Multicenter, Phase III, Randomized, Double-Blind, Placebo-Controlled Trial of Pravastatin Added to First-Line Standard Chemotherapy in Small-Cell Lung Cancer (LUNGSTAR)

Abstract

PurposeTreating small-cell lung cancer (SCLC) remains a therapeutic challenge. Experimental studies show that statins exert additive effects with agents, such as cisplatin, to impair tumor growth, and observational studies suggest that statins combined with anticancer therapies delay relapse and prolong life in several cancer types. To our knowledge, we report the first large, randomized, placebo-controlled, double-blind trial of a statin with standard-of-care for patients with cancer, specifically SCLC.Patients and MethodsPatients with confirmed SCLC (limited or extensive disease) and performance status 0 to 3 were randomly assigned to receive daily pravastatin 40 mg or placebo, combined with up to six cycles of etoposide plus cisplatin or carboplatin every 3 weeks, until disease progression or intolerable toxicity. Primary end point was overall survival (OS), and secondary end points were progression-free survival (PFS), response rate, and toxicity.ResultsEight hundred forty-six patients from 91 United Kingdom hospitals were recruited. The median age of recruited patients was 64 years of age, 43% had limited disease, and 57% had extensive disease. There were 758 deaths and 787 PFS events. No benefit was found for pravastatin, either in all patients or in several subgroups. For pravastatin versus placebo, the 2-year OS rate was 13.2% (95% CI, 10.0 to 16.7) versus 14.1% (95% CI, 10.9 to 17.7), respectively, with a hazard ratio of 1.01 (95% CI, 0.88 to 1.16; P = .90. The median OS was 10.7 months v 10.6 months, respectively. The median PFS was 7.7 months v 7.3 months, respectively. The median OS (pravastatin v placebo) was 14.6 months in both groups for limited disease and 9.1 months versus 8.8 months, respectively, for extensive disease. Adverse events were similar between groups.ConclusionPravastatin 40 mg combined with standard SCLC therapy, although safe, does not benefit patients. Our conclusions are the same as those found in all four much smaller, randomized, placebo-controlled trials specifically designed to evaluate statin therapy in patients with cancer.

Risk of Cause‐Specific Death in Individuals with Cancer—Modifying Role Diabetes, Statins and Metformin

“…This raises a question if the observed effect of statin use in this study is at least partly due to confounding. In a trial of pravastatin added to first‐line standard chemotherapy in small‐cell lung cancer, no effect on overall survival was detected . In subpopulation of our study subpopulation analyses with 445 small cell lung cancers cases likewise gave similar result, no association between statin usage and all‐cause mortality was observed.…”

“…Statin therapy is frequently used in diabetic patients for the prevention of cardiovascular complications, but a recent large meta‐analysis showed that statin therapy was associated with reduced cancer‐specific mortality as well (HR 0.60, 0.47–0.77) . Conversely, recently some observational studies, and clinical trials have not detected any effect on survival. Thus, the prognosis in diabetic patient with cancer is driven by several factors and cardiovascular and cancer‐specific causes being the main competing causes.…”

Adjuvant statin therapy for oesophageal adenocarcinoma: the STAT-ROC feasibility study

“…Completion of both the QLQ-C30 and QLQ-OG25 questionnaires was high overall (98⋅3 per cent) and at each follow-up visit, suggesting the feasibility of assessing quality of life in a future phase III RCT. Published trials (3 of which were phase III and have been summarized previously 34 ) have assessed the effect of allocation to statins on mortality outcomes in patients with solid tumours 30,31,35 -41 including gastro-oesophageal 30,31 , colorectal 35 , pancreatic 36 , hepatocellular 37 and lung 38,40,41 . In line with guidance on the conduct of feasibility studies, this study was not powered to test efficacy.…”

Do Statins Improve Survival in Small-Cell Lung Cancer?

“…In the article that accompanies this editorial, Seckl et al 9 report the results of the LUNGSTAR trial, which was designed to test the hypothesis that statin use improves overall survival (OS) in patients with SCLC. In this study, 846 patients with either limited or extensive stage and performance status 0 to 3 were prospectively randomly assigned during a 5-year period to pravastatin (40 mg daily) or placebo for 2 years in a blinded manner, aiming to detect a hazard ratio (HR) of 0.82 assuming a median survival of 12 months.…”

“…Notwithstanding the potential biases above, several prospective, blinded trials have now also confirmed no benefit for statins in improving OS or progressionfree survival, as highlighted by the investigators themselves. 9 LUNGSTAR is by far the largest prospective study to answer this question in any given cancer type and has definitely demonstrated no benefit. Was this because pravastatin did not have the desired biologic effect in LUNGSTAR?…”