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

Abstract

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/m2 on days 1, 8, and 15 plus simvastatin 40 mg once daily) or GP (gemcitabine 1,000 mg/m2 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.

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References

  1. 1.

    Burris HA 3rd, Moore MJ, Andersen J, Green MR, Rothenberg ML, Modiano MR, Cripps MC, Portenoy RK, Storniolo AM, Tarassoff P, Nelson R, Dorr FA, Stephens CD, Von Hoff DD (1997) Improvements in survival and clinical benefit with gemcitabine as first-line therapy for patients with advanced pancreas cancer: a randomized trial. J Clin Oncol 15:2403–2413

    CAS  PubMed  Google Scholar 

  2. 2.

    Moore MJ, Goldstein D, Hamm J, Figer A, Hecht JR, Gallinger S, Au HJ, Murawa P, Walde D, Wolff RA, Campos D, Lim R, Ding K, Clark G, Voskoglou-Nomikos T, Ptasynski M, Parulekar W, National Cancer Institute of Canada Clinical Trials G (2007) Erlotinib plus gemcitabine compared with gemcitabine alone in patients with advanced pancreatic cancer: a phase III trial of the national cancer institute of Canada clinical trials group. J Clin Oncol 25:1960–1966

    CAS  PubMed  Article  Google Scholar 

  3. 3.

    Miksad RA, Schnipper L, Goldstein M (2007) Does a statistically significant survival benefit of erlotinib plus gemcitabine for advanced pancreatic cancer translate into clinical significance and value? J Clin Oncol 25:4506–4507; author reply 4508

    Google Scholar 

  4. 4.

    Conroy T, Desseigne F, Ychou M, Bouche O, Guimbaud R, Becouarn Y, Adenis A, Raoul JL, Gourgou-Bourgade S, de la Fouchardiere C, Bennouna J, Bachet JB, Khemissa-Akouz F, Pere-Verge D, Delbaldo C, Assenat E, Chauffert B, Michel P, Montoto-Grillot C, Ducreux M, Groupe tumeurs digestives of U, intergroup P (2011) FOLFIRINOX versus gemcitabine for metastatic pancreatic cancer. N Engl J Med 364:1817–1825

    CAS  PubMed  Article  Google Scholar 

  5. 5.

    Reni M, Cordio S, Milandri C, Passoni P, Bonetto E, Oliani C, Luppi G, Nicoletti R, Galli L, Bordonaro R, Passardi A, Zerbi A, Balzano G, Aldrighetti L, Staudacher C, Villa E, Di Carlo V (2005) Gemcitabine versus cisplatin, epirubicin, fluorouracil, and gemcitabine in advanced pancreatic cancer: a randomised controlled multicentre phase III trial. Lancet Oncol 6:369–376

    CAS  PubMed  Article  Google Scholar 

  6. 6.

    Graaf MR, Beiderbeck AB, Egberts AC, Richel DJ, Guchelaar HJ (2004) The risk of cancer in users of statins. J Clin Oncol 22:2388–2394

    CAS  PubMed  Article  Google Scholar 

  7. 7.

    Poynter JN, Gruber SB, Higgins PD, Almog R, Bonner JD, Rennert HS, Low M, Greenson JK, Rennert G (2005) Statins and the risk of colorectal cancer. N Engl J Med 352:2184–2192

    CAS  PubMed  Article  Google Scholar 

  8. 8.

    Chiu HF, Ho SC, Chen CC, Yang CY (2011) Statin use and the risk of liver cancer: a population-based case-control study. Am J Gastroenterol 106:894–898

    PubMed  Article  Google Scholar 

  9. 9.

    Ahern TP, Pedersen L, Tarp M, Cronin-Fenton DP, Garne JP, Silliman RA, Sorensen HT, Lash TL (2011) Statin prescriptions and breast cancer recurrence risk: a Danish nationwide prospective cohort study. J Natl Cancer Inst 103:1461–1468

    CAS  PubMed  Article  Google Scholar 

  10. 10.

    Nielsen SF, Nordestgaard BG, Bojesen SE (2012) Statin use and reduced cancer-related mortality. N Engl J Med 367:1792–1802

    CAS  PubMed  Article  Google Scholar 

  11. 11.

    Jakobisiak M, Golab J (2003) Potential antitumor effects of statins (Review). Int J Oncol 23:1055–1069

    CAS  PubMed  Google Scholar 

  12. 12.

    Chan KKW, Oza AM, Siu LL (2003) The statins as anticancer agents. Clin Cancer Res 9:10–19

    CAS  PubMed  Google Scholar 

  13. 13.

    Dimitroulakos J, Marhin WH, Tokunaga J, Irish J, Gullane P, Penn LZ, Kamel-Reid S (2002) Microarray and biochemical analysis of lovastatin-induced apoptosis of squamous cell carcinomas. Neoplasia 4:337–346

    CAS  PubMed Central  PubMed  Article  Google Scholar 

  14. 14.

