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Atorvastatin in combination with radiotherapy and temozolomide for glioblastoma: a prospective phase II study

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Summary

Glioblastoma is a fast-growing primary brain tumor observed in adults with the worst prognosis. Preclinical studies have demonstrated the encouraging anticancer activity of statins. This study evaluated the efficacy of atorvastatin in combination with standard therapy in patients with glioblastoma. In this prospective, open-label, single-arm, phase II study, patients were treated with atorvastatin in combination with the standard glioblastoma therapy comprising radiotherapy and temozolomide. The primary endpoint was progression-free survival (PFS) at 6 months (PFS-6). Among 36 patients enrolled from January 2014 to January 2017, the median age was 52 (20–69) years; 22% of the patients were aged ≥60 years, and 62% were male. Patients received atorvastatin for a median duration of 6.2 (0.3–28) months. At a median follow-up of 19 months, the PFS-6 rate was 66%, with a median PFS of 7.6 (5.7–9.4) months. In terms of Grade ≥ 3 hematological adverse events, thrombocytopenia and neutropenia occurred in 7% and 12% of patients, respectively. In multivariate analyses, high baseline low-density lipoprotein levels were associated with worse survival (P = 0.046). Atorvastatin was not shown to improve PFS-6. However, this study identified that high low-density lipoprotein levels are an independent predictor of poor cancer-related outcomes. Future clinical trials testing statins should aim to enroll patients with slow-growing tumors.

Clinical trial information: NCT0202957 (December 12, 2013)

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References

  1. Cancer Stat Facts: Brain and Other Nervous System Cancer. Available at https://seer.cancer.gov/statfacts/html/brain.html. Accessed July 19, 2019

  2. Ostrom QT, Gittleman H, Truitt G, Boscia A, Kruchko C, Barnholtz-Sloan JS (2018) CBTRUS statistical report: primary brain and other central nervous system tumors diagnosed in the United States in 2011–2015. Neuro-Oncology 20:1–86. https://doi.org/10.1093/neuonc/noy131

    Article  Google Scholar 

  3. Patel AP, Fisher JL, Nichols E, Abd-Allah F, Abdela J, Abdelalim A, Abraha HN, Agius D, Alahdab F, Alam T, Allen CA, Anber NH, Awasthi A, Badali H, Belachew AB, Bijani A, Bjørge T, Carvalho F, Catalá-López F, Choi JYJ, Daryani A, Degefa MG, Demoz GT, Do HP, Dubey M, Fernandes E, Filip I, Foreman KJ, Gebre AK, Geramo YCD, Hafezi-Nejad N, Hamidi S, Harvey JD, Hassen HY, Hay SI, Irvani SSN, Jakovljevic M, Jha RP, Kasaeian A, Khalil IA, Khan EA, Khang YH, Kim YJ, Mengistu G, Mohammad KA, Mokdad AH, Nagel G, Naghavi M, Naik G, Nguyen HLT, Nguyen LH, Nguyen TH, Nixon MR, Olagunju AT, Pereira DM, Pinilla-Monsalve GD, Poustchi H, Qorbani M, Radfar A, Reiner RC, Roshandel G, Safari H, Safiri S, Samy AM, Sarvi S, Shaikh MA, Sharif M, Sharma R, Sheikhbahaei S, Shirkoohi R, Singh JA, Smith M, Tabarés-Seisdedos R, Tran BX, Tran KB, Ullah I, Weiderpass E, Weldegwergs KG, Yimer EM, Zadnik V, Zaidi Z, Ellenbogen RG, Vos T, Feigin VL, Murray CJL, Fitzmaurice C (2019) Global, regional, and national burden of brain and other CNS cancer, 1990–2016: a systematic analysis for the global burden of disease study. Lancet Neurol 18:376–393. https://doi.org/10.1016/S1474-4422(18)30468-X

    Article  Google Scholar 

  4. Gazzerro P, Proto MC, Gangemi G, Malfitano AM, Ciaglia E, Pisanti S, Santoro A, Laezza C, Bifulco M (2012) Pharmacological actions of statins: a critical appraisal in the management of cancer. Pharmacol Rev 64:102–146. https://doi.org/10.1124/pr.111.004994

