Effects of concentrated long-chain omega-3 polyunsaturated fatty acid supplementation before radical prostatectomy on prostate cancer proliferation, inflammation, and quality of life: study protocol for a phase IIb, randomized, double-blind, placebo-controlled trial

Marie-Hélène Guertin, Karine Robitaille, Jean-François Pelletier, Thierry Duchesne, Pierre Julien, Josée Savard, Isabelle Bairati, Vincent Fradet, Marie-Hélène Guertin, Karine Robitaille, Jean-François Pelletier, Thierry Duchesne, Pierre Julien, Josée Savard, Isabelle Bairati, Vincent Fradet

Abstract

Background: Prostate cancer is the most commonly diagnosed cancer in north-American men. Few dietary or lifestyle interventions have been tested to prevent prostate cancer progression. Omega-3 fatty acid supplementation represents a promising intervention for prostate cancer patients. The aim of the study is to evaluate the effects of long-chain omega-3 polyunsaturated fatty acids (LCn3), more precisely eicosapentaenoic acid monoacylglyceride (MAG-EPA) supplementation, on prostate cancer proliferation, inflammation mediators and quality of life among men who will undergo radical prostatectomy.

Methods/design: We propose a phase IIb, randomized, double-blind placebo-controlled trial of MAG-EPA supplementation for 130 men who will undergo radical prostatectomy as treatment for a prostate cancer of Gleason score ≥ 7 in an academic cancer center in Quebec City. Participants will be randomized to 6 capsules of 625 mg of fish oil (MAG-EPA) per capsule containing 500 mg of EPA daily or to identically looking capsules of high oleic acid sunflower oil (HOSO) as placebo. The intervention begins 4 to 10 weeks prior to radical prostatectomy (baseline) and continues for one year after surgery. The primary endpoint is the proliferative index (Ki-67) measured in prostate cancer cells at radical prostatectomy. A secondary endpoint includes prostate tissue levels of inflammatory mediators (cytokines and proteins) at time of radical prostatectomy. Changes in blood levels of inflammatory mediators, relative to baseline levels, at time of radical prostatectomy and 12 months after radical prostatectomy will also be evaluated. Secondary endpoints also include important aspects of psychosocial functioning and quality of life such as depression, anxiety, sleep disturbances, fatigue, cognitive complaints and prostate cancer-specific quality of life domains. The changes in these outcomes, relative to baseline levels, will be evaluated at 3, 6, 9 and 12 months after radical prostatectomy.

Discussion: The results from this trial will provide crucial information to clarify the role of omega-3 supplementation on prostate cancer proliferation, inflammation and quality of life.

Trial registration: ClinicalTrials.gov Identifier: NCT02333435. Registered on December 17, 2014. Last updated September 6, 2016.

Keywords: Inflammation; Omega-3; Proliferation; Prostate cancer; Quality of life.

Conflict of interest statement

Ethics approval and consent to participate

The study protocol has been approved by the ethics committee of CHU de Québec - Université Laval (2012–1012). Written informed consent was obtained from all recruitment patients for study participation as well as for biobanking of their biological specimen (blood, urine, tissue).

Consent for publication

Not applicable.

Competing interests

The authors declare that they have no competing interests. SCF Pharma and Solutex (Spain) provide capsules (intervention and placebo) for the study, free of charge. They, not have any competing interests regarding our study.

