Skip to main content

Advertisement

Springer Nature Link
Log in

A multicenter phase II trial of gemcitabine and candesartan combination therapy in patients with advanced pancreatic cancer: GECA2

  • PHASE II STUDIES
  • Published:
Investigational New Drugs Aims and scope Submit manuscript

Summary

Background Our retrospective study and phase I trial of gemcitabine and candesartan combination therapy suggested the inhibition of renin-angiotensin system potentially has a role in the treatment of advanced pancreatic cancer. The aim of this multicenter phase II trial was to assess the efficacy and toxicity of gemcitabine and candesartan combination therapy for advanced pancreatic cancer. Methods Chemotherapy-naive patients with histologically or cytologically proven advanced pancreatic cancer were enrolled. Gemcitabine was administered at a dose of 1,000 mg/m2 over 30 min on days 1, 8, and 15 and oral candesartan at a dose of 16 mg in normotensive patients, and 8 mg initially in hypertensive patients, with dose escalation to 16 mg allowed, from days 1 to 28, repeated every 4 weeks. Results A total of 35 patients with advanced pancreatic cancer were enrolled. Overall response rate and disease control rate were 11.4 % and 62.9 %. The median PFS and OS were 4.3 and 9.1 months with 1-year survival rate of 34.2 %. The median PFS was significantly longer in patients receiving 16 mg compared with 8 mg of candesartan (4.6 vs. 3.5 months, p = 0.031). Major severe toxicities were neutropenia (23 %), leukopenia (17 %) and thrombocytopenia (11 %). Grade 2 hypotension was observed in 3 patients (9 %) and candesartan was discontinued in 2 patients due to hypotension. Conclusions In this multicenter phase 2 trial, gemcitabine and candesartan combination therapy was tolerable but failed to demonstrate activity against advanced pancreatic cancer. (UMIN CTR: UMIN000005580)

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Subscribe and save

Springer+ Basic
$34.99 /Month
  • Get 10 units per month
  • Download Article/Chapter or eBook
  • 1 Unit = 1 Article or 1 Chapter
  • Cancel anytime
Subscribe now

Buy Now

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2

Similar content being viewed by others

Explore related subjects

Discover the latest articles and news from researchers in related subjects, suggested using machine learning.

References

  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(6):2403–2413

    Article  CAS  Google Scholar 

  2. Nakai Y, Isayama H, Sasaki T, Sasahira N, Tsujino T, Toda N, Kogure H, Matsubara S, Ito Y, Togawa O, Arizumi T, Hirano K, Tada M, Omata M, Koike K (2012) A multicentre randomised phase II trial of gemcitabine alone vs gemcitabine and S-1 combination therapy in advanced pancreatic cancer: GEMSAP study. Br J Cancer 106(12):1934–1939. doi:https://doi.org/10.1038/bjc.2012.183

    Article  CAS  Google Scholar 

  3. 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(15):1960–1966. doi:https://doi.org/10.1200/JCO.2006.07.9525

    Article  CAS  Google Scholar 

  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(19):1817–1825. doi:https://doi.org/10.1056/NEJMoa1011923

    Article  CAS  Google Scholar 

  5. Von Hoff DD, Ervin TJ, Arena FP, Chiorean EG, Infante JR, Moore MJ, Seay TE, Tjulandin S, Ma WW, Saleh MN, Harris M, Reni M, Ramanathan RK, Tabernero J, Hidalgo M, Van Cutsem E, Goldstein D, Wei X, Iglesias JL, Renschler MF (2013) Randomized phase III study of weekly nab-paclitaxel plus gemcitabine versus gemcitabine alone in patients with metastatic adenocarcinoma of the pancreas (MPACT). ASCO Meet Abstr 31(4_suppl):LBA148

    Google Scholar 

  6. Sipahi I, Debanne SM, Rowland DY, Simon DI, Fang JC (2010) Angiotensin-receptor blockade and risk of cancer: meta-analysis of randomised controlled trials. Lancet Oncol 11(7):627–636. doi:https://doi.org/10.1016/S1470-2045(10)70106-6