    Article  CAS  PubMed  Google Scholar 

  5. Altwairgi AK (2015) Statins are potential anticancerous agents (review). Oncol Rep 33:1019–1039. https://doi.org/10.3892/or.2015.3741

    Article  CAS  PubMed  Google Scholar 

  6. Chen Y-A, Shih H-W, Lin Y-C, Hsu HY, Wu TF, Tsai CH, Wu CL, Wu HY, Hsieh JT, Tang CH, Lai CH (2018) Simvastatin sensitizes Radioresistant prostate Cancer cells by compromising DNA double-Strand break repair. Front Pharmacol 9:600. https://doi.org/10.3389/fphar.2018.00600

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Vuletic S, Riekse RG, Marcovina SM, Peskind ER, Hazzard WR, Albers JJ (2006) Statins of different brain penetrability differentially affect CSF PLTP activity. Dement Geriatr Cogn Disord 22:392–398. https://doi.org/10.1159/000095679

    Article  CAS  PubMed  Google Scholar 

  8. Athyros VG, Tziomalos K, Karagiannis A, Mikhailidis DP (2010) Atorvastatin: safety and tolerability. Expert Opin Drug Saf 9:667–674. https://doi.org/10.1517/14740338.2010.495385

    Article  CAS  PubMed  Google Scholar 

  9. Adams SP, Tsang M, Wright JM (2012) Lipid lowering efficacy of atorvastatin. Cochrane Database Syst Rev 12:CD008226. https://doi.org/10.1002/14651858.CD008226.pub2

    Article  PubMed  Google Scholar 

  10. Search of: atorvastatin | Completed Studies - List Results - ClinicalTrials.gov. Available at https://clinicaltrials.gov/ct2/results?cond=&term=atorvastatin&cntry=&state=&city=&dist=&Search=Search&recrs=e. Accessed July 21, 2019

  11. Atorvastatin Crystalline 40 mg film-coated Tablets - Summary of Product Characteristics (SmPC) - (eMC). Available at https://www.medicines.org.uk/emc/product/4178/smpc. Accessed July 21, 2019

  12. Newman C, Tsai J, Szarek M, Luo D, Gibson E (2006) Comparative safety of atorvastatin 80 mg versus 10 mg derived from analysis of 49 completed trials in 14,236 patients. Am J Cardiol 97:61–67. https://doi.org/10.1016/j.amjcard.2005.07.108

    Article  CAS  PubMed  Google Scholar 

  13. Stupp R, Mason WP, van den Bent MJ, Weller M, Fisher B, Taphoorn MJ, Belanger K, Brandes AA, Marosi C, Bogdahn U, Curschmann J, Janzer RC, Ludwin SK, Gorlia T, Allgeier A, Lacombe D, Cairncross JG, Eisenhauer E, Mirimanoff RO, European Organisation for Research and Treatment of Cancer Brain Tumor and Radiotherapy Groups, National Cancer Institute of Canada Clinical Trials Group (2005) Radiotherapy plus concomitant and adjuvant temozolomide for glioblastoma. N Engl J Med 352:987–996. https://doi.org/10.1056/NEJMoa043330

    Article  CAS  PubMed  Google Scholar 

  14. Altwairgi AK, Algareeb W, Yahya G et al (2016) Outcome of patients with glioblastoma in Saudi Arabia: single center experience. Mol Clin Oncol 4:756–762. https://doi.org/10.3892/mco.2016.818

    Article  PubMed  PubMed Central  Google Scholar 

  15. Adnan M, Mohammad KI, Manik MEH (2017) Anticancer agents in combination with statins. J Bioequivalence Bioavailab 9:463–466. https://doi.org/10.4172/jbb.1000345

    Article  CAS  Google Scholar 

  16. Rozados VR, Hinrichsen LI, McDonnell J, Scharovsky OG (2005) Lovastatin enhances in vitro radiation-induced apoptosis of rat B-cell lymphoma cells. J Exp Clin Cancer Res 24:55–61