Publisher’s Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Figures

Fig. 1
Fig. 1
Randomized Controlled Trial flow chart. 130 men diagnosed with intermediate-risk PCa treated by RP are being randomized either to LCn3 supplementation (MAG-EPA) or placebo. Intervention starts 6 weeks (acceptable range 4–10 weeks) before radical prostatectomy (RP) and ends 12 months after RP. PCa: Prostate cancer; Web-FFQ: online Food frequency questionnaire; QoL: Quality of life; PF: Psychosocial functioning; LCn3: Long chain omega-3 fatty acids; RP: Radical prostatectomy; MAG-EPA: Monoglycerides of eicosapentaenoic acid; HOSO: High oleic acid sunflower oil

References

    1. Prostate Cancer Statistics. Canadian Cancer Society, 2017. (Accessed March 28 2017, at .)
    1. Donovan JL, Hamdy FC, Lane JA, et al. Patient-reported outcomes after monitoring, surgery, or radiotherapy for prostate cancer. N Engl J Med. 2016;375:1425–1437. doi: 10.1056/NEJMoa1606221.
    1. Fossa SD, Bengtsson T, Borre M, Ahlgren G, Rannikko A, Dahl AA. Reduction of quality of life in prostate cancer patients: experience among 6200 men in the Nordic countries. Scand J Urol. 2016;50:330–337. doi: 10.1080/21681805.2016.1201859.
    1. Lin PH, Aronson W, Freedland SJ. Nutrition, dietary interventions and prostate cancer: the latest evidence. BMC Med. 2015;13:3. doi: 10.1186/s12916-014-0234-y.
    1. Reese AC, Fradet V, Witte JS. Omega-3 fatty acids, genetic variants in COX-2 and prostate cancer. J Nutrigenet Nutrigenomics. 2009;2:149–158. doi: 10.1159/000235565.
    1. Mauermann J, Pouliot F, Fradet V. Dietary omega-3 fatty acids, genetic variation and risk of breast and prostate cancers. World Rev Nutr Diet. 2011;102:156–171. doi: 10.1159/000327805.
    1. Szymanski KM, Wheeler DC, Mucci LA. Fish consumption and prostate cancer risk: a review and meta-analysis. Am J Clin Nutr. 2010;92:1223–1233. doi: 10.3945/ajcn.2010.29530.
    1. Masko EM, Allott EH, Freedland SJ. The relationship between nutrition and prostate cancer: is more always better? Eur Urol. 2013;63:810–820. doi: 10.1016/j.eururo.2012.11.012.
    1. Gerber M. Omega-3 fatty acids and cancers: a systematic update review of epidemiological studies. Br J Nutr. 2012;107(Suppl 2):S228–S239. doi: 10.1017/S0007114512001614.
    1. Alexander DD, Bassett JK, Weed DL, Barrett EC, Watson H, Harris W. Meta-analysis of long-chain Omega-3 polyunsaturated fatty acids (LComega-3PUFA) and prostate cancer. Nutr Cancer. 2015;67:543–554. doi: 10.1080/01635581.2015.1015745.
    1. Dinwiddie MT, Terry PD, Whelan J, Patzer RE. Omega-3 fatty acid consumption and prostate cancer: a review of exposure measures and results of epidemiological studies. J Am Coll Nutr. 2016;35:452–468. doi: 10.1080/07315724.2015.1032444.
    1. Aucoin M, Cooley K, Knee C, et al. Fish-derived Omega-3 fatty acids and prostate cancer: a systematic review. Integr Cancer Ther. 2016;
    1. Fu YQ, Zheng JS, Yang B, Li D. Effect of individual omega-3 fatty acids on the risk of prostate cancer: a systematic review and dose-response meta-analysis of prospective cohort studies. J Epidemiol. 2015;25:261–274. doi: 10.2188/jea.JE20140120.
    1. Chua ME, Sio MC, Sorongon MC, Dy JS. Relationship of dietary intake of omega-3 and omega-6 fatty acids with risk of prostate cancer development: a meta-analysis of prospective studies and review of literature. Prostate Cancer. 2012;2012:826254. doi: 10.1155/2012/826254.
