Middle East Journal of Cancer

A Phase III Randomized Clinical Trial Study of Chemoradiation using Lovastatin/Cisplatin in Patients with Head and Neck Squamous Cell Carcinoma

Document Type : Original Article(s)

Authors

Sasan Razmjoo 1, 2
Seyed Mohammad Hosseini 1, 2
Hojatollah Shahbazian 1, 2
Shole Arvandi 1, 2
Pari Ghadamgahi 1, 2

1 Department of Clinical Oncology, Faculty of Medicine, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran

2 Cancer Research Center, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran

https://doi.org/10.30476/mejc.2021.87318.1407
Abstract
Background: Target therapy of apoptosis signaling has been previously shown to have a therapeutic role in the treatment of head and neck squamous cell carcinoma (HNSCC). The present study aimed to investigate the safety and maximum dose of Lovastatin (80 mg/day) in additional standard therapy with cisplatin.
Method: The current study is a phase III randomized clinical trial, conducted to determine the effect of Lovastatin on HNSCC. To eliminate the interference effect of previous treatments and surgeries, newly-diagnosed HNSCC patients were included. A total of 45 patients from May 2017 to February 2018 were enrolled. The intervention group received Lovastatin/cisplatin chemoradiotherapy and the control group received only cisplatin. All the subjects were evaluated on a weekly basis during the treatment and three and six weeks after that for related adverse events (AEs). The response rate to the treatment was assessed eight weeks following the treatment.
Results: No significant differences were found between the two groups concerning the objective response (OR) rate (95.8% vs. 95.2%, P = 1, 95% confidence interval). In the intervention group, tumors were entirely removed in 70.8% of the subjects and partial response was seen in 25% of them. No patient was excluded due to the AEs. The gastrointestinal AE (31.1%) was the most frequent one.
Conclusion: In the present study, comparing the intervention and control groups, no significant differences were observed concerning OR, but unlike previous investigations, the related cardiac AEs were not seen. This observation confirmed the hypothesis that there is a possible association of Lovastatin use with better OR compared with standard chemoradiation (cisplatin) in the initial point of the treatment. However, further research is needed to investigate different doses of Lovastatin with longer follow-ups and new diagnoses of HNSCC patients.

Keywords

Carcinoma
Squamous cell
Chemoradiation
Cisplatin
Lovastatin

How to cite this article:

Razmjoo S, Hoseyni M, Shahbazian H, Arvandi S, Ghadamgahi P. A phase III randomized clinical trial study of chemoradiation using lovastatin/cisplatin in patients with head and neck squamous cell carcinoma. Middle East J Cancer. 2022;13(1):120-7. doi: 10.30476/mejc.2021.87318. 1407.