    Article  CAS  Google Scholar 

  7. Bangalore S, Kumar S, Kjeldsen SE, Makani H, Grossman E, Wetterslev J, Gupta AK, Sever PS, Gluud C, Messerli FH (2011) Antihypertensive drugs and risk of cancer: network meta-analyses and trial sequential analyses of 324,168 participants from randomised trials. Lancet Oncol 12(1):65–82. doi:https://doi.org/10.1016/S1470-2045(10)70260-6

    Article  CAS  Google Scholar 

  8. Chang CH, Lin JW, Wu LC, Lai MS (2011) Angiotensin receptor blockade and risk of cancer in type 2 diabetes mellitus: a nationwide case–control study. J Clin Oncol 29(22):3001–3007. doi:https://doi.org/10.1200/JCO.2011.35.1908

    Article  CAS  Google Scholar 

  9. Lever AF, Hole DJ, Gillis CR, McCallum IR, McInnes GT, MacKinnon PL, Meredith PA, Murray LS, Reid JL, Robertson JW (1998) Do inhibitors of angiotensin-I-converting enzyme protect against risk of cancer? Lancet 352(9123):179–184. doi:https://doi.org/10.1016/S0140-6736(98)03228-0

    Article  CAS  Google Scholar 

  10. Ager EI, Neo J, Christophi C (2008) The renin-angiotensin system and malignancy. Carcinogenesis 29(9):1675–1684. doi:https://doi.org/10.1093/carcin/bgn171

    Article  CAS  Google Scholar 

  11. Khakoo AY, Sidman RL, Pasqualini R, Arap W (2008) Does the renin-angiotensin system participate in regulation of human vasculogenesis and angiogenesis? Cancer Res 68(22):9112–9115. doi:https://doi.org/10.1158/0008-5472.CAN-08-0851

    Article  CAS  Google Scholar 

  12. Mc Menamin UC, Murray LJ, Cantwell MM, Hughes CM (2012) Angiotensin-converting enzyme inhibitors and angiotensin receptor blockers in cancer progression and survival: a systematic review. Cancer Causes Control 23(2):221–230. doi:https://doi.org/10.1007/s10552-011-9881-x

    Article  Google Scholar 

  13. Kim ST, Park KH, Oh SC, Seo JH, Kim JS, Shin SW, Kim YH (2012) How does inhibition of the renin-angiotensin system affect the prognosis of advanced gastric cancer patients receiving platinum-based chemotherapy? Oncology 83(6):354–360. doi:https://doi.org/10.1159/000337979

    Article  CAS  Google Scholar 

  14. Nakai Y, Isayama H, Ijichi H, Sasaki T, Sasahira N, Hirano K, Kogure H, Kawakubo K, Yagioka H, Yashima Y, Mizuno S, Yamamoto K, Arizumi T, Togawa O, Matsubara S, Tsujino T, Tateishi K, Tada M, Omata M, Koike K (2010) Inhibition of renin-angiotensin system affects prognosis of advanced pancreatic cancer receiving gemcitabine. Br J Cancer 103(11):1644–1648. doi:https://doi.org/10.1038/sj.bjc.6605955

    Article  CAS  Google Scholar 

  15. Nakai Y, Isayama H, Ijichi H, Sasaki T, Kogure H, Yagioka H, Miyabayashi K, Mizuno S, Yamamoto K, Mouri D, Kawakubo K, Yamamoto N, Hirano K, Sasahira N, Tateishi K, Tada M, Koike K (2012) Phase I trial of gemcitabine and candesartan combination therapy in normotensive patients with advanced pancreatic cancer: GECA1. Cancer Sci 103(8):1489–1492. doi:https://doi.org/10.1111/j.1349-7006.2012.02311.x