    1. Serra-Majem L, Nissensohn M, Overby NC, Fekete K. Dietary methods and biomarkers of omega 3 fatty acids: a systematic review. Br J Nutr 2012;107 Suppl 2:S64–S76.
    1. Crowe FL, Appleby PN, Travis RC, et al. Circulating fatty acids and prostate cancer risk: individual participant meta-analysis of prospective studies. J Natl Cancer Inst. 2014;106
    1. Brasky TM, Till C, white E, et al. serum phospholipid fatty acids and prostate cancer risk: results from the prostate cancer prevention trial. Am J Epidemiol. 2011;173:1429–1439. doi: 10.1093/aje/kwr027.
    1. Brasky TM, Darke AK, Song X, et al. Plasma phospholipid fatty acids and prostate cancer risk in the SELECT trial. J Natl Cancer Inst. 2013;105:1132–1141. doi: 10.1093/jnci/djt174.
    1. Moreel X, Allaire J, Leger C, et al. Prostatic and dietary omega-3 fatty acids and prostate cancer progression during active surveillance. Cancer Prev Res (Phila) 2014;7:766–776. doi: 10.1158/1940-6207.CAPR-13-0349.
    1. Bettencourt MC, Bauer JJ, Sesterhenn IA, Mostofi FK, McLeod DG, Moul JW. Ki-67 expression is a prognostic marker of prostate cancer recurrence after radical prostatectomy. J Urol. 1996;156:1064–1068. doi: 10.1016/S0022-5347(01)65703-3.
    1. Bubendorf L, Sauter G, Moch H, et al. Ki67 labelling index: an independent predictor of progression in prostate cancer treated by radical prostatectomy. J Pathol. 1996;178:437–441. doi: 10.1002/(SICI)1096-9896(199604)178:4<437::AID-PATH484>;2-4.
    1. Inoue T, Segawa T, Shiraishi T, et al. Androgen receptor, Ki67, and p53 expression in radical prostatectomy specimens predict treatment failure in Japanese population. Urology. 2005;66:332–337. doi: 10.1016/j.urology.2005.02.028.
    1. Nariculam J, Freeman A, Bott S, et al. Utility of tissue microarrays for profiling prognostic biomarkers in clinically localized prostate cancer: the expression of BCL-2, E-cadherin, Ki-67 and p53 as predictors of biochemical failure after radical prostatectomy with nested control for clinical and pathological risk factors. Asian J Androl. 2009;11:109–118. doi: 10.1038/aja.2008.22.
    1. Sulik M, Guzinska-Ustymowicz K. Expression of Ki-67 and PCNA as proliferating markers in prostate cancer. Rocz Akad Med Bialymst. 2002;47:262–269.
    1. Kim SH, Park WS, Park BR, et al. PSCA, cox-2, and Ki-67 are independent, predictive markers of biochemical recurrence in clinically localized prostate cancer: a retrospective study. Asian J Androl. 2016;
    1. Verma R, Gupta V, Singh J, et al. Significance of p53 and ki-67 expression in prostate cancer. Urol Ann. 2015;7:488–493. doi: 10.4103/0974-7796.158507.
    1. Desmeules P, Hovington H, Nguile-Makao M, et al. Comparison of digital image analysis and visual scoring of KI-67 in prostate cancer prognosis after prostatectomy. Diagn Pathol. 2015;10:67. doi: 10.1186/s13000-015-0294-0.
    1. Aronson WJ, Kobayashi N, Barnard RJ, et al. Phase II prospective randomized trial of a low-fat diet with fish oil supplementation in men undergoing radical prostatectomy. Cancer Prev Res (Phila) 2011;4:2062–2071. doi: 10.1158/1940-6207.CAPR-11-0298.
    1. Demark-Wahnefried W, Polascik TJ, George SL, et al. Flaxseed supplementation (not dietary fat restriction) reduces prostate cancer proliferation rates in men presurgery. Cancer Epidemiol Biomark Prev. 2008;17:3577–3587. doi: 10.1158/1055-9965.EPI-08-0008.
