development and clinical implementation of targeted therapies, the technique of drug repositioning (DR) of selected non-anticancer drugs is being investigated (10). Various concomitant medications in RCC patients undergoing surgery are investigated to explore the potential for improving survival and preventing disease recurrence, including insulin, beta-blockers, met- formin, statins, and other therapies (11). Statins are the most widely used drugs for the treatment of hypercholes- terolemia, and several authors discovered the anti-tumor activities in this medication. These drugs have been observed to induce apoptosis, thereby inhibiting tumor growth and angiogenesis (12). Even though the exact mechanism is still unclear, clinical trials have been con- ducted to explore the potential benefits of statin in several cancers such as lung cancer, liver cancer, and colorectal cancer (13-15). Several cohorts are also currently being conducted to evaluate the impact of statins on the onco- logical outcomes of RCC patients having surgery (5, 16- 19). The results are encouraging but often conflicting, and there are currently no strong recommendations regarding the use of statins as either neo-adjuvant or adjuvant thera- py in RCC. Therefore, we aimed to perform a systematic Introduction: Renal cell carcinoma (RCC) is regarded as one of the most common malig- nant tumors. Various concomitant medications in RCC patients undergoing surgery are investigated to explore the potential for improving survival and preventing disease recurrence, including statin. It has been observed that these drugs induce apoptosis, thereby inhibiting tumor growth and angiogenesis. We aimed to perform a systematic review and meta-analysis to enhance the level of evidence for statin in RCC. Methods: A systematic literature search was conducted in sever- al online databases, including PubMed, Scopus, and Science- direct, using terms relevant to the use of statins in RCC patients undergoing nephrectomy for publications published up to July 2023, according to a registered review procedure (CRD42023452318). The Newcastle-Ottawa Scale (NOS) was used to assess the risk of bias of the included study. Review Manager 5.4 was used for all analyses. Results: Seven articles was eligible for our study. The analysis revealed that patients receiving statin had a better overall sur- vival compared to patients who does not receive statin (HR 0.71, 95% CI 0.51-0.97, p = 0.03, I2 = 76%). However, there was insignificant difference in terms of CSS, DFS, and PFS between RCC patients receiving statin and without statin. Conclusions: Statin has substantial benefits for improving OS. Even though the outcomes for CSS, DFS, and PFS were insignif- icant, the potential role of statins as a supplementary therapy in surgically treated RCC still requires further investigation. KEY WORDS: Statin; Renal cell carcinoma; Nephrectomy; Survival rate; Outcome. Submitted 24 August 2023; Accepted 31 August 2023 INTRODUCTION Renal cell carcinoma (RCC) is regarded as one of the most common malignant tumors, accounting for approximately 2% of all tumors and 90% of all kidney malignancies. Renal cancer is expected to remain a major threat to global health as the global incidence of this disease has been steadily growing in recent decades (1). In order to manage the dis- ease, surgical resection of the tumor is the cornerstone treatment. As a curative or palliative treatment, surgical therapy is performed using either partial or radical Impact of statin on renal cell carcinoma patients undergoing nephrectomy. Does it affect cancer progression and improves survival? A Systematic Review and Meta-Analysis Ghazian Adli 1, 2, Niwanda Yogiswara 1, 2, Ida Bagus Gde Tirta Yoga Yatindra 1, 2, Rheza Maulana Putra 1, 2, Wahjoe Djatisoesanto 1, 2 1 Department of Urology, Faculty of Medicine, Universitas Airlangga, Indonesia; 2 Dr. Soetomo General-Academic Hospital, Surabaya, East Java, Indonesia. DOI: 