    Park HJ, Kong D, Iruela-Arispe L, Begley U, Tang D, Galper JB (2002) 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors interfere with angiogenesis by inhibiting the geranylgeranylation of RhoA. Circ Res 91:143–150

    CAS  PubMed  Article  Google Scholar 

  15. 15.

    Kusama T, Mukai M, Iwasaki T, Tatsuta M, Matsumoto Y, Akedo H, Inoue M, Nakamura H (2002) 3-hydroxy-3-methylglutaryl-coenzyme a reductase inhibitors reduce human pancreatic cancer cell invasion and metastasis. Gastroenterology 122:308–317

    CAS  PubMed  Article  Google Scholar 

  16. 16.

    Dulak J, Jozkowicz A (2005) Anti-angiogenic and anti-inflammatory effects of statins: relevance to anti-cancer therapy. Curr Cancer Drug Targets 5:579–594

    CAS  PubMed Central  PubMed  Article  Google Scholar 

  17. 17.

    Jakobisiak M, Bruno S, Skierski JS, Darzynkiewicz Z (1991) Cell cycle-specific effects of lovastatin. Proc Natl Acad Sci USA 88:3628–3632

    CAS  PubMed  Article  Google Scholar 

  18. 18.

    Lee J, Lee I, Park C, Kang WK (2006) Lovastatin-induced RhoA modulation and its effect on senescence in prostate cancer cells. Biochem Biophys Res Commun 339:748–754

    CAS  PubMed  Article  Google Scholar 

  19. 19.

    Gbelcova H, Lenicek M, Zelenka J, Knejzlik Z, Dvorakova G, Zadinova M, Pouckova P, Kudla M, Balaz P, Ruml T, Vitek L (2008) Differences in antitumor effects of various statins on human pancreatic cancer. Int J Cancer 122:1214–1221

    CAS  PubMed  Article  Google Scholar 

  20. 20.

    Bocci G, Fioravanti A, Orlandi P, Bernardini N, Collecchi P, Del Tacca M, Danesi R (2005) Fluvastatin synergistically enhances the antiproliferative effect of gemcitabine in human pancreatic cancer MIAPaCa-2 cells. Br J Cancer 93:319–330

    CAS  PubMed Central  PubMed  Article  Google Scholar 

  21. 21.

    Xiong HQ, Rosenberg A, LoBuglio A, Schmidt W, Wolff RA, Deutsch J, Needle M, Abbruzzese JL (2004) Cetuximab, a monoclonal antibody targeting the epidermal growth factor receptor, in combination with gemcitabine for advanced pancreatic cancer: a multicenter phase II Trial. J Clin Oncol 22:2610–2616

    CAS  PubMed  Article  Google Scholar 

  22. 22.

    Bruns CJ, Harbison MT, Davis DW, Portera CA, Tsan R, McConkey DJ, Evans DB, Abbruzzese JL, Hicklin DJ, Radinsky R (2000) Epidermal growth factor receptor blockade with C225 plus gemcitabine results in regression of human pancreatic carcinoma growing orthotopically in nude mice by antiangiogenic mechanisms. Clin Cancer Res 6:1936–1948

    CAS  PubMed  Google Scholar 

  23. 23.

    Philip PA, Benedetti J, Corless CL, Wong R, O’Reilly EM, Flynn PJ, Rowland KM, Atkins JN, Mirtsching BC, Rivkin SE, Khorana AA, Goldman B, Fenoglio-Preiser CM, Abbruzzese JL, Blanke CD (2010) Phase III study comparing gemcitabine plus cetuximab versus gemcitabine in patients with advanced pancreatic adenocarcinoma: southwest oncology group-directed intergroup trial S0205. J Clin Oncol 28:3605–3610

    CAS  PubMed  Article  Google Scholar 

  24. 24.

    Lee J, Lee I, Han B, Park JO, Jang J, Park C, Kang WK (2011) Effect of simvastatin on cetuximab resistance in human colorectal cancer with KRAS mutations. J Natl Cancer Inst 103:674–688

    CAS  PubMed  Article  Google Scholar 

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Acknowledgments

This work was supported by Grants from the Korean Health Technology R&D Project, Ministry of Health and Welfare, Republic of Korea (A102166).

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Correspondence to Young Suk Park.

Additional information

Jung Yong Hong and Eun Mi Nam have contributed equally to the work presented here.

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Hong, J.Y., Nam, E.M., Lee, J. et al. Randomized double-blinded, placebo-controlled phase II trial of simvastatin and gemcitabine in advanced pancreatic cancer patients. Cancer Chemother Pharmacol 73, 125–130 (2014). https://doi.org/10.1007/s00280-013-2328-1

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Keywords

  • Chemotherapy
  • Pancreatic cancer
  • Gemcitabine
  • Simvastatin