    1. De Marzo AM, DeWeese TL, Platz EA, et al. Pathological and molecular mechanisms of prostate carcinogenesis: implications for diagnosis, detection, prevention, and treatment. J Cell Biochem. 2004;91:459–477. doi: 10.1002/jcb.10747.
    1. Sciarra A, Mariotti G, Salciccia S, et al. Prostate growth and inflammation. J Steroid Biochem Mol Biol. 2008;108:254–260. doi: 10.1016/j.jsbmb.2007.09.013.
    1. Bouraoui Y, Ricote M, Garcia-Tunon I, et al. Pro-inflammatory cytokines and prostate-specific antigen in hyperplasia and human prostate cancer. Cancer Detect Prev. 2008;32:23–32. doi: 10.1016/j.cdp.2008.02.007.
    1. Sfanos KS, De Marzo AM. Prostate cancer and inflammation: the evidence. Histopathology. 2012;60:199–215. doi: 10.1111/j.1365-2559.2011.04033.x.
    1. Mechergui YB, Ben Jemaa A, Mezigh C, et al. The profile of prostate epithelial cytokines and its impact on sera prostate specific antigen levels. Inflammation. 2009;32:202–210. doi: 10.1007/s10753-009-9121-7.
    1. Schroten C, Dits NF, Steyerberg EW, et al. The additional value of TGFbeta1 and IL-7 to predict the course of prostate cancer progression. Cancer Immunol Immunother. 2012;61:905–910. doi: 10.1007/s00262-011-1159-3.
    1. Stark JR, Li H, Kraft P, et al. Circulating prediagnostic interleukin-6 and C-reactive protein and prostate cancer incidence and mortality. Int J Cancer. 2009;124:2683–2689. doi: 10.1002/ijc.24241.
    1. Mengus C, Le Magnen C, Trella E, et al. Elevated levels of circulating IL-7 and IL-15 in patients with early stage prostate cancer. J Transl Med. 2011;9:162. doi: 10.1186/1479-5876-9-162.
    1. de Pablo MA, Alvarez de Cienfuegos G. Modulatory effects of dietary lipids on immune system functions. Immunol Cell Biol. 2000;78:31–39. doi: 10.1046/j.1440-1711.2000.00875.x.
    1. Abbate R, Gori AM, Martini F, et al. N-3 PUFA supplementation, monocyte PCA expression and interleukin-6 production. Prostaglandins Leukot Essent Fatty Acids. 1996;54:439–444. doi: 10.1016/S0952-3278(96)90028-9.
    1. Blok WL, Deslypere JP, Demacker PN, et al. Pro- and anti-inflammatory cytokines in healthy volunteers fed various doses of fish oil for 1 year. Eur J Clin Investig. 1997;27:1003–1008. doi: 10.1046/j.1365-2362.1997.2240775.x.
    1. Cooper AL, Gibbons L, Horan MA, Little RA, Rothwell NJ. Effect of dietary fish oil supplementation on fever and cytokine production in human volunteers. Clin Nutr. 1993;12:321–328. doi: 10.1016/0261-5614(93)90027-2.
    1. Trebble T, Arden NK, Stroud MA, et al. Inhibition of tumour necrosis factor-alpha and interleukin 6 production by mononuclear cells following dietary fish-oil supplementation in healthy men and response to antioxidant co-supplementation. Br J Nutr. 2003;90:405–412. doi: 10.1079/BJN2003892.
    1. Pot GK, Brouwer IA, Enneman A, Rijkers GT, Kampman E, Geelen A. No effect of fish oil supplementation on serum inflammatory markers and their interrelationships: a randomized controlled trial in healthy, middle-aged individuals. Eur J Clin Nutr. 2009;63:1353–1359. doi: 10.1038/ejcn.2009.63.
    1. Caughey GE, Mantzioris E, Gibson RA, Cleland LG, James MJ. The effect on human tumor necrosis factor alpha and interleukin 1 beta production of diets enriched in n-3 fatty acids from vegetable oil or fish oil. Am J Clin Nutr. 1996;63:116–122. doi: 10.1093/ajcn/63.1.116.
