Randomized double-blinded, placebo-controlled phase II trial of simvastatin and gemcitabine in advanced pancreatic cancer patients

• Published in: Cancer chemotherapy and pharmacology Vol. 73; no. 1; pp. 125 - 130
• Main Authors: Hong, Jung Yong, Nam, Eun Mi, Lee, Jeeyun, Park, Joon Oh, Lee, Sang-Cheol, Song, Seo-Young, Choi, Seong Ho, Heo, Jin Seok, Park, Se Hoon, Lim, Ho Yeong, Kang, Won Ki, Park, Young Suk
• Format: Journal Article
• Language: English
• Published: Berlin/Heidelberg Springer Berlin Heidelberg 2014; Springer; Springer Nature B.V
• Subjects: Adult; Aged; Aged, 80 and over; Antineoplastic agents; Antineoplastic Combined Chemotherapy Protocols - therapeutic use; Biological and medical sciences; Cancer Research; Deoxycytidine - administration & dosage; Deoxycytidine - analogs & derivatives; Double-Blind Method; Female; Gastroenterology. Liver. Pancreas. Abdomen; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors - administration & dosage; Liver. Biliary tract. Portal circulation. Exocrine pancreas; Male; Medical sciences; Medicine; Medicine & Public Health; Middle Aged; Multiple tumors. Solid tumors. Tumors in childhood (general aspects); Mutation; Oncology; Original Article; Pancreatic cancer; Pancreatic Neoplasms - drug therapy; Pancreatic Neoplasms - mortality; Pharmacology. Drug treatments; Pharmacology/Toxicology; Proto-Oncogene Proteins - genetics; Proto-Oncogene Proteins p21(ras); ras Proteins - genetics; Receptor, Epidermal Growth Factor - antagonists & inhibitors; Simvastatin - administration & dosage; Tumors; Chemotherapy; Gemcitabine; Pancreatic cancer; Simvastatin; Antineoplastic agent; Toxicity; Randomization; HMG-CoA reductase inhibitor; Pancreas cancer; Phase II trial; Advanced stage; Pyrimidine nucleoside; Pancreatic disease; Human; Enzyme; Enzyme inhibitor; Statin derivative; Malignant tumor; Treatment; Antimetabolic; Placebo; Double blind study; Pyrimidine derivatives; Hydroxymethylglutaryl-CoA reductase; Digestive diseases; Fluorine Organic compounds; Oxidoreductases; Cancer
• ISSN: 0344-5704; 1432-0843
• DOI: 10.1007/s00280-013-2328-1

Background Statins have potential antineoplastic properties via arrest of cell-cycle progression and induction of apoptosis. A previous study demonstrated in vitro and in vivo antineoplastic synergism between statins and gemcitabine. The present randomized, double-blinded, phase II trial compared the efficacy and safety of gemcitabine plus simvastatin (GS) with those of gemcitabine plus placebo (GP) in patients with locally advanced and metastatic pancreatic cancer. Methods Patients were randomly assigned to receive a 3-week regimen with GS (gemcitabine 1,000 mg/m 2 on days 1, 8, and 15 plus simvastatin 40 mg once daily) or GP (gemcitabine 1,000 mg/m 2 on days 1, 8, and 15 plus placebo). The primary end point was time to progression (TTP). Results Between December 2008 and April 2012, 114 patients were enrolled. The median TTP was not significantly different between the two arms, being 2.4 months (95 % CI 0.7–4.1 months) and 3.6 months (95 % CI 3.1–4.1 months) in the GS and GP arms, respectively ( P  = 0.903). The overall disease control rate was 39.7 % (95 % CI 12.2–33.8 %) and 57.1 % (95 % CI 19.8–44.2 %) in the GS and GP arms, respectively ( P  = 0.09). The 1-year expected survival rates were similar (27.7 and 31.7 % in the GS and GP arms, respectively; P  = 0.654). Occurrence of grade 3 or 4 adverse events was similar in both arms, and no patients had rhabdomyolysis. Conclusions Adding low-dose simvastatin to gemcitabine in advanced pancreatic cancer does not provide clinical benefit, although it also does not result in increased toxicity. Given the emerging role of statins in overcoming resistance to anti-EGFR treatment, further studies are justified to evaluate the efficacy and safety of combined simvastatin and anti-EGFR agents, such as erlotinib or cetuximab, plus gemcitabine for treating advanced pancreatic cancer.