Elsevier

European Journal of Cancer

Volume 46, Issue 18, December 2010, Pages 3200-3204
European Journal of Cancer

The addition of pravastatin to chemotherapy in advanced gastric carcinoma: A randomised phase II trial

https://doi.org/10.1016/j.ejca.2010.07.036Get rights and content

Abstract

Purpose

Statins have for long been considered to play a potential role in anticancer treatment based upon their ability to inhibit the mevalonate synthesis pathway. This randomised phase II trial compared the efficacy and safety of pravastatin added to epirubicin, cisplatin and capecitabine (ECC versus ECC + P) in patients with advanced gastric carcinoma.

Methods

Patients were randomised to receive up to six cycles of 3-weekly ECC with or without pravastatin (40 mg, once daily from day 1 of the first cycle until day 21 of the last cycle). Primary end-point was progression-free rate at 6 months (PFR6months). Secondary end-points were response rate (RR), progression-free survival (PFS), overall survival (OS) and safety. For early termination in case of futility, a two-stage design was applied (P0 = 50%; P1 = 70%; α = 0.05; β = 0.10).

Results

Thirty patients were enrolled. PFR6months was 6/14 patients (42.8%) in the ECC + P arm, and 7/15 patients (46.7%) in the control arm, and therefore the study was terminated after the first stage. In the ECC and ECC + P arm, RR was 7/15 (46.7%) and 5/15 (33.3%), median PFS was 5 and 6 months and median OS was 6 and 8 months, respectively. Toxicity data showed no significant differences, although there was a trend towards more gastrointestinal side-effects such as diarrhoea and stomatitis in the ECC + P arm.

Conclusion

In this randomised phase II trial the addition of pravastatin to ECC did not improve outcome in patients with advanced gastric cancer. Therefore, further testing of this combination in a randomised phase III trial cannot be recommended.

Introduction

Worldwide, gastric adenocarcinoma is the fourth most common cancer type.1 Patients with advanced, non-resectable disease have a dismal prognosis with a median overall survival of 3–5 months. In advanced gastric carcinoma 5-fluorouracil-containing chemotherapy has shown to increase overall survival when compared to best supportive care, making chemotherapy a viable treatment option for these patients.2, 3, 4 In addition, several randomised phase III trials have established the combination of epirubicin, cisplatin and capecitabine (ECC) as a potential standard of care.5 Still, prognosis of patients with advanced gastric carcinoma remains poor with a median progression-free survival and overall survival of 6–7 and 9–11 months, respectively.6

HMG-CoA-reductase inhibitors, frequently referred to as statins, are commonly prescribed drugs to lower serum cholesterol. Statins act by decreasing synthesis of mevalonate, the precursor of cholesterol. Mevalonate is also a precursor for isoprenoids, which play an important role in the membrane attachment of several GTP-binding proteins. These are pivotal in down-stream signalling of many plasma membrane receptors involved in cellular processes such as proliferation, differentiation and apoptosis. By decreasing synthesis of isoprenoids and other yet unknown mechanisms, statins exert antiproliferative effects, attenuate metastatic potential, inhibit angiogenesis and enhance antitumour immunity in tumour cells.7 By these mechanisms, statins exhibit antitumour activity against a wide range of tumour types including gastric carcinoma.8, 9 Moreover, in patients with advanced gastric carcinoma, high-dose statins induced disease stabilisation for 16 weeks in some patients.9

Statins have shown in vitro and in animal models to interact synergistically with several chemotherapeutic agents including cisplatin,10 5-fluorouracil11 and doxorubicin,12 the latter being structurally almost identical to epirubicin. The exact mechanism underlying this synergism is not fully elucidated, but might involve a statin-induced decrease in Bcl-2.11

Pravastatin is one of the most commonly prescribed statins and is known for its mild toxicity profile. It is more hydrophilic than other statins resulting in higher concentrations in peripheral tissues such as the stomach.13 Clinically pravastatin demonstrated preliminary hints of efficacy in patients with hepatocellular carcinoma, where patients treated with pravastatin 40 mg once daily (OD) after chemotherapy showed increased survival compared to patients without pravastatin.14

Based upon its mechanism of action, non-overlapping toxicity profile and the synergistic interaction in particular, the combination of ECC with pravastatin was chosen in this randomised phase II study to assess its role in patients with advanced gastric carcinoma.