    1. Endres S, Ghorbani R, Kelley VE, et al. The effect of dietary supplementation with n-3 polyunsaturated fatty acids on the synthesis of interleukin-1 and tumor necrosis factor by mononuclear cells. N Engl J Med. 1989;320:265–271. doi: 10.1056/NEJM198902023200501.
    1. Gallai V, Sarchielli P, Trequattrini A, et al. Cytokine secretion and eicosanoid production in the peripheral blood mononuclear cells of MS patients undergoing dietary supplementation with n-3 polyunsaturated fatty acids. J Neuroimmunol. 1995;56:143–153. doi: 10.1016/0165-5728(94)00140-J.
    1. Hervouet S, Savard J, Simard S, et al. Psychological functioning associated with prostate cancer: cross-sectional comparison of patients treated with radiotherapy, brachytherapy, or surgery. J Pain Symptom Manag. 2005;30:474–484. doi: 10.1016/j.jpainsymman.2005.05.011.
    1. Hoffmire CA, Block RC, Thevenet-Morrison K, van Wijngaarden E. Associations between omega-3 poly-unsaturated fatty acids from fish consumption and severity of depressive symptoms: an analysis of the 2005-2008 National Health and nutrition examination survey. Prostaglandins Leukot Essent Fatty Acids. 2012;86:155–160. doi: 10.1016/j.plefa.2012.03.003.
    1. McNamara RK. Evaluation of docosahexaenoic acid deficiency as a preventable risk factor for recurrent affective disorders: current status, future directions, and dietary recommendations. Prostaglandins Leukot Essent Fatty Acids. 2009;81:223–231. doi: 10.1016/j.plefa.2009.05.017.
    1. McNamara RK. Role of Omega-3 fatty acids in the etiology, treatment, and prevention of depression: current status and future directions. J Nutr Intermed Metab. 2016;5:96–106. doi: 10.1016/j.jnim.2016.04.004.
    1. Kiecolt-Glaser JK, Belury MA, Andridge R, Malarkey WB, Glaser R. Omega-3 supplementation lowers inflammation and anxiety in medical students: a randomized controlled trial. Brain Behav Immun. 2011;25:1725–1734. doi: 10.1016/j.bbi.2011.07.229.
    1. Kiecolt-Glaser JK, Belury MA, Andridge R, Malarkey WB, Hwang BS, Glaser R. Omega-3 supplementation lowers inflammation in healthy middle-aged and older adults: a randomized controlled trial. Brain Behav Immun. 2012;26:988–995. doi: 10.1016/j.bbi.2012.05.011.
    1. Alfano CM, Imayama I, Neuhouser ML, et al. Fatigue, inflammation, and omega-3 and omega-6 fatty acid intake among breast cancer survivors. J Clin Oncol. 2012;30:1280–1287. doi: 10.1200/JCO.2011.36.4109.
    1. de Roos B, Geelen A, Ross K, et al. Identification of potential serum biomarkers of inflammation and lipid modulation that are altered by fish oil supplementation in healthy volunteers. Proteomics. 2008;8:1965–1974. doi: 10.1002/pmic.200700457.
    1. Ottestad I, Vogt G, Retterstol K, et al. Oxidised fish oil does not influence established markers of oxidative stress in healthy human subjects: a randomised controlled trial. Br J Nutr. 2012;108:315–326. doi: 10.1017/S0007114511005484.
    1. Monograph: Fish Oil. Health Canada; 2015.
    1. Szymanski KM, Wei JT, Dunn RL, Sanda MG. Development and validation of an abbreviated version of the expanded prostate cancer index composite instrument for measuring health-related quality of life among prostate cancer survivors. Urology. 2010;76:1245–1250. doi: 10.1016/j.urology.2010.01.027.
    1. Vigneault E, Savard J, Ivers H, et al. Validation of a French-Canadian Version of the Expanded Prostate Cancer Index Composite Instrument. Can Urol Ass J 2017;In Press.