10.4081/aiua.2023.11672 Summary Archivio Italiano di Urologia e Andrologia 2023; 95(3):11672 G. Adli, N. Yogiswara, I. Bagus Gde Tirta Yoga Yatindra, R. Maulana Putra, W. Djatisoesanto 2 review and meta-analysis to enhance the level of evidence for statin in RCC. METHODS Review protocol and search strategy This study evaluates the impact of statin on RCC patients who underwent nephrectomy on the oncological out- comes through systematic review and meta-analysis design (20), following the latest Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) state- ment in PubMed, Science-direct, and Scopus. The literature search followed Medical Subject Headings (MeSH®) Terms related to the use of statin in RCC patients who under- went nephrectomy for articles published up to July 2023. The protocol has been registered in PROSPERO (CRD42023452318). Eligibility criteria for review The inclusion criteria are (1) observational studies (2) eval- uation of RCC patients who underwent open or laparo- scopic. nephrectomy diagnosed with histopathological examination, (3) compare patients who receive statin and without statin (4) and reporting the outcome. The outcomes analysed in this study were overall survival (OS), cancer- specific survival (CSS), disease-free survival (DFS), and progression-free survival (PFS). We excluded non- English studies, studies without full text, and duplicate studies. Data extraction and risk of bias assessment Baseline characteristics of the study were extracted by two independent authors, while the third author resolved all disagreements through a discussion. The extracted data con- sisting of publication details as first author name and year of publication, study design, sample size, and sam- ple characteristics such as age, RCC grade, cell type, stage of RCC, and surgical methods were collected in spreadsheet software Microsoft Excel® 2021. The risk of bias was assessed with the Newcastle-Ottawa Scale (NOS), which has the domain of selection, comparison, and exposure. Data analysis and presentation The analysis effect size was estimat- ed in a Forest plot with a hazard ratio (HR) with a 95% confidence interval (95% CI) and a p-value below 0.05 was considered statisti- cally significant using the software Review Manager 5.4 (Cochrane Collaboration). Heterogeneity between studies was evaluated using I2, where an I2 value above 50% indicated high heterogene- ity and a random-effects model was applied for pooled analysis. RESULTS Study search Our preliminary search found 298 results. Twenty-five full articles were retrieved for eligibility. Following the assess- ment of the full-text articles, sixteen were eliminated for several reasons, including differences in intervention, pop- ulation, and incomplete data. The remaining seven publi- cations were investigated further, as shown in Figure 1. The clinical characteristics of the included participants are described in Table 1. Baseline characteristics and quality assessment All of the included studies were retrospective cohorts. The majority of the populations of the included studies were American, ranging from 55-66 years. The type of statins that were used in the study comprised Atorvastatin, Figure 1. Identification of included studies. Archivio Italiano di Urologia e Andrologia 2023; 95(3):11672 3 Statin affecting survival in surgically treated RCC Simvastatin, Lovastatin, Pravastatin, Rosuvastatin, Fluvastatin, and Cerivastatin. The techniques used for surgical resection were varied such as open, laparoscopic, and robotic approach. The follow-up of the studies ranged from 25 to 93 months. The risk of bias assessed using NOS revealed a moderate score ranging from 5 to 9, with a median of 7 as presented in Table 2. Impact of statin on overall survival Six articles were included in the analysis of overall sur- vival using the random-effect model, as presented in Figure 2. Table 2. Quality assessment using Newcastle-ottawa scale. Author Selection