  1. Marur S, Forastiere AA. Head and neck squamous cell carcinoma: Update on epidemiology, diagnosis, and treatment. Mayo Clin Proc. 2016;91(3):386-96. doi:10.1016/j.mayocp.2015.12.017.
  2. Curado MP, Boyle P. Epidemiology of head and neck squamous cell carcinoma not related to tobacco or alcohol. Curr Opin Oncol. 2013;25(3):229-34. doi:10.1097/CCO.0b013e32835ff48c.
  3. Lee DH, Roh JL, Baek S, Jung JH, Choi SH, Nam SY, et al. Second cancer incidence, risk factor, and specific mortality in head and neck squamous cell carcinoma. Otolaryngol Head Neck Surg. 2013;149(4): 579-86. doi:10.1177/0194599813496373.
  4. Ang K, Zhang QE, Wheeler RH, Rosenthal DI, Nguyen-Tan F, Kim H, et al. A phase III trial (RTOG 0129) of two radiation-cisplatin regimens for head and neck carcinomas (HNC): Impact of radiation and cisplatin intensity on outcome. J Clin Oncol. 2010; 28(15): 5507.
  5. Szturz P, Wouters K, Kiyota N, Tahara M, Prabhash K, Noronha V, et al. Weekly low-dose versus three-weekly high-dose cisplatin for concurrent chemoradiation in locoregionally advanced non-nasopharyngeal head and neck cancer: A systematic review and meta-analysis of aggregate data. Oncologist. 2017;22(9):1056-66. doi: 10.1634/theoncologist.2017-0015.
  6. Homma A, Inamura N, Oridate N, Suzuki S, Hatakeyama H, Mizumachi T, et al. Concomitant weekly cisplatin and radiotherapy for head and neck cancer. Jpn J Clin Oncol. 2011;41(8):980-6. doi: 10.1093/jjco/hyr086.
  7. Collins R, Armitage J, Parish S, Sleigh P, Peto R; Heart Protection Study Collaborative Group. MRC/BHF heart protection study of cholesterol-lowering with simvastatin in 5963 people with diabetes: a randomised placebo-controlled trial. Lancet. 2003;361(9374):2005-16. doi: 10.1016/s0140-6736(03)13636-7.
  8. Goldstein JL, Brown MS. Regulation of the mevalonate pathway. Nature. 1990;343(6257):425-30. doi: 10.1038/343425a0.
  9. Young-Xu Y, Jabbour S, Goldberg R, Blatt CM, Graboys T, Bilchik B, et al. Usefulness of statin drugs in protecting against atrial fibrillation in patients with coronary artery disease. Am J Cardiol. 2003;92(12):1379-83. doi: 10.1016/j.amjcard. 2003.08.040.
  10. Poldermans D, Bax JJ, Kertai MD, Krenning B, Westerhout CM, Schinkel AF, et al. Statins are associated with a reduced incidence of perioperative mortality in patients undergoing major non-cardiac vascular surgery. Circulation. 2003;107(14):1848-51. doi: 10.1161/01.CIR.0000066286.15621.98.
  11. .Lee DY, Lim JH, Kim YJ, Kim SD, Park SW, Kwon SK, et al. Effect of Celecoxib on survival of mobile tongue cancer. Anticancer Res. 2015;35(7):4235-41.
  12. Liu HW, Bian SY, Zhu QW, Zhao YX. Cancer risk in older people receiving statin therapy: a meta-analysis of randomized controlled trials. J Geriatr Cardiol. 2016;13(8):693-700. doi: 10.11909/j.issn.1671-5411.2016.08.008.
  13. Dimitroulakos J, Marhin WH, Tokunaga J, Irish J, Gullane P, Penn LZ, et al. Microarray and biochemical analysis of lovastatin-induced apoptosis of squamous cell carcinomas. Neoplasia. 2002;4(4):337-46. doi: 10.1038/sj.neo.7900247.
  14. Hanahan D, Weinberg RA. Hallmarks of cancer: the next generation. Cell. 2011;144(5):646-74. doi: 10.1016/j.cell.2011.02.013.
  15. Zhong WB, Hsu SP, Ho PY, Liang YC, Chang TC, Lee WS. Lovastatin inhibits proliferation of anaplastic thyroid cancer cells through up-regulation of p27 by interfering with the Rho/ROCK-mediated pathway. Biochem Pharmacol. 2011;82(11):1663-72. doi: 10.1016/j.bcp.2011.08.021.
  16. Dimitroulakos J, Ye LY, Benzaquen M, Moore MJ, Kamel-Reid S, Freedman MH, et al. Differential sensitivity of various pediatric cancers and squamous cell carcinomas to lovastatin-induced apoptosis: therapeutic implications. Clin Cancer Res. 2001;7(1): 158-67.
  17. Castelli J, Simon A, Lafond C, Perichon N, Rigaud B, Chajon E, et al. Adaptive radiotherapy for head and neck cancer. Acta Oncol. 2018;57(10):1284-92. doi: 10.1080/0284186X.2018.1505053.