    1. Savard J, Laberge B, Gauthier JG, Ivers H, Bergeron MG. Evaluating anxiety and depression in HIV-infected patients. J Pers Assess. 1998;71:349–367. doi: 10.1207/s15327752jpa7103_5.
    1. Morin CM, Belleville G, Belanger L, Ivers H. The insomnia severity index: psychometric indicators to detect insomnia cases and evaluate treatment response. Sleep. 2011;34:601–608. doi: 10.1093/sleep/34.5.601.
    1. Hann DM, Denniston MM, Baker F. Measurement of fatigue in cancer patients: further validation of the fatigue symptom inventory. Qual Life Res. 2000;9:847–854. doi: 10.1023/A:1008900413113.
    1. Bastien CH, Vallieres A, Morin CM. Validation of the insomnia severity index as an outcome measure for insomnia research. Sleep Med. 2001;2:297–307. doi: 10.1016/S1389-9457(00)00065-4.
    1. Cella DF, Tulsky DS, Gray G, et al. The functional assessment of cancer therapy scale: development and validation of the general measure. J Clin Oncol. 1993;11:570–579. doi: 10.1200/JCO.1993.11.3.570.
    1. Simard S, Savard J. Fear of cancer recurrence inventory: development and initial validation of a multidimensional measure of fear of cancer recurrence. Support Care Cancer. 2009;17:241–251. doi: 10.1007/s00520-008-0444-y.
    1. Ware JE, Jr, Sherbourne CD. The MOS 36-item short-form health survey (SF-36). I. Conceptual framework and item selection. Med Care. 1992;30:473–483. doi: 10.1097/00005650-199206000-00002.
    1. Godin G, Shephard R. Godin Leisure-Time Exercise Questionnaire. Med Sci Sports Exerc. 1997;29:S36–SS8.
    1. Labonte ME, Cyr A, Baril-Gravel L, Royer MM, Lamarche B. Validity and reproducibility of a web-based, self-administered food frequency questionnaire. Eur J Clin Nutr. 2012;66:166–173. doi: 10.1038/ejcn.2011.163.
    1. Allaire J, Moreel X, Labonte ME, et al. Validation of the omega-3 fatty acid intake measured by a web-based food frequency questionnaire against omega-3 fatty acids in red blood cells in men with prostate cancer. Eur J Clin Nutr. 2015;69:1004–1008. doi: 10.1038/ejcn.2015.7.
    1. O'Brien RG, Muller KE. Unified power analysis for t-tests through multivariate hypothesis. In: Edwards LK, editor. Applied analysis of variance in the behavioral sciences. New York: Marcel Dekker; 1993. pp. 297–344.
    1. Self SG, Mauritsen RH, Ohara J. Power calculations for the likelihood ratio tests in generalized linear models. Biometrics. 1992;48:31–39. doi: 10.2307/2532736.
    1. Kirk R. Experimental design: procedures for the behavioral sciences. Pacific Grove, Calif: Brooks/Cole; 1995.
    1. Lin PY, Mischoulon D, Freeman MP, et al. Are omega-3 fatty acids antidepressants or just mood-improving agents? The effect depends upon diagnosis, supplement preparation, and severity of depression. Mol Psychiatry. 2012;17:1161–1163. doi: 10.1038/mp.2012.111.
    1. Institute of Medicine, Food and Nutrition Board . Dietary reference intakes for energy, carbohydrate, fiber, fat, fatty acids, cholesterol, protein, and amino acids (macronutrients) Washington, DC: National Academy Press; 2005.
    1. U.S. Department of Health and Human Services, U.S. Department of Agriculture. 2015–2020 dietary guidelines for Americans. 2015.
    1. Avery KN, Donovan JL, Horwood J, et al. The importance of dietary change for men diagnosed with and at risk of prostate cancer: a multi-centre interview study with men, their partners and health professionals. BMC Fam Pract. 2014;15:81. doi: 10.1186/1471-2296-15-81.

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