The effect of tinzaparin on biomarkers in FIGO stages III-IV ovarian cancer patients undergoing neoadjuvant chemotherapy – the TABANETOC trial: study protocol for a randomized clinical multicenter trial

Anna Karlsson; Gabriel  Lindahl; Anna-Clara Spetz Holm; Karin Bergmark; Pernilla Dahm Kähler; Boglarka Fekete; Ulrika Ottander; Charlotte Öfverman; Pernilla  Israelsson; Laila  Falknäs; Anders  Rosenmüller; Malena  Tiefenthal Thrane; Shefqet  Halili; Tomas L.  Lindahl; Maria C.  Jenmalm; Preben  Kjølhede

doi:10.2340/1651-226X.2024.40207

Authors

Anna Karlsson Department of Obstetrics and Gynecology, Department of Biomedical and Clinical Sciences, Linköping University, Linköping, Sweden https://orcid.org/0000-0001-5355-2501
Gabriel Lindahl Department of Oncology, Department of Biomedical and Clinical Sciences, Linköping University, Linköping, Sweden https://orcid.org/0000-0001-9494-1765
Anna-Clara Spetz Holm Department of Obstetrics and Gynecology, Department of Biomedical and Clinical Sciences, Linköping University, Linköping, Sweden https://orcid.org/0000-0002-0268-2901
Karin Bergmark Department of Oncology, Sahlgrenska University Hospital, Gothenburg, Sweden https://orcid.org/0000-0002-3548-2949
Pernilla Dahm Kähler Department of Obstetrics and Gynecology, Sahlgrenska Academy at University of Gothenburg, Gothenburg, Sweden https://orcid.org/0000-0002-6699-893X
Boglarka Fekete Department of Oncology, Sahlgrenska University Hospital, Gothenburg, Sweden https://orcid.org/0000-0002-2382-3072
Ulrika Ottander Department of Clinical Sciences, Obstetrics and Gynecology, Umeå University, Umeå, Sweden https://orcid.org/0000-0002-1383-7753
Charlotte Öfverman Department of Diagnostics and Intervention, Oncology, Umeå University, Umeå, Sweden https://orcid.org/0009-0002-4971-7961
Pernilla Israelsson Department of Diagnostics and Intervention, Oncology, Umeå University, Umeå, Sweden https://orcid.org/0009-0003-8605-8122
Laila Falknäs Department of Obstetrics and Gynecology, Ryhov hospital, Jönköping, Sweden https://orcid.org/0009-0007-3448-3329
Anders Rosenmüller Department of Obstetrics and Gynecology, Västervik hospital, Västervik, Sweden
Malena Tiefenthal Thrane Department of Obstetrics and Gynecology, Höglandssjukhuset, Eksjö, Sweden https://orcid.org/0009-0001-7775-1799
Shefqet Halili Department of Obstetrics and Gynecology, Värnamo hospital, Värnamo, Sweden
Tomas L. Lindahl Department of Biomedical and Clinical Sciences, Division of Clinical Chemistry and Pharmacology, Linköping University, Linköping, Sweden https://orcid.org/0000-0003-0174-8152
Maria C. Jenmalm Division of Inflammation and Infection, Department of Biomedical and Clinical Sciences, Linköping University, Linköping, Sweden https://orcid.org/0000-0002-2117-5366
Preben Kjølhede Department of Obstetrics and Gynecology, Department of Biomedical and Clinical Sciences, Linköping University, Linköping, Sweden https://orcid.org/0000-0001-5702-4116

DOI:

https://doi.org/10.2340/1651-226X.2024.40207

Keywords:

clinical trial, neoadjuvant chemotherapy, ovarian cancer, tinzaparin

Abstract

Background: Tinzaparin, a low-molecular weight heparin (LMWH), has shown anti-neoplastic properties in animal models and in in vitro studies of human cancer cell lines. The reduction of CA-125 levels during neoadjuvant chemotherapy (NACT) in patients with epithelial ovarian cancer (EOC) co-varies with the prognosis; the larger the decrease in CA-125, the better the prognosis.

Purpose: This study aims to evaluate the potential anti-neoplastic effects of tinzaparin by investigating changes in serum CA-125 levels in advanced EOC patients who receive NACT.

Material and methods: This is an open randomized multicenter pilot trial. Forty patients with EOC selected to receive NACT will be randomized 1:1 to receive daily addition of tinzaparin or no tinzaparin. The processing and treatment of the patients will otherwise follow the recommendations in the Swedish National Guidelines for Ovarian Cancer. Before every cycle of chemotherapy, preoperatively, and 3 weeks after the last cycle of chemotherapy, a panel of biomarkers, including CA-125, will be measured.

