**6. Discussion**

Is there enough evidence to say that statins are useful in the treatment of sarcomas? From the epidemiological studies' point of view, the results are not clear enough to advise their use since the conclusions are not homogeneous and are objectionable. Most studies are observational and retrospective [71], mainly phase I and/or phase II clinical trials, with small sample size and poor statistical support [93]. The few prospective articles published cannot assess the true extent of statins in cancer treatment. It is also difficult to draw valid conclusions from heterogeneous articles, therapeutic regimens with different types and doses of statins; not systematized frequency of administration; dispensing or not concomitantly with chemotherapy; lipophilic *vs* hydrophilic statins, etc. In addition, it is also necessary to investigate what dose and how long statin treatment is needed to prevent cancer; or what mechanism of death (apoptosis *vs* autophagy) is responsible for the observed effects [94]. In addition, it is not well known whether statins reduce the degree of tumor aggressiveness [71] or allow them to be diagnosed earlier [95]. Second, the response to statins may depend on interindividual variability that may explain the variation in pharmacological response to them [93]. HMGCoAR expression is known as a tumor biomarker. Thus, in ovarian cancer, is associated with greater survival without recurrence [96]. In colorectal cancer, the chemopreventive capacity of statins depends on polymorphisms in the HMGCoAR gene [72]. Even so, population studies have shown chemopreventive and survival benefits of statins in several types of cancer [93]. Thus, in a casecontrol study, cancer was diagnosed less frequently among patients who took statins (28%) [78]. Also, the use of statins in cancer patients is associated with a reduction in cancer-related mortality [74]. But in a clinical trial, designed to evaluate the effect of pravastatin combined with sorafenib on hepatocellular carcinoma, no improvement in survival was observed in these patients [73]. On the other hand, is the use of statins effective and safe in the treatment of these neoplasms? While epidemiological studies

are contradictory, preclinical studies confirm the anticancer efficacy of statins in controlling metastatic disease [20, 93] due to growth inhibition and cell death, both *in vitro* and *in vivo* [20]. These contradictory epidemiological data generate uncertainty regarding the role of cholesterol in the development of cancer [97]. Based on data from long-term studies of cardiovascular disease, neither taking statins nor lowering serum cholesterol levels increases cancer risk [76]. These discrepant data may be due to inadequate methodological designs (retrospective *vs* prospective), insufficient follow-up, and/or the different types of statins used [98]. In this sense, some mechanisms can alter cholesterol homeostasis and lead to cancer development [97]. Are statins safe or do they have any degree of toxicity? Toxicity caused by statins it is more selective in tumor than in healthy cells [99]. This fact has been observed in osteosarcoma cell lines with simvastatin [24]; or in Ewing's sarcoma cells, with lovastatin [75]. These data are critical, because these drugs are safe and well tolerated, and the achievable plasma concentration (0.1−4 μM) at a dose of 24 mg/kg/day corresponds to the dose range that can trigger apoptosis in vitro [100]. Moreover, treatment with atorvastatin, evaluated for 3 years in growing patients diagnosed with heterozygous familial hypercholesterolemia, was effective, safe, and well tolerated [9], with no impact on child growth or maturation, with only a few adverse events responsible for a 2.2% treatment withdrawal. With respect to the toxic effects of fluvastatin in terminal pediatric Ewing's sarcoma patients, fluvastatin showed that can be used safely at a dose of 8 mg/kg/day in this population [77].

In conclusion, for the above-mentioned reasons, even though many aspects remain to be resolved, we consider statins to be good potential candidates for being reprofiled in sarcomas. However, further studies in sarcoma patients, with large phase III prospective randomized controlled trials are warranted to establish the effect of statins in cancer prevention and treatment [93], and to answer the question of whether statins can be used to prevent and/or treat various types of cancer [71], including sarcomas.
