Pilot study evaluating broccoli sprouts in advanced pancreatic cancer (POUDER trial) - study protocol for a randomized controlled trial

Vladimir J Lozanovski, Philipp Houben, Ulf Hinz, Thilo Hackert, Ingrid Herr, Peter Schemmer, Vladimir J Lozanovski, Philipp Houben, Ulf Hinz, Thilo Hackert, Ingrid Herr, Peter Schemmer

Abstract

Background: Pancreatic ductal adenocarcinoma (PDA) is one of the most aggressive malignancies with marked resistance to chemo- and radiotherapy. PDA-cancer stem cells (CSCs) are not targeted by current therapies and may be a reason for poor prognosis. Studies indicate that diets rich in cabbage, broccoli, and cauliflower offer cancer preventative and therapeutic benefits. Recent experimental studies have confirmed these findings and demonstrated that isothiocyanate, sulforaphane, and the polyphenol, quercetin, effectively reduced tumor growth and enhanced the sensitivity of the cancer cells to current chemotherapeutics. The aim of the present study is to test the feasibility of a randomized controlled trial on the application of freeze-dried broccoli sprouts in patients with advanced PDA.

Methods and study design: The study is designed as a prospective randomized, double-blinded pilot trial with a treatment and a placebo-controlled arm in a single center setting. A total number of forty patients (18 years or older) in two parallel groups with advanced, surgically non-resectable PDA under palliative chemotherapy are planned for recruitment. Patients in the treatment group will receive fifteen capsules of the study substance per day (90 mg of active sulforaphane) during the chemotherapy treatment course. Patients in the placebo group will receive the same capsule size and portion distribution with inactive substances (mainly methylcellulose). The follow-up duration is one year. Feasibility of the study substance, adverse effects, and patient compliance, as well as levels of serum tumor markers (CEA, CA 19-9), quality of life, and patient overall survival rates will be assessed at defined points of time.

Discussion: The POUDER trial is expected to transfer promising experimental and epidemiological data into a clinical pilot study to assess the effectiveness of broccoli sprout extracts in the treatment of advanced PDA. The study objectives will provide data on the clinical feasibility and acceptability of a supportive treatment option accompanying palliative chemotherapy. Based on these results, future clinical studies to create further evidence in this field are possible.

Trial registration: The POUDER trial has been registered at ClinicalTrials.gov with an ID NCT01879878 and WHO with an ID U1111-1144-2013 on June 13th 2013.

Figures

Figure 1
Figure 1
Flow chart of the POUDER-Trial. PDA, pancreatic ductal adenocarcinoma: AE, adverse event: SAE, serious adverse event: CT, computed tomography; MRI, magnetic resonance imaging. Tumor markers: CEA and CA 19-9.

