Skip to main content

Advertisement

SpringerLink
Log in

Risk factor analysis for regorafenib-induced severe hypertension in metastatic colorectal cancer treatment

  • Research
  • Published:
Supportive Care in Cancer Aims and scope Submit manuscript

Abstract

Regorafenib, a multikinase inhibitor, is effective in treating metastatic colorectal cancer (mCRC). Hypertension is a frequently occurring adverse effect caused by regorafenib regardless of previous treatment with vascular endothelial growth factor (VEGF) inhibitors in almost all patients. We identified the risk factors associated with regorafenib-induced severe hypertension. Patients with mCRC (n = 100) who received regorafenib were evaluated retrospectively. The primary endpoint was the evaluation of the risk factors for grade ≥ 3 hypertension. The association between pre-existing hypertension at baseline and grade ≥ 3 hypertension symptoms was also assessed. Patients with pre-existing hypertension at baseline accounted for 55% of the total patients. The starting doses of regorafenib were 160 mg (49.0% of patients), 120 mg (29.0%), and 80 mg (22.0%). The incidence of grade ≥ 3 hypertension was 30.0%. The median time to grade ≥ 3 symptom development was 7 days (range: 1–56 days). Additional antihypertensive treatment was administered to 83.6% of patients who developed hypertension. Logistic regression analyses revealed that baseline pre-existing hypertension complications and previous anti-VEGF treatment for ≥ 700 days were independent risk factors for grade ≥ 3 hypertension development. Further analyses revealed that pre-existing hypertension before anti-VEGF treatment (primary hypertension) was significantly related to the symptom development (adjusted odds ratio, 8.74; 95% confidence interval, 2.86–26.72; P = 0.0001). Our study suggests that pre-existing primary hypertension and previous anti-VEGF treatment for ≥ 700 days are independent risk factors for regorafenib-induced severe hypertension. Deeper understanding of the symptom nature and management can significantly contribute to safer interventions, necessitating further studies.

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

Access this article

Log in via an institution

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

Data availability

The datasets used and/or analyzed during the current study are available from the corresponding author upon reasonable request.

References

  1. Grothey A, Van Cutsem E, Sobrero A, Siena S, Falcone A, Ychou M et al (2013) Regorafenib monotherapy for previously treated metastatic colorectal cancer (CORRECT): an international, multicentre, randomised, placebo-controlled, phase 3 trial. Lancet 381:303–312

    Article  CAS  PubMed  Google Scholar 

  2. Yoshino T, Komatsu Y, Yamada Y, Yamazaki K, Tsuji A, Ura T et al (2015) Randomized phase III trial of regorafenib in metastatic colorectal cancer: analysis of the CORRECT Japanese and non-Japanese subpopulations. Invest New Drugs 33:740–750

    Article  CAS  PubMed  Google Scholar 

  3. Yamaguchi K, Komatsu Y, Satoh T, Uetake H, Yoshino T, Nishida T et al (2019) Large-scale, prospective observational study of regorafenib in Japanese patients with metastatic colorectal cancer in a real-world clinical setting. Oncologist 24:e450-457

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Wang Z, Xu J, Nie W, Huang G, Tang J, Guan X (2014) Risk of hypertension with regorafenib in cancer patients: a systematic review and meta-analysis. Eur J Clin Pharmacol 70:225–231

    Article  CAS  PubMed  Google Scholar 

  5. Dong M, Wang R, Sun P, Zhang D, Zhang Z, Zhang J et al (2021) Clinical significance of hypertension in patients with different types of cancer treated with antiangiogenic drugs. Oncol Lett 21:315

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Aronow WS (2016) Optimal blood pressure goals in patients with hypertension at high risk for cardiovascular events. Am J Ther 23:e218-223

    Article  PubMed  Google Scholar 

  7. Escudier B, Eisen T, Stadler WM, Szczylik C, Oudard S, Siebels M et al (2007) Sorafenib in advanced clear-cell renal-cell carcinoma. N Engl J Med 356:125–134

    Article  CAS  PubMed  Google Scholar 

  8. Dobbin SJH, Petrie MC, Myles RC, Touyz RM, Lang NN (2021) Cardiotoxic effects of angiogenesis inhibitors. Clin Sci (Lond) 135:71–100

    Article  CAS  PubMed  Google Scholar 

  9. Chu TF, Rupnick MA, Kerkela R, Dallabrida SM, Zurakowski D, Nguyen L et al (2007) Cardiotoxicity associated with tyrosine kinase inhibitor sunitinib. Lancet 370:2011–2019