  18. Eisenhauer EA, Therasse P, Bogaerts J, Schwartz LH, Sargent D, Ford R, et al. New response evaluation criteria in solid tumours: revised RECIST guideline (version 1.1). Eur J Cancer. 2009;45(2):228-47. doi: 10.1016/j.ejca.2008.10.026.
  19. Savarese DMF, Drews RE, Tirnauer JS. Common terminology criteria for adverse events [Internet]. UpToDate; [updated 2020 Jan 21; cited 2020 Feb 15]. Available from: https://www.uptodate.com/contents/ common-terminology-criteria-for-adverse-events
  20. Tsai HK, Katz MS, Coen JJ, Zietman AL, Kaufman DS, Shipley WU. Association of statin use with improved local control in patients treated with selective bladder preservation for muscle-invasive bladder cancer. Urology. 2006;68(6):1188-92. doi: 10.1016/j .urology.2006.08.1078.
  21. Katz MS, Minsky BD, Saltz LB, Riedel E, Chessin DB, Guillem JG. Association of statin use with a pathologic complete response to neoadjuvant chemoradiation for rectal cancer. Int J Radiat Oncol Biol Phys. 2005;62(5):1363-70. doi: 10.1016/j.ijrobp. 2004.12.033.
  22. Krüger K, Ziegler V, Hartmann C, Henninger C, Thomale J, Schupp N, et al. Lovastatin prevents cisplatin-induced activation of pro-apoptotic DNA damage response (DDR) of renal tubular epithelial cells. Toxicol Appl Pharmacol. 2016;292:103-14. doi: 10.1016/j.taap.2015.12.023.
  23. Ziegler V, Albers A, Fritz G. Lovastatin protects keratinocytes from DNA damage-related pro-apoptotic stress responses stimulated by anticancer therapeutics. Biochim Biophys Acta. 2016;1863(6 Pt A):1082-92. doi: 10.1016/j.bbamcr.2016.02.009.
  24. Cancer Genome Atlas Network. Comprehensive genomic characterization of head and neck squamous cell carcinomas. Nature. 2015;517(7536):576-82. doi: 10.1038/nature14129.
  25. Huang SW, Chyuan IT, Shiue C, Yu MC, Hsu YF, Hsu MJ. Lovastatin-mediated MCF-7 cancer cell death involves LKB1-AMPK-p38MAPK-p53-survivin signalling cascade. J Cell Mol Med. 2020;24(2):1822-36. doi: 10.1111/jcmm.14879.
  26. Aznar S, Lacal JC. Rho signals to cell growth and apoptosis. Cancer Lett. 2001;165(1):1-10. doi: 10.1016/s0304-3835(01)00412-8.
  27. Wang W, Le W, Cho DY, Hwang PH, Upadhyay D. Novel effects of statins in enhancing efficacy of chemotherapy in vitro in nasopharyngeal carcinoma. Int Forum Allergy Rhinol. 2011;1(4):284-9. doi: 10.1002/alr.20039.
  28. Pavan LM, Rêgo DF, Elias ST, De Luca Canto G, Guerra EN. In vitro anti-tumor effects of statins on head and neck squamous cell carcinoma: A systematic review. PLoS One. 2015;10(6):e0130476. doi: 10.1371/journal.pone.0130476.
  29. Osmak M. Statins and cancer: current and future prospects. Cancer Lett. 2012;324(1):1-12. doi: 10.1016/j.canlet.2012.04.011.
  30. Altwairgi AK. Statins are potential anticancerous agents (review). Oncol Rep. 2015;33(3):1019-39. doi: 10.3892/or.2015.3741.
  31. Zhong WB, Tsai YC, Chin LH, Tseng JH, Tang LW, Horng S, et al. A synergistic anti-cancer effect of troglitazone and lovastatin in a human anaplastic thyroid cancer cell line and in a mouse xenograft model. Int J Mol Sci. 2018;19(7):1834. doi: 10.3390/ijms19071834.
  32. Kim WS, Kim MM, Choi HJ, Yoon SS, Lee MH, Park K, et al. Phase II study of high-dose lovastatin in patients with advanced gastric adenocarcinoma. Invest New Drugs. 2001;19(1):81-3. doi: 10.1023/a:100648 1423298.
  33. Knox JJ, Siu LL, Chen E, Dimitroulakos J, Kamel-Reid S, Moore MJ, et al. A phase I trial of prolonged administration of lovastatin in patients with recurrent or metastatic squamous cell carcinoma of the head and neck or of the cervix. Eur J Cancer. 2005;41(4):523-30. doi: 10.1016/j.ejca.2004.12.013.
  34. Thibault A, Samid D, Tompkins AC, Figg WD, Cooper MR, Hohl RJ, et al. Phase I study of lovastatin, an inhibitor of the mevalonate pathway, in patients with cancer. Clin Cancer Res. 1996;2(3):483-91.

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