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