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Weisstuch JM, Dworkin LD (1992) Does essential hypertension cause end-stage renal disease? Kidney Int Suppl 36:S33–S37

    CAS  PubMed  Google Scholar 

  11. van Dorst DCH, Dobbin SJH, Neves KB, Herrmann J, Herrmann SM, Versmissen J et al (2021) Hypertension and prohypertensive antineoplastic therapies in cancer patients. Circ Res 128:1040–1061

    Article  PubMed  PubMed Central  Google Scholar 

  12. Hamnvik OP, Choueiri TK, Turchin A, McKay RR, Goyal L, Davis M et al (2015) Clinical risk factors for the development of hypertension in patients treated with inhibitors of the VEGF signaling pathway. Cancer 121:311–319

    Article  CAS  PubMed  Google Scholar 

  13. Wicki A, Hermann F, Prêtre V, Winterhalder R, Kueng M, von Moos R et al (2014) Pre-existing antihypertensive treatment predicts early increase in blood pressure during bevacizumab therapy: the prospective AVALUE cohort study. Oncol Res Treat 37:230–236

    Article  CAS  PubMed  Google Scholar 

  14. Nishihara M, Morikawa N, Yokoyama S, Nishikura K, Yasuhara M, Matsuo H (2018) Risk factors increasing blood pressure in Japanese colorectal cancer patients treated with bevacizumab. Pharmazie 73:671–675

    CAS  PubMed  Google Scholar 

  15. Price TJ, Zannino D, Wilson K, Simes RJ, Cassidy J, Van Hazel GA et al (2012) Bevacizumab is equally effective and no more toxic in elderly patients with advanced colorectal cancer: a subgroup analysis from the AGITG MAX trial: an international randomised controlled trial of capecitabine, bevacizumab and mitomycin C. Ann Oncol 23:1531–1536

    Article  CAS  PubMed  Google Scholar 

  16. Sun L, Ma JT, Zhang SL, Zou HW, Han CB (2015) Efficacy and safety of chemotherapy or tyrosine kinase inhibitors combined with bevacizumab versus chemotherapy or tyrosine kinase inhibitors alone in the treatment of non-small cell lung cancer: a systematic review and meta-analysis. Med Oncol 32:473

    Article  PubMed  Google Scholar 

  17. Brahmer JR, Dahlberg SE, Gray RJ, Schiller JH, Perry MC, Sandler A et al (2011) Sex differences in outcome with bevacizumab therapy: analysis of patients with advanced-stage non-small cell lung cancer treated with or without bevacizumab in combination with paclitaxel and carboplatin in the Eastern Cooperative Oncology Group Trial 4599. J Thorac Oncol 6:103–108

    Article  PubMed  PubMed Central  Google Scholar 

  18. Chiorean EG, Nandakumar G, Fadelu T, Temin S, Alarcon-Rozas AE, Bejarano S et al (2020) Treatment of patients with late-stage colorectal cancer: ASCO resource-stratified guideline. JCO Glob Oncol 6:414–438

    Article  PubMed  Google Scholar 

  19. Komatsu Y, Doi T, Sawaki A, Kanda T, Yamada Y, Kuss I et al (2015) Regorafenib for advanced gastrointestinal stromal tumors following imatinib and sunitinib treatment a subgroup analysis evaluating Japanese patients in the phase III GRID trial. Int J Clin Oncol 20:905–912

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Bekaii-Saab TS, Ou FS, Ahn DH, Boland PM, Ciombor KK, Heying EN et al (2019) Regorafenib dose-optimisation in patients with refractory metastatic colorectal cancer (ReDOS): a randomised, multicentre, open-label, phase 2 study. Lancet Oncol 20:1070–1082

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Stivarga tablets® [package insert on the internet]. Bayer Yakuhin., 2019. https://pharma-navi.bayer.jp/sites/g/files/vrxlpx9646/files/2020-11/STI_MPI_201909240_1568962296.pdf. accessed May 5, 2022

  22. Zamorano JL, Lancellotti P, Rodriguez Munoz D, Aboyans V, Asteggiano R, Galderisi M et al (2016) ESC Scientific Document Group. 2016 ESC position paper on cancer treatments and cardiovascular toxicity developed under the auspices of the ESC committee for practice guidelines: the task force for cancer treatments and cardiovascular toxicity of the European Society of Cardiology (ESC). Eur Heart J 37:2768–2801