Comparability Exposure Score Berquist, 2017 *** ** *** 8 Haddad, 2015 **** ** ** 8 Choi, 2012 *** * * 5 Hamilton, 2013 **** ** ** 8 Kaffenberger, 2014 *** ** *** 8 Nayan, 2016 **** ** **** 9 Neumann, 2019 *** ** *** 8 Viers, 2015 *** ** *** 8 Haide, 2019 *** ** *** 8 Table 1. Baseline characteristics of the included study. Author Country Study Sample Intervention N Age Follow Up Nephrectomy Cancer Outcome Adjusted variable Type size (n) (years) (month) (n) histology analyzed in multivariate Median (IQR) analysis Choi, 2012 Korea Retrospective 115 Statin 21 58.95 ± 12.33 40 Radical and Clear Cell, Papillary, PFS, RFS Age, gender, BMI cohort Non Statin 94 65.24 ± 6.82 Partial (115) Chromophobe, Collecting Duct, Sarcomatoid Hamilton, 2013 America Retrospective 2608 Statin 708 66 (59-72) 36 Radical (1580) Clear Cell, Papillary, Progression, Age, gender, race, cohort Non Statin 1900 59 (50-68) Partial (1028) Chromophobe, overall mortality type of surgery, commorbidity, Unclassified renal function, tumor stage, year of surgery, local and systemic symptoms Kaffenberg, 2014 America Retrospective 916 Statin 270 60.8 (51.3–69.3) 42.5 (19.1–67.1) Radical (584) Clear Cell, DSS, OS Age, ASA score, staging, nodes, cohort Non Statin 646 Partial (332) Non-Clear Cell metastatic status, blood group, corrected hypercalcemia Viers, 2015 America Retrospective 2357 Statin 630 66 (59–73) 93.6 (63.6-134.4) Radical (1727) Clear Cell, Papillary, PFS, CSS, OS Age, gender, type of surgery, cohort Non Statin 1727 61 (52–70) Partial (630) Chromophobe, Clear Cell, smoking status, tumor stage, Mucinous-Spindle Cell. tumor grade, sarcomatoid Translocation-Associated differentiation Collecting Duct, NOS Haddad, 2015 America Retrospective 850 Statin 342 62 (19-92) 25 (7.8-52.3) Radical (384) Clear cell, Non-Clear Cell RFS,OS Tumor stage, tumor grade, cohort Non Statin 508 55 (20-87) Partial (466) lymphovascular invasion, LDL, TG Nayan, 2016 Canada Retrospective 839 Statin 259 66 ± 16 47 (20-80) Radical (477) Clear Cell, Papillary, DFS, CSS, OS Age, gender, type of surgery, cohort Non Statin 634 57 ± 18 Partial (259) Chromophobe, tumor stage Unclassified Berquist, 2017 America Retrospective 283 Statin 180 57.5 ± 15 68 (50-90) Radical (204) Clear Cell, Papillary, DFS Tumor stage and grade cohort Non Statin 103 Partial (77) Chromophobe RCC, Other histology Neumann, 2019 Germany Retrospective 388 Statin 207 64.26 (17.12–90.32) 57.93 (0–237.18) Radical Clear Cell OS Commedication, tumor stage, cohort Non Statin 39 Partial Haide, 2019 Germany Retrospective 104 Statin 41 62 (53-70 35.4 (12.3-73.3) Radical Clear Cell, Non-Clear Cell CSS Tumor stage, hypertension cohort Non Statin 63 Partial Figure 2. Impact of statin on Overall Survival. Archivio Italiano di Urologia e Andrologia 2023; 95(3):11672 G. Adli, N. Yogiswara, I. Bagus Gde Tirta Yoga Yatindra, R. Maulana Putra, W. Djatisoesanto 4 The meta-analysis revealed that RCC patients receiving statin had better overall survival compared to patients who did not receive statin (HR 0.71, 95% CI 0.51-0.97, p = 0.03, I2 = 76%). Impact of statin on cancer-specific survival, disease-free survival, and progression-free survival Four studies were included in the analysis of CSS. The meta-analysis using the random-effects model in Figure 3 revealed that there was an insignificant differ- ence in terms of CSS between RCC patients receiving statin and those without statin (HR: 0.85 95% CI 0.54- 1.33, p = 0.47, I2 = 55%). Analysis of DFS was per- formed using two studies. The meta-analysis result using the random-effects model in Figure 4 showed that there was an insignificant differ- ence in terms of DFS between RCC patients receiving statin and without statin (HR: 0.76 95% CI 0.38-1.52; p = 0.44, I2 = 73%). Based on the result from the Forest plot shown in the Figure 5, there was an insignificant dif- ference in PFS between RCC patients receiving statin and those without statin (HR: 0.92 95% CI 0.51-1.65; p = 0.77, I2 = 86%). DISCUSSION This meta-analysis includes seven retrospective cohorts investigating oncological outcomes in the form of OS, DFS, CSS, and PFS in statin administration in surgically treated RCC patients (5, 11, 16-19, 21). The pooled analysis revealed that RCC patients receiving statin had a better OS compared to patients who did not receive statin, while there are no differences in DFS, CSS, and PFS. Overall survival is a critical parameter for evaluating the efficacy, safety, and clinical benefits of a cancer inter- vention. The effect of statins on improving OS has been explored in many tumors in urology, including patients with RCC, although investigations in RCC patients hav- ing nephrectomy were limited to a retrospective cohort and the results were contradictory. Based on the results of combined observational studies, we discovered higher overall survival in RCC patients who received statin ther- apy compared to those without statins. The results of this meta-analysis are consistent with the previous meta- analysis by Nayan et al. which reported that statins were significantly associated with an improvement in OS in all patients kidney cancer patients with HR of 0.74 (22). Our finding also aligns with a recent meta-analysis conducted Figure 3. Impact of statin on cancer-specific survival. Figure 4. Impact of statin on disease-free survival. Figure 5. Impact of statin on progression-free survival. Archivio Italiano di Urologia e Andrologia 2023; 95(3):11672 5 Statin affecting survival in surgically treated RCC by Luo et al. (23), who incorporated 35 studies to evalu- ate on the beneficial effects of statins in various urological cancers and discovered a significant improvement in OS in patients with RCC and bladder cancer. However, Wu et al. (24) observed no significant difference in OS in RCC patients, but their analysis only included American cohorts, which can be biased if generalized in the global population. The strength of the current analysis is that this review mainly focused on RCC patients undergoing surgical treatment, whereas prior meta-analyses included all RCC patients, surgical or non-surgical (22). Statin improves the OS of RCC patients undergoing surgery by several mechanisms. One possible mechanism of statins in improving the OS of cancer patients is by inhibiting the proliferation and progression of RCC and inducing apop- tosis of cancer cells thereby directly improving OS (11). Another possible mechanism is lowering cholesterol lev- els by blocking the active site of the HMG-CoA reductase enzyme, reducing the risk of coronary artery blockage and deadly cardiovascular events such as myocardial infarction or stroke which indirectly improves OS (17). Tumor cells can activate the coagulation process by releasing procoagulants, tissue factors, and fibrinolytic proteins, or by invading the vessel wall. In cancer patients including RCC, increased blood hypercoagulation can occur which causes an increased risk of arterial thrombo- sis and thromboembolic events, whereas one of the ways statins reduce death is by preventing thrombosis (17). Furthermore, our study tried to evaluate comprehensive- ly the synergistic effect of statin in RCC patients receiving targeted therapy. McKay et al. (25) discovered that patients who had targeted therapies and concomitant statins had improved OS compared to non-statin patients (25.6 versus 18.9 months, respectively) with insignificant differences in drug-related toxicity. Although statin has been proven to improve the OS, this parameter has a weakness because it can be affected by bias from external factors and confounding factors. There is currently no high level of evidence demonstrat- ing the advantage of adjuvant radiation therapy, VEGFR, or mTOR inhibitors for improving survival, and these treatments are not recommended in adjunctive contexts due to unfavorable tolerability. Given that a third of RCC patients will develop recurrence or advancement