    Article  CAS  Google Scholar 

  16. Therasse P, Arbuck SG, Eisenhauer EA, Wanders J, Kaplan RS, Rubinstein L, Verweij J, Van Glabbeke M, van Oosterom AT, Christian MC, Gwyther SG (2000) New guidelines to evaluate the response to treatment in solid tumors. European Organization for Research and Treatment of Cancer, National Cancer Institute of the United States, National Cancer Institute of Canada. J Natl Cancer Inst 92(3):205–216

    Article  CAS  Google Scholar 

  17. Gong Q, Davis M, Chipitsyna G, Yeo CJ, Arafat HA (2010) Blocking angiotensin II type 1 receptor triggers apoptotic cell death in human pancreatic cancer cells. Pancreas 39(5):581–594. doi:https://doi.org/10.1097/MPA.0b013e3181c314cd

    Article  CAS  Google Scholar 

  18. Erkan M, Hausmann S, Michalski CW, Fingerle AA, Dobritz M, Kleeff J, Friess H (2012) The role of stroma in pancreatic cancer: diagnostic and therapeutic implications. Nat Rev Gastroenterol Hepatol 9(8):454–467. doi:https://doi.org/10.1038/nrgastro.2012.115

    Article  CAS  Google Scholar 

  19. Arnold SA, Rivera LB, Carbon JG, Toombs JE, Chang CL, Bradshaw AD, Brekken RA (2012) Losartan slows pancreatic tumor progression and extends survival of SPARC-null mice by abrogating aberrant TGFbeta activation. PLoS One 7(2):e31384. doi:https://doi.org/10.1371/journal.pone.0031384

    Article  CAS  Google Scholar 

  20. Masamune A, Hamada S, Kikuta K, Takikawa T, Miura S, Nakano E, Shimosegawa T (2013) The angiotensin II type I receptor blocker olmesartan inhibits the growth of pancreatic cancer by targeting stellate cell activities in mice. Scand J Gastroenterol. doi:https://doi.org/10.3109/00365521.2013.777776

  21. Chaturvedi N, Porta M, Klein R, Orchard T, Fuller J, Parving HH, Bilous R, Sjolie AK, Group DPS (2008) Effect of candesartan on prevention (DIRECT-Prevent 1) and progression (DIRECT-Protect 1) of retinopathy in type 1 diabetes: randomised, placebo-controlled trials. Lancet 372(9647):1394–1402. doi:https://doi.org/10.1016/S0140-6736(08)61412-9

    Article  CAS  Google Scholar 

  22. Sjolie AK, Klein R, Porta M, Orchard T, Fuller J, Parving HH, Bilous R, Chaturvedi N, Group DPS (2008) Effect of candesartan on progression and regression of retinopathy in type 2 diabetes (DIRECT-Protect 2): a randomised placebo-controlled trial. Lancet 372(9647):1385–1393. doi:https://doi.org/10.1016/S0140-6736(08)61411-7

    Article  Google Scholar 

  23. Osmak M (2012) Statins and cancer: current and future prospects. Cancer Lett 324(1):1–12. doi:https://doi.org/10.1016/j.canlet.2012.04.011

    Article  CAS  Google Scholar 

  24. Nakai Y, Isayama H, Sasaki T, Mizuno S, Sasahira N, Kogure H, Kawakubo K, Yamamoto N, Hirano K, Ijichi H, Tateishi K, Tada M, Koike K (2013) Clinical outcomes of chemotherapy for diabetic and nondiabetic patients with pancreatic cancer: better prognosis with statin use in diabetic patients. Pancreas 42(2):202–208. doi:https://doi.org/10.1097/MPA.0b013e31825de678

    Article  CAS  Google Scholar 

Download references

Acknowledgments

We thank Drs. Dai Mohri, Syuhei Kawahata, Tomotaka Saito, Takeo Watanabe, at Department of Gastroenterology, Graduate School of Medicine, The University of Tokyo for the care of patients, and Drs. Ryo Nakata at Japanese Red Cross Medical Center, Kei Ogura at Tokyo Metropolitan Police Hospital, Takao Kawase at Kanto Central Hospital, Makoto Okamoto at JR Tokyo General Hospital and Nobuo Toda at Mitsui Memorial Hospital for the support.