Patients: Inclusion criteria are women aged 18 years or older, World Health Organization performance status 0–1, histologically confirmed high-grade serous, endometrioid or clear cell EOC, International Federation of Gynecology and Obstetrics (FIGO) stages III-IV. In addition, a CA-125 level of ≥ 250 kIE/L at diagnosis. Exclusion criteria are contraindications to LMWH, ongoing or recent treatment with unfractionated heparin, LMWH, warfarin or non-vitamin K antagonist oral anticoagulants.

Interpretation: This study will make an important contribution to the knowledge of the anti-neoplastic effects of tinzaparin in EOC patients and may thus guide the planning of a future study on the impact of tinzaparin on survival in EOC.

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References

Regionala Cancercentrum i Samverkan. Svenska kvalitetsregistret för gynekologisk cancer [Internet]. In Swedish [cited 2024 Jan 18]. Available from: https://www.cancercentrum.se/samverkan/cancerdiagnoser/gynekologi/kvalitetsregister/

Kurman RJ, Shih IeM. The dualistic model of ovarian carcinogenesis: revisited, revised, and expanded. Am J Pathol. 2016;186(4):733–47.

https://doi.org/10.1016/j.ajpath.2015.11.011 DOI: https://doi.org/10.1016/j.ajpath.2015.11.011

Zhang M, Cheng S, Jin Y, Zhao Y, Wang Y. Roles of CA125 in diagnosis, prediction, and oncogenesis of ovarian cancer. Biochim Biophys Acta Rev Cancer. 2021;1875(2):188503.

https://doi.org/10.1016/j.bbcan.2021.188503 DOI: https://doi.org/10.1016/j.bbcan.2021.188503

Wang Q, Feng X, Liu X, Zhu S. Prognostic value of elevated pre-treatment serum CA-125 in epithelial ovarian cancer: a meta-analysis. Front Oncol. 2022;12:868061.

https://doi.org/10.3389/fonc.2022.868061 DOI: https://doi.org/10.3389/fonc.2022.868061

Kessous R, Wissing MD, Piedimonte S, Abitbol J, Kogan L, Laskov I, et al. CA-125 reduction during neoadjuvant chemotherapy is associated with success of cytoreductive surgery and outcome of patients with advanced high-grade ovarian cancer. Acta Obstet Gynecol Scand. 2020;99(7):933–40.

https://doi.org/10.1111/aogs.13814 DOI: https://doi.org/10.1111/aogs.13814

Lee M, Chang MY, Yoo H, Lee KE, Chay DB, Cho H, et al. Clinical significance of CA125 level after the first cycle of chemotherapy on survival of patients with advanced ovarian cancer. Yonsei Med J. 2016;57(3):580–7.

https://doi.org/10.3349/ymj.2016.57.3.580 DOI: https://doi.org/10.3349/ymj.2016.57.3.580

Chen Y, Zhang L, Liu WX, Liu XY. Prognostic significance of preoperative anemia, leukocytosis and thrombocytosis in Chinese women with epithelial ovarian cancer. Asian Pac J Cancer Prev. 2015;16(3):933–9.

https://doi.org/10.7314/APJCP.2015.16.3.933 DOI: https://doi.org/10.7314/APJCP.2015.16.3.933

Ayhan A, Günakan E, Alyazıcı İ, Haberal N, Altundağ Ö, Dursun P. The preoperative albumin level is an independent prognostic factor for optimally debulked epithelial ovarian cancer. Arch Gynecol Obstet. 2017;296(5):989–95.

https://doi.org/10.1007/s00404-017-4511-9 DOI: https://doi.org/10.1007/s00404-017-4511-9

Dobrzycka B, Mackowiak-Matejczyk B, Terlikowska KM, Kulesza-Bronczyk B, Kinalski M, Terlikowski SJ. Serum levels of IL-6, IL-8 and CRP as prognostic factors in epithelial ovarian cancer. Eur Cytokine Netw. 2013;24(3):106–13.

https://doi.org/10.1684/ecn.2013.0340 DOI: https://doi.org/10.1684/ecn.2013.0340

Sanna E, Tanca L, Cherchi C, Gramignano G, Oppi S, Chiai MG, et al. Decrease in neutrophil-to-lymphocyte ratio during neoadjuvant chemotherapy as a predictive and prognostic marker in advanced ovarian cancer. Diagnostics (Basel). 2021;20;11(7):1298.

https://doi.org/10.3390/diagnostics11071298 DOI: https://doi.org/10.3390/diagnostics11071298

Dimakakos EP, Vathiotis I, Syrigos K. The role of tinzaparin in oncology. Clin Appl Thromb Hemost. 2018;24(5):697–707.

https://doi.org/10.1177/1076029617729215 DOI: https://doi.org/10.1177/1076029617729215

Mousavi S, Moradi M, Khorshidahmad T, Motamedi M. Anti-Inflammatory effects of heparin and its derivatives: a systematic review. Adv Pharmacol Sci. 2015;2015:507151.

