Role of Statins in the Treatment of Pancreatic Ductal Adenocarcinoma (PDAC)

Pancreatic ductal adenocarcinoma (PDAC) is a common cause of cancer-related mortality [1]. Moreover, a majority of patients (80%) are diagnosed at an advanced stage at presentation precluding surgical resection which is the mainstay of curative treatment options [1,2]. Multi-agent chemotherapy has been developed in recent years and have shown improved survival rates, even in patients with locally advanced and metastatic tumours [3,4]. In addition, adjuvant chemotherapy has also conferred a survival advantage in patients with resected pancreatic cancer [5,6]. However, despite these developments, PDAC related mortality remains high, with a 5 year survival rate of 6 7% across all stages [7,8]. This has Crimson Publishers Wings to the Research Research Article

Statins are a class of drugs that are primarily 3-hydroxy-3methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors. They are commonly used for their lipid lowering effects which in turn lead to lower cardiovascular morbidity and mortality in patients with coronary artery diseases [13,14]. In addition, statins have also been shown to have anti-inflammatory and immunomodulatory effects that seem to exert an anti-neoplastic effect by inducing apoptosis, inhibiting angiogenesis and preventing tumour metastasis [14]. Anti-tumour activity is mainly mediated by HMG-CoA reductase inhibition which is a rate limiting enzyme in the mevalonate/cholesterol synthesis pathway [15,16]. In addition, pre-clinical studies in K-Ras mutant mice have demonstrated delayed progression of Pancreatic Intraepithelial Neoplasia (PanIN) lesions to PDAC with statins [17,18]. The role of statins in the treatment of PDAC however, remains controversial. Recent observational studies and meta-analyses support the role of statin use to prevent development of PDAC [11,19]. Moreover, statins have also shown benefit in specific subgroups of patients with resectable and unresectable PDAC [20][21][22]. However, heterogenous patient population and inconsistent results among the observational studies limit generalizability of these findings. In addition, the dose response relationship and varying effect of the different types of statins needs more clarity. In order to further elucidate the protective role of statins with overall survival in patients with PDAC, we performed an observational cohort study at a large tertiary care referral centre. In addition, we also studied the differential effects of the type of statins and the dose-response relationship of statins with PDAC outcomes.

Study participants and design
This was a single centre, prospective observational cohort study conducted in a high-volume tertiary care centre, between Based on criteria used in the modified Glasgow prognostic score for cancers. the cut-off for CRP and albumin was taken as 10mg/L and 3.5gm/dL respectively [23]. Patients with metastatic disease were considered for chemotherapy with either modified FOLFIRINOX regimen or Gemcitabine plus nab-Paclitaxel regimen based on clinical parameters and performance status [24,25]. Patients with poor functional status were managed conservatively with palliative biliary drainage and optimal pain management. Palliative biliary drainage was achieved by the endoscopic placement of an endobiliary prosthesis (plastic biliary stent/Self Expanding Metal Stent (SEMS)) using Endoscopic Retrograde Cholangiography (ERC). The 7 th edition of the tumour-node-metastasis system from the American Joint Committee on Cancer was used to determine the clinical stage of the study patients [26]. In inoperable patients, clinical cancer stage was confirmed by imaging studies, including ultrasonography, computed tomography, magnetic resonance imaging, and positron emission tomography.

Outcomes of the study
Overall Survival (OS) was defined as the interval from the diagnosis date to the date of death from any cause or last follow-up

Statistical analysis
Statistical analysis was performed using IBM SPSS Statistics for Windows, version 20.0 (IBM Corp., Armonk, N.Y., USA). Categorical variables were expressed using frequency and percentage.
Continuous variables were presented by mean and standard deviation. Univariate analysis was first performed to assess the association of known factors that affect overall survival. Following this multivariate logistic regression analysis was performed to adjust for confounding variables in order to compute a hazard ratio with 95% Confidence Interval (CI) for overall survival as well as progression free survival. A p value ≤ 0.05 was considered statistically significant. Survival probability of patients on statins and the comparison of all factors that affect survival was performed using Kaplan Meier analysis and log rank test was used to test significance. A multivariate Cox regression analysis was performed to then ascertain level of significance of statins with overall survival.  Table 1.

Outcome analysis
Overall mortality at 1 year in this study was 85/86 patients

Discussion
Pancreatic Ductal Adenocarcinoma (PDAC) is a disease that causes significant morbidity and mortality [1]. Despite progress made in multimodality treatment with surgery, chemotherapy, radiotherapy and immunotherapy, the mortality rate of pancreatic cancer has remained considerably high. This is largely attributable to a late diagnosis, as most patients with pancreatic cancer remain asymptomatic until the disease develops to an advanced stage [29]. Statins (HMG-CoA reductase inhibitors) are one of the most commonly used drugs used primarily for both primary and secondary prevention of cardiovascular events [30]. The antitumour activity of statins has been well documented in pre-clinical studies [31]. Multiple studies have shown that statins may inhibit the growth of a variety of cancer cell types, including hepatocellular cancer, renal cell carcinoma, breast cancer, medulloblastoma and glioblastoma multiforme [32][33][34]. Inhibition of the key enzyme of the mevalonate pathway, HMG-CoA reductase, results in the reduced production of important compounds essential for cancer cell survival, like isoprenoids, dolichol, ubiquinone, and isopentenyl adenine [35]. The role of statins in the prevention of PDAC in high risk subgroups has been documented in the past [20,22,36].

Conclusion
In conclusion, Statins (especially atorvastatin) were found to reduce the risk of mortality by 66% (HR 0.34, 95% CI 0.19 -0.78) in patients with PDAC. This association was maintained in multivariate analysis after adjusting for all confounding factors. The effect of statins was most evident in patients with metastatic disease and in those who were managed conservatively with no chemotherapy/ surgical interventions. A dose-response relationship was observed among patients on Atorvastatin and is an important aspect that needs further validation. Future interventional trials with predesigned type and dosage of statins in patients with PDAC are warranted to establish their efficacy in specified treatment groups.

Strobe Statement
Strobe Statement have been adopted.

Institutional Review Board Statement
The study was reviewed and approved by the institutional review boards of Amrita Institute of Medical Sciences, Kochi, Kerala.

Informed Consent Statement
All study participants, or their legal guardian, provided written consent prior to study enrollment.