Section snippets

Eligibility criteria

Patients with a histologically proven gastric adenocarcinoma not amenable for curative resection and with evaluable disease according to Response Evaluation Criteria in Solid Tumours (RECIST) were eligible.15 No prior chemotherapy, radiotherapy or the use of HMG-CoA-reductase inhibitors was allowed. Other eligibility criteria included: age ⩾18 years; Eastern Cooperative Oncology Group (ECOG) performance ⩽2; adequate bone marrow function (white blood cell count (WBC) >3.0 × 109/L, absolute

Patient characteristics

From February 2005 to May 2009, 30 patients were enrolled. Baseline characteristics are summarised in Table 1. The study groups were well balanced in terms of their baseline characteristics, with a median age of 58 years (range 36–74 years) and a male–female ratio of approximately 4:1. Most patients had ECOG-performance score 1 and the most frequent sites of metastatic spread were to lymph nodes (90%) and peritoneum (30%). Forty-three percent of patients had two or more sites of metastases.

Treatment

A

Discussion

In recent years, the possible beneficial effect of statins in cancer prevention and treatment has repeatedly been suggested. In particular, the role of statins in cancer prevention has been extensively investigated, but recently published large meta-analyses did not reveal such a protective effect.17, 18 The potential role of statins to potentiate antitumour activity of conventional chemotherapeutic drugs has also been explored in clinical studies; one study assessed the combination of

Conflict of interest statement

The authors declare no conflicts of interest.

References (22)

  • D. Cunningham et al.

    Capecitabine and oxaliplatin for advanced esophagogastric cancer

    N Engl J Med

    (2008)
  • Cited by (50)

    • Unearthing the Janus-face cholesterogenesis pathways in cancer

      2022, Biochemical Pharmacology
      Citation Excerpt :

      It was noted that administration of pravastatin to patients with unresectable advanced hepatocellular carcinoma (HCC) resulted in a doubling of median survival in comparison to controls [127]. In a randomized phase II clinical trial that investigated the addition of pravastatin to epirubicin, cisplatin and capecitabine chemotherapy in patients with advanced gastric carcinoma resulted in no improved outcome for patients [128]. In a randomized phase II clinical trial that evaluated the efficacy and safety of gefitinib versus gefitinib + simvastatin in previously treated patients with advanced non-small cell lung cancer (NSCLC), no significant difference in responses rate and survival was observed between these two groups in unselected patients [129].

    • Effect of frequently prescribed drugs on gastric cancer risk

      2021, Best Practice and Research: Clinical Gastroenterology
      Citation Excerpt :

      Several studies investigated the effect of statins as concomitant therapy in addition to cancer treatment. Pravastatin in patients with advanced gastric carcinoma undergoing chemotherapy did not improve response rate, progression-free survival or overall survival [73]. Neither did concomitant simvastatin treatment in a double-blind placebo-controlled study on stage IV gastric cancer patients improve the outcome [74].

    • TPK1 as a predictive marker for the anti-tumour effects of simvastatin in gastric cancer

      2020, Pathology Research and Practice
      Citation Excerpt :

      Several studies have reported the anti-tumour effect of statins in vitro. Clinical trials including patients with GC have been performed based on these preclinical results, but none of have reported positive outcomes [6–8]. This lack of data highlights the need for adequate predictive markers of the ability of statins to act as anti-tumour agents in GC.

    View all citing articles on Scopus
    View full text