https://doi.org/10.1155/2015/507151 DOI: https://doi.org/10.1155/2015/507151

Bruno V, Svensson-Arvelund J, Rubér M, Berg G, Piccione E, Jenmalm MC, et al. Effects of low molecular weight heparin on the polarization and cytokine profile of macrophages and T helper cells in vitro. Sci Rep. 2018;8(1):4166.

https://doi.org/10.1038/s41598-018-22418-2 DOI: https://doi.org/10.1038/s41598-018-22418-2

Hanahan D, Weinberg RA. Hallmarks of cancer: the next generation. Cell. 2011;144(5):646–74.

https://doi.org/10.1016/j.cell.2011.02.013 DOI: https://doi.org/10.1016/j.cell.2011.02.013

Masoumi Moghaddam S, Amini A, Morris DL, Pourgholami MH. Significance of vascular endothelial growth factor in growth and peritoneal dissemination of ovarian cancer. Cancer Metastasis Rev. 2012;31(1–2):143–62.

https://doi.org/10.1007/s10555-011-9337-5 DOI: https://doi.org/10.1007/s10555-011-9337-5

Mitsis M, Koliou P, Bali C, Ntounousi E, Tatsis V, Nousias V, et al. In surgical colon cancer patients extended-duration thromboprophylaxis (30 days) with the highest dose of tinzaparin (4,500 IU s.c./q.d.) normalizes the postoperative VEGF levels. J Cancer. 2017;25;8(15):2899–906.

https://doi.org/10.7150/jca.20107 DOI: https://doi.org/10.7150/jca.20107

Pfankuchen DB, Stölting DP, Schlesinger M, Royer HD, Bendas G. Low molecular weight heparin tinzaparin antagonizes cisplatin resistance of ovarian cancer cells. Biochem Pharmacol. 2015;15;97(2):147–57.

https://doi.org/10.1016/j.bcp.2015.07.013 DOI: https://doi.org/10.1016/j.bcp.2015.07.013

Karamouzis MV, Athanasiadis I, Samelis G, Vallilas C, Bokas A, Nikolaidi A, et al. The impact of thromboprophylaxis on the survival of patients with advanced pancreatic cancer. The pancreatic cancer and tinzaparin (PaCT) study. Cancers (Basel). 2021;13(12):2884.

https://doi.org/10.3390/cancers13122884 DOI: https://doi.org/10.3390/cancers13122884

Auer RC, Ott M, Karanicolas P, Brackstone MR, Ashamalla S, Weaver J, et al. Efficacy and safety of extended duration to perioperative thromboprophylaxis with low molecular weight heparin on disease-free survival after surgical resection of colorectal cancer (PERIOP-01): multicentre, open label, randomised controlled trial. BMJ. 2022;378:e071375.

https://doi.org/10.1136/bmj-2022-071375 DOI: https://doi.org/10.1136/bmj-2022-071375

Meyer G, Besse B, Doubre H, Charles-Nelson A, Aquilanti S, Izadifar A, et al. Anti-tumour effect of low molecular weight heparin in localised lung cancer: a phase III clinical trial. Eur Respir J. 2018;52(4):1801220.

https://doi.org/10.1183/13993003.01220-2018 DOI: https://doi.org/10.1183/13993003.01220-2018

Regionala Cancer Centrum i Samverkan. Nationellt vårdprogram epitelial äggstockscancer. Version 4.2 [Internet]. In Swedish [cited 2024 Jan 18]. Available from: https://kunskapsbanken.cancercentrum.se/globalassets/cancerdiagnoser/gynekologi/aggstockscancer/nationellt-vardprogram-aggstockscancer.pdf

Assarsson E, Lundberg M, Holmquist G, Björkesten J, Thorsen SB, Ekman D, et al. Homogenous 96-plex PEA immunoassay exhibiting high sensitivity, specificity, and excellent scalability. PLoS One. 2014;9(4):e95192.

https://doi.org/10.1371/journal.pone.0095192 DOI: https://doi.org/10.1371/journal.pone.0095192

Simple Interactive Statistical Analysis. Allocation [Internet]. [cited 2024 January 18]. Available from: https://www.quantitativeskills.com/sisa/.

Chan A-W, Tetzlaff JM, Altman DG, Lauoacis A, Gøtzsche PC, Krleža-Jerić K, et al. SPIRIT 2013 statement: defining standard protocol items for clinical trials. Ann Intern Med. 2013;158(3):200–7. DOI: https://doi.org/10.7326/0003-4819-158-3-201302050-00583

https://doi.org/

Chan A-W, Tetzlaff JM, Gøtzsche PC, Altman DG, Mann H, Berlin JA, et al. SPIRIT 2013 explanation and elaboration: guidance for protocols of clinical trials. BMJ. 2013;346:e7586.

https://doi.org/10.1136/bmj.e7586 DOI: https://doi.org/10.1136/bmj.e7586

The effect of tinzaparin on biomarkers in FIGO stages III-IV ovarian cancer patients undergoing neoadjuvant chemotherapy – the TABANETOC trial: study protocol for a randomized clinical multicenter trial

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