    CAS  PubMed  Google Scholar 

  17. Seliger C, Schaertl J, Gerken M, Luber C, Proescholdt M, Riemenschneider MJ, Leitzmann MF, Hau P, Klinkhammer-Schalke M (2018) Use of statins or NSAIDs and survival of patients with high-grade glioma. PLoS One 13:e0207858. https://doi.org/10.1371/journal.pone.0207858

    Article  PubMed  PubMed Central  Google Scholar 

  18. Gaist D, Hallas J, Friis S, Hansen S, Sørensen HT (2014) Statin use and survival following glioblastoma multiforme. Cancer Epidemiol 38:722–727. https://doi.org/10.1016/j.canep.2014.09.010

    Article  PubMed  Google Scholar 

  19. Ding X, Zhang W, Li S et al (2019) The role of cholesterol metabolism in cancer. Am J Cancer Res 9:219–227

    CAS  PubMed  PubMed Central  Google Scholar 

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Authorship

All authors were involved in study conceptualization, reviewing and editing, formal analysis, and writing.

Funding

The study was supported by the King Fahad Medical City (KFMC) Intramural Fund (Grant: 13–200).

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Authors and Affiliations

  1. Medical Oncology Department, Comprehensive Cancer Center, King Fahad Medical City, Riyadh, Saudi Arabia

    Abdullah K. Altwairgi, Waleed A. Alghareeb & Abdullah A. Alsharm

  2. Clinical Pharmacy Department, King Fahad Medical City, Riyadh, Saudi Arabia

    Fouad H. AlNajjar

  3. Radiation Oncology Department, Comprehensive Cancer Center, King Fahad Medical City, Riyadh, Saudi Arabia

    Hussain Alhussain, Eyad Alsaeed & Ali Abdullah O. Balbaid

  4. Pathology Department, King Fahad Medical City, Riyadh, Saudi Arabia

    Sadeq Aldanan

  5. National Neuroscience Institute, King Fahad Medical City, Riyadh, Saudi Arabia

    Yasser Orz

Authors
  1. Abdullah K. Altwairgi
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  2. Waleed A. Alghareeb
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  3. Fouad H. AlNajjar
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  4. Hussain Alhussain
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  6. Ali Abdullah O. Balbaid
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  8. Yasser Orz
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  9. Abdullah A. Alsharm
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Corresponding author

Correspondence to Abdullah K. Altwairgi.

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Conflict of interest

All authors declare no conflicts of interest related to this study.

Ethical approval

All procedures involving human participants were 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.

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Informed consent was obtained from all participants included in the study

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Electronic supplementary material

Supplementary Figure S1.

Anticipated synergism of combination treatment with atorvastatin, radiation, and temozolomide (PNG 156 kb)

High Resolution (TIF 418 kb)

Supplementary Fig. S2

Treatment schema (PNG 136 kb)

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Supplementary Fig. S3

Timing of tumor response assessment (PNG 141 kb)

High Resolution (TIF 381 kb)

Supplementary Fig. S4

CONSORT diagram of screened and enrolled patients. CONSORT, Consolidated Standards of Reporting Trials; ECOG PS, Eastern Cooperative Oncology Group performance status; Rx, prescription (PNG 150 kb)

High Resolution (TIF 460 kb)

Supplementary Fig. S5

Prespecified Kaplan–Meier estimates of overall survival (high baseline LDL vs. normal baseline LDL levels). CI, confidence interval; HR, hazard ratio; LDL, low-density lipoprotein (PNG 160 kb)

High Resolution (TIF 524 kb)

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Altwairgi, A.K., Alghareeb, W.A., AlNajjar, F.H. et al. Atorvastatin in combination with radiotherapy and temozolomide for glioblastoma: a prospective phase II study. Invest New Drugs 39, 226–231 (2021). https://doi.org/10.1007/s10637-020-00992-5

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  • DOI: https://doi.org/10.1007/s10637-020-00992-5

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