    Article  PubMed  Google Scholar 

  23. Williams B, Mancia G, Spiering W, Rosei EA, Azizi M, Burnier M et al (2018) 2018 practice guidelines for the management of arterial hypertension of the European society of cardiology and the European society of hypertension ESC/ESH task force for the management of arterial hypertension. J Hypertens 36:1953–2041

    Article  CAS  PubMed  Google Scholar 

  24. Ueda T, Uemura H, Tomita Y, Tsukamoto T, Kanayama H, Shinohara N et al (2013) Efficacy and safety of axitinib versus sorafenib in metastatic renal cell carcinoma: subgroup analysis of Japanese patients from the global randomized Phase 3 AXIS trial. Jpn J Clin Oncol 43:616–628

    Article  PubMed  PubMed Central  Google Scholar 

  25. Yamashita T, Kudo M, Ikeda K, Izumi N, Tateishi R, Ikeda M et al (2020) REFLECT-a phase 3 trial comparing efficacy and safety of lenvatinib to sorafenib for the treatment of unresectable hepatocellular carcinoma: an analysis of Japanese subset. J Gastroenterol 55:113–122

    Article  CAS  PubMed  Google Scholar 

  26. Kawai A, Araki N, Hiraga H, Sugiura H, Matsumine A, Ozaki T et al (2016) A randomized, double-blind, placebo-controlled, phase III study of pazopanib in patients with soft tissue sarcoma: results from the Japanese subgroup. Jpn J Clin Oncol 46:248–253

    Article  PubMed  PubMed Central  Google Scholar 

  27. Taguchi D, Inoue M, Fukuda K, Yoshida T, Shimazu K, Fujita K et al (2020) Therapeutic drug monitoring of regorafenib and its metabolite M5 can predict treatment efficacy and the occurrence of skin toxicities. Int J Clin Oncol 25:531–540

    Article  CAS  PubMed  Google Scholar 

  28. Kobayashi K, Sugiyama E, Shinozaki E, Wakatsuki T, Tajima M, Kidokoro H et al (2021) Associations among plasma concentrations of regorafenib and its metabolites, adverse events, and ABCG2 polymorphisms in patients with metastatic colorectal cancers. Cancer Chemother Pharmacol 87:767–777

    Article  CAS  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Pharmacy, Hokkaido University Hospital, Kita 14-jo, Nishi 5-chome, Kita-ku, Sapporo, 060-8648, Japan

    Yoshitaka Saito, Yoh Takekuma & Mitsuru Sugawara

  2. Cancer Center, Hokkaido University Hospital, Kita 14-jo, Nishi 5-chome, Kita-ku, Sapporo, 060-8648, Japan

    Yoshito Komatsu

  3. Laboratory of Pharmacokinetics, Faculty of Pharmaceutical Sciences, Hokkaido University, Kita 12-jo, Nishi 6-chome, Kita-ku, Sapporo, 060-0812, Japan

    Mitsuru Sugawara

Authors
  1. Yoshitaka Saito
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Yoh Takekuma
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Yoshito Komatsu
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Mitsuru Sugawara
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

Participated in research design: YS and YK. Conducted experiments: YS. Performed data analysis: YS. Drafting of the manuscript: YS. All authors have read and approved the manuscript.

Corresponding author

Correspondence to Mitsuru Sugawara.

Ethics declarations

Ethical approval

All procedures performed in this study involving human participants were performed in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki Declaration and its later amendments or comparable ethical standards. For this type of study, the need for formal consent was waived by the Ethical Review Board for Life Science and Medical Research at Hokkaido University Hospital.

Consent to participate

Formal consent was not required for this type of study.

Consent for publication

Not applicable.

Conflict of interest

YS, YT, and MS have no conflicts of interest. YK reports receiving grants and personal fees from Ono, TAIHO, CHUGAI, Eli Lilly, Yakult, Bristol-Myers, Merck, Takeda, Novartis, Bayer, and Daiichi-Sankyo and grants from Iqvia outside the submitted work.

Additional information

Publisher's note

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

Rights and permissions

Springer Nature or its licensor holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Saito, Y., Takekuma, Y., Komatsu, Y. et al. Risk factor analysis for regorafenib-induced severe hypertension in metastatic colorectal cancer treatment. Support Care Cancer 30, 10203–10211 (2022). https://doi.org/10.1007/s00520-022-07381-z

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00520-022-07381-z

Keywords

Search

Navigation