Urologic Oncology: Seminars and Original Investigations
Original articleStatin use is associated with improved survival in patients undergoing surgery for renal cell carcinoma☆
Introduction
Nearly 65,000 new cases of renal cell carcinoma (RCC) are diagnosed each year in the United States, and it is expected to account for almost 13,500 deaths in 2012 [1]. Surgery, by nephron-sparing approaches or radical nephrectomy, is the mainstay of curative treatment for RCC [2]. Several predictors of mortality after nephrectomy for locoregional RCC have been identified, including age, race, gender, stage, grade, tumor size, nutritional status, performance status, and ABO blood type [3], [4], [5], [6]. Although these risk factors may provide important prognostic information, with exception to nutritional status, most provide little potential for intervention to alter the course of the disease.
Supported by a number of epidemiologic risk studies, there has been an increasing interest in the antineoplastic properties of statins in recent years [7], [8], [9], [10], [11], [12], [13]. Statins are widely used cholesterol-lowering medications that act by inhibiting 3-hydroxy-3-methyl glutaryl-coenzyme A reductase, the rate-limiting enzyme of the mevalonate pathway. Disruption of this pathway is thought to inhibit cancer growth and metastasis by affecting critical cellular functions, including cell proliferation, maintenance of membrane integrity, cell signaling, protein synthesis, and cell-cycle progression [14].
Despite plausible mechanistic links for a protective role of statins in the development of cancer, epidemiologic studies evaluating the association between statin use and cancer risk have been controversial [14], [15], [16], [17], [18]. Although earlier studies had suggested an increased risk of cancer associated with statin use, other studies have reported a neutral effect, and the remaining have described protective effects for some cancers of up to a 50% relative risk reduction in cancer incidence [7], [8], [10], [18], [19]. Results from the evaluation of statin use and cancer-related mortality have been mixed as well, although a recent, well-performed nationwide study of patients with cancer in the Danish population found a 15% reduction in cancer-related mortality associated with statin use [13], [18], [20].
A limited number of studies have evaluated statin use and the risk of developing RCC, with conflicting results [7], [11], [12], [21], [22]. A nested case-control study of almost 500,000 veteran patients in the south-central United States found a 48% risk reduction of RCC associated with statin use [11]. More recently, a smaller, prospective population-based study of 2 cohorts of US health professionals confirmed this protective effect of statins on the risk of developing RCC, but only in women without a history of hypertension [12]. In regard to statins and prognosis after surgery for RCC, a recent single-institution study suggested a significant association between statin use at time of surgery and RCC progression (defined as development of metastases or RCC-specific death), although this result was not statistically significant when modeling statin usage as a time-dependent postoperative variable and when accounting for those who initiated statin therapy after surgery for RCC [23]. Furthermore, statin use at time of surgery for RCC was not independently associated with overall survival (OS), and no independent analysis of disease-specific survival (DSS) was reported. Therefore, although statin use has been associated with reduced cancer-related mortality in other malignancies, its effect on RCC prognosis following surgical treatment has not been definitively established [13], [23]. We therefore sought to evaluate whether statin use is associated with survival following surgery for RCC. Given the evidence supporting a protective effect of statins in cancer as well as the presumed metabolic nature of RCC, we hypothesized that current statin use at time of surgery would be associated with improved OS and DSS in patients undergoing radical or partial nephrectomy for RCC [24].
Section snippets
Patients and methods
We performed a retrospective cohort study of 916 consecutive patients with information on statin use who underwent radical or partial nephrectomy for RCC of all stages from 2000 to 2010. All RCC histologic subtypes were included. All surgeries were performed at Vanderbilt University Medical Center, with preoperative evaluation and postoperative care standardized to institutional protocol. Follow-up was at the discretion of the treating physician. Cause of death was determined by the treating
Results
The median age of the cohort was 60.8 years (interquartile range [IQR]: 51.3–69.3 y). Median follow-up of the entire cohort was 42.5 months (IQR: 19.1–67.1 mo). The median follow-up of patients alive at last follow-up was 52.1 months (IQR: 27.1–74.2 mo). Table 1 gives the distribution of clinicopathologic variables by statin use. Statin use was associated with increased age, male sex, higher ASA class, less preoperative hypoalbuminemia and hypercalcemia, partial nephrectomy, and N category. There
Discussion
Although there is increasing evidence suggesting beneficial effects of statins on cancer risk and cancer mortality, there has yet to be a randomized controlled trial evaluating statin use for the specific purpose of reducing cancer-specific mortality [10], [11], [12], [13]. We showed that statin use at time of surgery is independently associated with improved OS and DSS in a large retrospective cohort of patients undergoing radical or partial nephrectomy for RCC of all stages. Specifically,
Conclusions
We found a significant and independent association between statin use at time of surgery and improved OS and DSS in patients undergoing radical or partial nephrectomy for RCC of all stages. This finding was highly robust as the association persisted in a number of additional exploratory analyses. Although statin use has previously been identified to be associated with RCC incidence and also has been shown to be associated with RCC progression, statin use has not been previously identified as an
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2016, Pharmacological ResearchCitation Excerpt :As such, controlling for these factors will not improve the estimation of the exposure-outcome relationship; rather, it would lead to overadjustment [41]. Additionally, many studies have shown that tumour stage was not significantly different in users vs. non-users of statins or metformin [16,19,21,23,24,39]. While there is conflicting evidence on the association of obesity and kidney cancer survival outcomes [42–45], data on obesity was not available in the databases used.
Statin use and kidney cancer outcomes: A propensity score analysis
2016, Urologic Oncology: Seminars and Original InvestigationsCitation Excerpt :In their time-varying analyses, patients who started a statin after surgery contributed person-time to the nonuser group until starting the statin, after which they contributed to the user group. Time-varying analyses are more robust than ever vs. never analyses, as was done in all other studies evaluating statin use and outcomes in RCC [10–13], including our study, because it can account for intermittent exposure. However, with institutional data, it is difficult to obtain reliable data regarding time on and off medication.
Patients with ClearCode34-identified molecular subtypes of clear cell renal cell carcinoma represent unique populations with distinct comorbidities
2016, Urologic Oncology: Seminars and Original Investigations
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The project described was supported in part by Award number K08 CA113452 (P.E.C.) from the National Institute of Health, USA, by the Vanderbilt Medical Scholars Program and the NIH CTSA Grant (TL1 TR000447) (O.L.T.).
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These authors contributed equally to this study.