after nephrectomy, any adjunctive therapies to reduce the pro- gression and improve cancer-related survival were con- sidered a substantial benefit. In this study, we assessed the effects of statin as adjunc- tive therapy on several other oncology outcomes includ- ing PFS, DFS, and CSS. Based on the results of the com- bined analysis, we found that statins had an insignificant effect on CSS in RCC patients undergoing nephrectomy procedures (p = 0.47). These results differ from a meta- analysis study by Nayan et al., which found that statins were significantly associated with improved cancer-spe- cific survival (HR 0.67) (26). The discrepancy could be attributed to several factors, including the inclusion of non-surgically treated RCC in the earlier review. According to the literature, the outcome of CSS in patients with surgically treated and non-surgically treated RCC differs, therefore combining the populations may have resulted in bias. After performing a combined analy- sis using Forest plots, we found that statins had no sig- nificant effect on DFS and PFS in RCC patients undergo- ing nephrectomy. These results are in accordance with a meta-analysis by Nayan et al. which included 2 studies, with the result that there was no relationship between statin administration in PFS and DFS in RCC patients in general (22). Various statin mechanisms for reducing cancer progres- sion and death in RCC patients have been discussed in the literature. Statins have previously been proven in vitro and in vivo to reduce proliferation, angiogenesis, and tumor invasion, thereby reducing cancer growth (27). Data suggests that in general statin reduces cancer growth by two possible mechanisms, including choles- terol-dependent and cholesterol-independent pathways. Statins limit mevalonate production and the generation of downstream lipid isoprenoid intermediates in the HMG- CoA pathway. The latter chemical regulates angiogenesis, apoptosis, and inflammation. In the cholesterol-inde- pendent process, interactions with proteasomes and lym- phocyte-function antigen 1 agents have impacts on inva- sion, cell adhesion, inflammation, and proliferation. The latest evidence suggests that statins can decrease RCC cell growth by prompting cell cycle arrest and apoptosis in a dose and time-dependent manner. Furthermore, statins suppress the phosphorylation of AKT, mTOR, and ERK, resulting in decreased RCC cell motility (28). Although there are various mechanisms through which statins have been shown to prevent cancer progression, in this meta-analysis, we discovered that statins did not pro- vide substantial benefits in preventing cancer progression. The insignificant results in this study could be attributed to lower statin bioavailability due to liver metabolism and variations in lipid metabolism in RCC (29). Statins are selectively absorbed by the liver, with less than 5% of the provided dose reaching the systemic circulation, resulting in limited statin penetrating RCC cells (28). Furthermore, lipid metabolism in RCC differs from that of other cancers. RCC has much lower expression of cho- lesterol synthase proteins including HMG-CoA reductase (HMGCR) than adjacent normal tissues (30). In fact, the major mechanism of statins is HMGCR downregulation. This might explain the reason that statins have a lower impact on RCC than on other forms of cancer. Statin plas- ma levels depend on dose, statin type, and liver function. The higher the dose the higher level of statin in the plas- ma. Lipophilic statin (atorvastatin, simvastatin, lovastatin, fluvastatin, and pitavastatin) tends to have higher uptake in the liver than hydrophilic statin (pravastatin and rosu- vastatin) which can affect the liver function and rising the creatinine kinase level (28). Statin plasma levels are high- er in altered liver function patients due to reduced statin metabolism and transport activities (31). In general, this review provided evidence of the beneficial