Effect of pravastatin on survival in patients with advanced hepatocellular carcinoma. A randomized controlled trial

Abstract

Summary Chemotherapy is not effective for hepatocellular carcinoma (HCC). HMG-CoA redutase inhibitors have cytostatic activity for cancer cells, but their clinical usefulness is unknown. To investigate whether pravastatin, a potent HMG-CoA reductase inhibitor, prolongs survival in patients with advanced HCC, this randomized controlled trial was conducted between February 1990 and February 1998 at Osaka University Hospital. 91 consecutive patients <71 years old (mean age 62) with unresectable HCC were enroled in this study. 8 patients were withdrawn because of progressive liver dysfunction; 83 patients were randomized to standard treatment with or without pravastatin. All patients underwent transcatheter arterial embolization (TAE) followed by oral 5-FU 200 mg -1 d for 2 months. Patients were then randomly assigned to control (n = 42) and pravastatin (n = 41) groups. Pravastatin was administered at a daily dose of 40 mg. The effect of pravastatin on tumour growth was assessed by ultrasonography. Primary endpoint was death due to progression of HCC. The duration of pravastatin administration was 16.5 ± 9.8 months (mean ± SD). No patients in either group were lost to follow-up. Median survival was 18 months in the pravastatin group versus 9 months in controls (P = 0.006). The Cox proportional hazards model showed that pravastatin was a significant factor contributing to survival. Pravastatin prolonged the survival of patients with advanced HCC, suggesting its value for adjuvant treatment.

Statins induce mammalian target of rapamycin (mTOR)-mediated inhibition of Akt signaling and sensitize p53-deficient cells to cytostatic drugs

“…However, in most of these studies, mutated or p53-null cell lines were used, and we show that this characteristic could be critical for the cell-killing effects. In a clinical trial on advanced human hepatocellular carcinoma, a synergistic effect between pravastatin and 5-FU was reported (9). Interestingly, in this study, >80% of the patients were infected by hepatitis C virus, which is associated with frequently mutated p53, especially in late stages of the disease (43,44).…”

“…Statin-induced Akt inhibition correlated with decreased phosphorylation of GSK3h on Ser 9 and with the inhibition of cell proliferation. Cells were blocked in G 1 phase without any signs of apoptosis.…”

“…In a recent study, simvastatin inhibited the small cell lung cancer tumor growth in vivo (5). Furthermore, pravastatin was found to prolong the survival of patients with advanced hepatocellular carcinoma in a randomized trial (9). The mechanisms for these anticancer effects are still not well characterized.…”

RhoA GTPase inactivation by statins induces osteosarcoma cell apoptosis by inhibiting p42/p44-MAPKs-Bcl-2 signaling independently of BMP-2 and cell differentiation

“…39 In preliminary experiments, we found that the addition of conventional cytotoxic drugs (doxorubicin, 100 ng/ml; cisplatin, 20 mM) to lipophilic statins enhanced by three-to 15-fold osteosarcoma cell death induced by statins (unpublished data), suggesting that statins may be of therapeutic interest when combined with standard therapeutic approaches to enhance osteosarcoma cell apoptosis. Further experimental studies, now in progress, are needed to determine the potential interest of low doses of statins in association with conventional cytotoxic drugs as apoptosistriggering agents on osteosarcoma cell development and tumour progression in vivo.…”

The association between 3‐hydroxy‐3‐methylglutaryl conenzyme A inhibitor use and breast carcinoma risk among postmenopausal women

“…25 Small clinical trials have evaluated the dosing and scheduling of statins as adjuncts to chemotherapeutic agents. 20,[41][42][43][44] The trials have found dosing to be significant, and dose-related toxicity to be minimal, but there has been only slight tumor response. One trial of longer duration (54 days) found a more favorable response among patients with leukemia.…”