References

    1. Hariharan D, Saied A, Kocher HM. Analysis of mortality rates for pancreatic cancer across the world. HPB (Oxford) 2008;10:58–62. doi: 10.1080/13651820701883148.
    1. Witkowski ER, Smith JK, Tseng JF. Outcomes following resection of pancreatic cancer. J Surg Oncol. 2013;107:97–103. doi: 10.1002/jso.23267.
    1. Schmidt J, Abel U, Debus J, Harig S, Hoffmann K, Herrmann T, Bartsch D, Klein J, Mansmann U, Jäger D, Capussotti L, Kunz R, Büchler MW. Open-label, multicenter, randomized phase III trial of adjuvant chemoradiation plus interferon Alfa-2b versus fluorouracil and folinic acid for patients with resected pancreatic adenocarcinoma. J Clin Oncol. 2012;30:4077–4083. doi: 10.1200/JCO.2011.38.2960.
    1. Siegel R, Naishadham D, Jemal A. Cancer statistics, 2013. CA Cancer J Clin. 2013;63:11–30. doi: 10.3322/caac.21166.
    1. Tuveson DA, Neoptolemos JP. Understanding metastasis in pancreatic cancer: a call for new clinical approaches. Cell. 2012;148:21–23. doi: 10.1016/j.cell.2011.12.021.
    1. Li D, Xie K, Wolff R, Abbruzzese JL. Pancreatic cancer. Lancet. 2004;363:1049–1057. doi: 10.1016/S0140-6736(04)15841-8.
    1. Oberstein PE, Saif MW. First-line treatment for advanced pancreatic cancer. Highlights from the “2011 ASCO Gastrointestinal Cancers Symposium”. San Francisco, CA, USA. January 20-22, 2011. JOP. 2011;12:96–100.
    1. Lapidot T, Sirard C, Vormoor J, Murdoch B, Hoang T, Caceres-Cortes J, Minden M, Paterson B, Caligiuri MA, Dick JE. A cell initiating human acute myeloid leukaemia after transplantation into SCID mice. Nature. 1994;367:645–648. doi: 10.1038/367645a0.
    1. Reya T, Morrison SJ, Clarke MF, Weissman IL. Stem cells, cancer, and cancer stem cells. Nature. 2001;414:105–111. doi: 10.1038/35102167.
    1. Rasheed ZA, Kowalski J, Smith BD, Matsui W. Concise review: emerging concepts in clinical targeting of cancer stem cells. Stem Cells. 2011;29:883–887. doi: 10.1002/stem.648.
    1. Al-Hajj M, Wicha MS, Benito-Hernandez A, Morrison SJ, Clarke MF. Prospective identification of tumorigenic breast cancer cells. Proc Natl Acad Sci USA. 2003;100:3983–3988. doi: 10.1073/pnas.0530291100.
    1. Singh SK, Hawkins C, Clarke ID, Squire JA, Bayani J, Hide T, Henkelman RM, Cusimano MD, Dirks PB. Identification of human brain tumour initiating cells. Nature. 2004;432:396–401. doi: 10.1038/nature03128.
    1. Simeone DM. Pancreatic cancer stem cells: implications for the treatment of pancreatic cancer. Clin Cancer Res. 2008;14:5646–5648. doi: 10.1158/1078-0432.CCR-08-0584.
    1. Abbott A. Cancer: the root of the problem. Nature. 2006;442:742–743. doi: 10.1038/442742a.
    1. Forman D, Burley V, Cade J, Greenwood D, Moreton J, Chan D, Tu Y-K, Gordon I, Thomas J, McColl K. World Cancer Research Fund. Food, nutrition, physical activity, and the prevention of cancer: a global perspective. Washington, DC: AICR; 2007. The associations between food, nutrition and physical activity and the risk of pancreatic cancer and underlying mechanisms.
    1. Kirsh VA, Peters U, Mayne ST, Subar AF, Chatterjee N, Johnson CC, Hayes RB. Prostate, lung, colorectal and ovarian cancer screening trial, prospective study of fruit and vegetable intake and risk of prostate cancer. J Natl Cancer Inst. 2007;99:1200–1209. doi: 10.1093/jnci/djm065.
    1. Richman EL, Carroll PR, Chan JM. Vegetable and fruit intake after diagnosis and risk of prostate cancer progression. Int J Cancer. 2012;131:201–210. doi: 10.1002/ijc.26348.
    1. Herr I, Lozanovski V, Houben P, Schemmer P, Büchler MW. Sulforaphane and related mustard oils in focus of cancer prevention and therapy. Wien Med Wochenschr. 2013;163:80–88. doi: 10.1007/s10354-012-0163-3.
    1. Fahey JW, Zhang Y, Talalay P. Broccoli sprouts: an exceptionally rich source of inducers of enzymes that protect against chemical carcinogens. Proc Natl Acad Sci USA. 1997;94:10367–10372. doi: 10.1073/pnas.94.19.10367.
    1. Kallifatidis G, Rausch V, Baumann B, Apel A, Beckermann BM, Groth A, Mattern J, Li Z, Kolb A, Moldenhauer G, Altevogt P, Wirth T, Werner J, Schemmer P, Büchler MW, Salnikov AV, Herr I. Sulforaphane targets pancreatic tumour-initiating cells by NF-kappaB induced antiapoptotic signalling. Gut. 2009;58:949–963. doi: 10.1136/gut.2008.149039.
    1. Li Y, Wicha MS, Schwartz SJ, Sun D. Implications of cancer stem cell theory for cancer chemoprevention by natural dietary compounds. J Nutr Biochem. 2011;22:799–806. doi: 10.1016/j.jnutbio.2010.11.001.
    1. Rausch V, Liu L, Kallifatidis G, Baumann B, Mattern J, Gladkich J, Wirth T, Schemmer P, Büchler MW, Zöller M, Salnikov AV, Herr I. Synergistic activity of sorafenib and sulforaphane abolishes pancreatic cancer stem cell characteristics. Cancer Res. 2010;70:5004–5013. doi: 10.1158/0008-5472.CAN-10-0066.