effect of statin on improving the OS of surgically treated RCC patients. Despite the insignificant result of CSS, DFS, and PFS, the potential role of statins as adjunctive therapy in surgically treated RCC still needs to be explored. This meta-analysis provides support for future prospective and randomized controlled studies to evalu- ate the potential benefit of statins in extending the sur- vival of surgically treated RCC patients, especially when Archivio Italiano di Urologia e Andrologia 2023; 95(3):11672 G. Adli, N. Yogiswara, I. Bagus Gde Tirta Yoga Yatindra, R. Maulana Putra, W. Djatisoesanto 6 considering the limited efficacy and toxicity of targeted therapies in adjunctive settings. There are several limitations to this review. This review was confined only to retrospective cohort studies, which cannot establish causality. Furthermore, there was signifi- cant heterogeneity among the studies due to variation of histological subgroups, surgical technique, intervention protocol, and RCC stage, which we could not further ana- lyze using subgroups analysis due to the lack of data. Moreover, the several included studies were conducted on small sample size and in a single institution. Therefore, larger cohorts, and multi-institutional or pop- ulation-based research are necessary. CONCLUSIONS In the context of limited recommendations for adjunctive immunotherapy or targeted therapy for improving OS of surgically treated RCC patients, the present review high- lights the substantial benefits of statin for improving OS in this population. Even though the outcomes for CSS, DFS, and PFS were insignificant, the potential role of statins as a supplementary therapy in surgically treated RCC still requires further investigation. To confirm the beneficial effects of statin on surgically treated RCC more evidence from prospective and clinical studies may be required. REFERENCES 1. Bray F, Ferlay J, Soerjomataram I, Siegel RL, et al. Global can- cer statistics 2018: GLOBOCAN estimates of incidence and mortali- ty worldwide for 36 cancers in 185 countries. CA Cancer J Clin 2018; 68:394-424. 2. Hanna N, Sun M, Meyer CP, et al. Survival Analyses of Patients With Metastatic Renal Cancer Treated With Targeted Therapy With or Without Cytoreductive Nephrectomy: A National Cancer Data Base Study. J Clin Oncol. 2016; 34:3267-75. 3. Krabbe LM, Bagrodia A, Margulis V, Wood CG. Surgical Management of Renal Cell Carcinoma. Semin Intervent Radiol 2014; 31:27. 4. Teloken PE, Thompson RH, Tickoo SK, et al. Prognostic Impact of Histological Subtype on Surgically Treated Localized Renal Cell Carcinoma. J Urol 2009; 182:2132-6. 5. Heide J, Ribback S, Klatte T, et al. Evaluation of the prognostic role of co-morbidities on disease outcome in renal cell carcinoma patients. World J Urol. 2020; 38:1525-33. 6. Brierley J, Gospodarowicz MD, Wittekind CT. TNM Classification of Malignant Tumors International Union Against Cancer. 8th. Oxford, England: Wiley; 2017. Wiley 2017 7. Larkin JMG, Eisen T. Kinase inhibitors in the treatment of renal cell carcinoma. Crit Rev Oncol Hematol 2006; 60:216-26. 8. Rini BI, Escudier B, Tomczak P, et al. Comparative effectiveness of axitinib versus sorafenib in advanced renal cell carcinoma (AXIS): a randomised phase 3 trial. Lancet 2011; 378:1931-9. 9. Sternberg CN, Davis ID, Mardiak J, et al. Pazopanib in locally advanced or metastatic renal cell carcinoma: results of a randomized phase III trial. J Clin Oncol 2010; 28:1061-8. 10. Li X, Shong K, Kim W, et al. Prediction of drug candidates for clear cell renal cell carcinoma using a systems biology-based drug repositioning approach. EBioMedicine 2022; 78:1039633. 11. Neumann E, Klaiber P, Freitag K, et al. Assessment of concomi- tant non-oncologic medication in patients with surgically treated renal cell carcinoma: impact on prognosis, cell-cycle progression and proliferation. J Cancer Res Clin Oncol 2019; 145:1835-43. 