Disclosures

The authors have declared no conflicts of interest

Author information

Authors and Affiliations

  1. Department of Gastroenterology, Graduate School of Medicine, The University of Tokyo, 7-3-1 Hongo Bunkyo-ku, Tokyo, Japan, 113-8655

    Yousuke Nakai, Hiroyuki Isayama, Hideaki Ijichi, Takashi Sasaki, Naminatsu Takahara, Tsuyoshi Hamada, Koji Miyabayashi, Suguru Mizuno, Keisuke Yamamoto, Hirofumi Kogure, Natsuyo Yamamoto, Kenji Hirano, Naoki Sasahira, Keisuke Tateishi, Minoru Tada & Kazuhiko Koike

  2. Department of Gastroenterology, Japanese Red Cross Medical Center, Tokyo, Japan

    Yukiko Ito

  3. Department of Gastroenterology, Tokyo Metropolitan Police Hospital, Tokyo, Japan

    Saburo Matsubara

  4. Department of Gastroenterology, Kanto Central Hospital, Tokyo, Japan

    Rie Uchino

  5. Department of Gastroenterology, JR Tokyo General Hospital, Tokyo, Japan

    Hiroshi Yagioka

  6. Department of Gastroenterology, Mitsui Memorial Hospital, Tokyo, Japan

    Toshihiko Arizumi

Authors
  1. Yousuke Nakai
    View author publications

    You can also search for this author inPubMed Google Scholar

  2. Hiroyuki Isayama
    View author publications

    You can also search for this author inPubMed Google Scholar

  3. Hideaki Ijichi
    View author publications

    You can also search for this author inPubMed Google Scholar

  4. Takashi Sasaki
    View author publications

    You can also search for this author inPubMed Google Scholar

  5. Naminatsu Takahara
    View author publications

    You can also search for this author inPubMed Google Scholar

  6. Yukiko Ito
    View author publications

    You can also search for this author inPubMed Google Scholar

  7. Saburo Matsubara
    View author publications

    You can also search for this author inPubMed Google Scholar

  8. Rie Uchino
    View author publications

    You can also search for this author inPubMed Google Scholar

  9. Hiroshi Yagioka
    View author publications

    You can also search for this author inPubMed Google Scholar

  10. Toshihiko Arizumi
    View author publications

    You can also search for this author inPubMed Google Scholar

  11. Tsuyoshi Hamada
    View author publications

    You can also search for this author inPubMed Google Scholar

  12. Koji Miyabayashi
    View author publications

    You can also search for this author inPubMed Google Scholar

  13. Suguru Mizuno
    View author publications

    You can also search for this author inPubMed Google Scholar

  14. Keisuke Yamamoto
    View author publications

    You can also search for this author inPubMed Google Scholar

  15. Hirofumi Kogure
    View author publications

    You can also search for this author inPubMed Google Scholar

  16. Natsuyo Yamamoto
    View author publications

    You can also search for this author inPubMed Google Scholar

  17. Kenji Hirano
    View author publications

    You can also search for this author inPubMed Google Scholar

  18. Naoki Sasahira
    View author publications

    You can also search for this author inPubMed Google Scholar

  19. Keisuke Tateishi
    View author publications

    You can also search for this author inPubMed Google Scholar

  20. Minoru Tada
    View author publications

    You can also search for this author inPubMed Google Scholar

  21. Kazuhiko Koike
    View author publications

    You can also search for this author inPubMed Google Scholar

Corresponding author

Correspondence to Hiroyuki Isayama.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Nakai, Y., Isayama, H., Ijichi, H. et al. A multicenter phase II trial of gemcitabine and candesartan combination therapy in patients with advanced pancreatic cancer: GECA2. Invest New Drugs 31, 1294–1299 (2013). https://doi.org/10.1007/s10637-013-9972-5

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10637-013-9972-5

Keywords

Profiles

  1. Keisuke Yamamoto View author profile