    1. Kallifatidis G, Labsch S, Rausch V, Mattern J, Gladkich J, Moldenhauer G, Büchler MW, Salnikov AV, Herr I. Sulforaphane increases drug-mediated cytotoxicity towards cancer stem-like cells of pancreas and prostate. Mol Ther. 2011;19:188–195. doi: 10.1038/mt.2010.216.
    1. Silverman DT, Swanson CA, Gridley G, Wacholder S, Greenberg RS, Brown LM, Hayes RB, Swanson GM, Schoenberg JB, Pottern LM, Schwartz AG, Fraumeni JF Jr, Hoover RN. Dietary and nutritional factors and pancreatic cancer: a case-control study based on direct interviews. J Natl Cancer Inst. 1998;90:1710–1719. doi: 10.1093/jnci/90.22.1710.
    1. Bertl E, Bartsch H, Gerhauser C. Inhibition of angiogenesis and endothelial cell functions are novel sulforaphanemediated mechanisms in chemoprevention. Mol Cancer Ther. 2006;5:575–585. doi: 10.1158/1535-7163.MCT-05-0324.
    1. Juge N, Mithen RF, Traka M. Molecular basis for chemoprevention by sulforaphane: a comprehensive review. Cell Mol Life Sci. 2007;64:1105–1127. doi: 10.1007/s00018-007-6484-5.
    1. Zhou W, Kallifatidis G, Baumann B, Rausch V, Mattern J, Gladkich J, Giese N, Moldenhauer G, Wirth T, Büchler MW, Salnikov AV, Herr I. Dietary polyphenol quercetin targets pancreatic cancer stem cells. Int J Oncol. 2010;37:551–561.
    1. Cornblatt BS, Ye L, Dinkova-Kostova AT, Erb M, Fahey JW, Singh NK, Chen MS, Stierer T, Garrett-Mayer E, Argani P, Davidson NE, Talalay P, Kensler TW, Visvanathan K. Preclinical and clinical evaluation of sulforaphane for chemoprevention in the breast. Carcinogenesis. 2007;28:1485–1490. doi: 10.1093/carcin/bgm049.
    1. Seow A, Yuan JM, Sun CL, Van Den Berg D, Lee HP, Yu MC. Dietary isothiocyanates, glutathione S-transferase polymorphisms and colorectal cancer risk in the Singapore Chinese Health Study. Carcinogenesis. 2002;23:2055–2061. doi: 10.1093/carcin/23.12.2055.
    1. Shapiro TA, Fahey JW, Dinkova-Kostova AT, Holtzclaw WD, Stephenson KK, Wade KL, Ye L, Talalay P. Safety, tolerance, and metabolism of broccoli sprout glucosinolates and isothiocyanates: a clinical phase I study. Nutr Cancer. 2006;55:53–62. doi: 10.1207/s15327914nc5501_7.
    1. Egner PA, Chen JG, Wang JB, Wu Y, Sun Y, Lu JH, Zhu J, Zhang YH, Chen YS, Friesen MD, Jacobson LP, Muñoz A, Ng D, Qian GS, Zhu YR, Chen TY, Botting NP, Zhang Q, Fahey JW, Talalay P, Groopman JD, Kensler TW. Bioavailability of Sulforaphane from two broccoli sprout beverages: results of a short-term, cross-over clinical trial in Qidong, China. Cancer Prev Res (Phila) 2011;4:384–395. doi: 10.1158/1940-6207.CAPR-10-0296.
    1. International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH) Guideline E6: Note for Guidance on good clinical practice (GCP) .
    1. World Medical Association Declaration of Helsinki. Recommendations Guiding Physicians in Biomedical Research Involving Human Subjects, Adopted by the 18th World Medical Assembly Helsinki, Finland, June 1964, amended by 64th WMA General Assembly, Fortaleza Brazil. 2013.
    1. Federal Data Protection Act (BDSG) In the version promulgated on 14 January 2003 (Federal Law Gazette I, p. 66), last amended by Article 1 of the Act of 14 August 2009 (Federal Law Gazette I, p. 2814) .
    1. Fahey JW, Zalcmann AT, Talalay P. The chemical diversity and distribution of glucosinolates and isothiocyanates among plants. Phytochemistry. 2001;56:5–51. doi: 10.1016/S0031-9422(00)00316-2.
    1. Shishu, Singla AK, Kaur IP. Inhibition of mutagenicity of food-derived heterocyclic amines by sulphoraphenean isothiocyanate isolated from radish. Planta Med. 2003;69:184–186. doi: 10.1055/s-2003-37713.
    1. Watzl B, Leitzmann C. Bioaktive Substanzen in Lebensmitteln. 3. Stuttgart: Hippokrates Verlag; 2005.
    1. Williamson G, Manach C. Bioavailability and bioefficacy of polyphenols in humans, II. Review of 93 intervention studies. Am J Clin Nutr. 2005;81:243–255.
    1. Ramos S. Effects of dietary flavonoids on apoptotic pathways related to cancer chemoprevention. J Nutr Biochem. 2007;18:427–442. doi: 10.1016/j.jnutbio.2006.11.004.
    1. Adikrisna R, Tanaka S, Muramatsu S, Aihara A, Ban D, Ochiai T, Irie T, Kudo A, Nakamura N, Yamaoka S, Arii S. Identification of pancreatic cancer stem cells and selective toxicity of chemotherapeutic agents. Gastroenterology. 2012;143:234–245. doi: 10.1053/j.gastro.2012.03.054.
    1. Halkier BA, Gershenzon J. Biology and biochemistry of glucosinolates. Annu Rev Plant Biol. 2006;57:303–333. doi: 10.1146/annurev.arplant.57.032905.105228.
    1. Lawenda BD, Kelly KM, Ladas EJ, Sagar SM, Vickers A, Blumberg JB. Should supplemental antioxidant administration be avoided during chemotherapy and radiation therapy? J Natl Cancer Inst. 2008;100:773–783. doi: 10.1093/jnci/djn148.
    1. D’Andrea GM. Use of antioxidants during chemotherapy and radiotherapy should be avoided. CA Cancer J Clin. 2005;55:319–321. doi: 10.3322/canjclin.55.5.319.

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