12. Santoni M, Monteiro FSM, Massari F, et al. Statins and renal cell carcinoma: Antitumor activity and influence on cancer risk and survival. Crit Rev Oncol Hematol. 2022; 176:103731. 13. Seckl MJ, Ottensmeier CH, Cullen M, et al. Multicenter, Phase III, Randomized, Double-Blind, Placebo-Controlled Trial of Pravastatin Added to First-Line Standard Chemotherapy in Small- Cell Lung Cancer (LUNGSTAR). J Clin Oncol. 2017; 35:1506-14. 14. Kawata S, Yamasaki E, Nagase T, et al. Effect of pravastatin on survival in patients with advanced hepatocellular carcinoma. A ran- domized controlled trial. Br J Cancer 2001; 84:886-91. 15. Alarfi H, Youssef LA, Salamoon M. A Prospective, Randomized, Placebo-Controlled Study of a Combination of Simvastatin and Chemotherapy in Metastatic Breast Cancer. J Oncol. 2020; 2020:4174395. 16. Nayan M, Finelli A, Jewett MAS, et al. Statin use and kidney cancer outcomes: A propensity score analysis. Urol Oncol. 2016; 34:487.e1-487.e6. 17. Viers BR, Houston Thompson R, Psutka SP, et al. The associa- tion of statin therapy with clinicopathologic outcomes and survival among patients with localized renal cell carcinoma undergoing nephrectomy. Urol Oncol. 2015; 33:388.e11-8. 18. Kaffenberger SD, Lin-Tsai O, Stratton KL, et al. Statin use is associated with improved survival in patients undergoing surgery for renal cell carcinoma. Urol Oncol. 2015; 33:21.e11-21.e17. 19. Hamilton RJ, Morilla D, Cabrera F, et al. The association between statin medication and progression after surgery for localized renal cell carcinoma. J Urol 2014; 191:914-9. 20. Higgins JP, Green S. Cochrane Handbook for Systematic Reviews of Interventions®. 21. Haddad AQ, Jiang L, Cadeddu JA, et al. Statin Use and Serum Lipid Levels Are Associated With Survival Outcomes After Surgery for Renal Cell Carcinoma. Urology. 2015; 86:1146-52. 22. Nayan M, Punjani N, Juurlink DN, et al. Statin use and kidney cancer survival outcomes: A systematic review and meta-analysis. Cancer Treat Rev 2017; 52:105-16. 23. Luo Y, She DL, Xiong H, et al. The Prognostic Effect of Statin Use on Urologic Cancers: An Updated Meta-Analysis of 35 Observational Studies. Medicine (Baltimore). 2015; 94:e1523. 24. Wu P, Xiang T, Wang J, et al. Statin use and the overall survival of renal cell carcinoma: A meta-analysis. Clin Invest Med. 2020; 43:E17-23. 25. McKay RR, Lin X, Albiges L, et al. Statins and survival outcomes in patients with metastatic renal cell carcinoma. Eur J Cancer. 2016; 52:155-62. 26. Nayan M, Hamilton RJ, Finelli A, et al. The value of comple- menting administrative data with abstracted information on smoking and obesity: A study in kidney cancer. Can Urol Assoc J 2017; 11:167-71. 27. Di Bello E, Zwergel C, Mai A, Valente S. The Innovative Potential of Statins in Cancer: New Targets for New Therapies. Front Chem. 2020; 8:516. Archivio Italiano di Urologia e Andrologia 2023; 95(3):11672 7 Statin affecting survival in surgically treated RCC 28. Petyaev IM. Improvement of hepatic bioavailability as a new step for the future of statin. Arch Med Sci. 2015; 11:406-10. 29. Petyaev IM. Improvement of hepatic bioavailability as a new step for the future of statin. Arch Med Sci 2015; 11:406. 30. Stepanovska Tanturovska B, Manaila R, Fabbro D, Huwiler A. Lipids as Targets for Renal Cell Carcinoma Therapy. Int J Mol Sci. 2023; 24:3272. 31. Calderon RM, Cubeddu LX, Goldberg RB, Schiff ER. Statins in the Treatment of Dyslipidemia in the Presence of Elevated Liver Aminotransferase Levels: A Therapeutic Dilemma. Mayo Clin Proc 2010; 85:349. Correspondence Ghazian Adli ghazianadli@gmail.com Niwanda Yogiswara niwandayogiswara@gmail.com Ida Bagus Gde Tirta Yoga Yatindra tirtayogastudi@gmail.com Rheza Maulana Putra putrarhe@gmail.com Wahjoe Djatisoesanto (Corresponding Author) djatisoe@gmail.com Department of Urology, Faculty of Medicine, Universitas Airlangga Dr. Soetomo General-Academic Hospital, Surabaya, East Java, Indonesia Conflict of interest: The authors declare no potential conflict of interest.