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The efficacy and safety of zoledronic acid and strontium-89 in treating non–small cell lung cancer: a systematic review and meta-analysis of randomized controlled trials

  • Zhigang HuEmail author
  • Yufeng Tian
  • Wenxin Li
  • Yushu Ruan
  • Fanjun Zeng
Original Article
  • 24 Downloads

Abstract

Background

Zoledronic acid (ZA) and strontium-89 have been widely used to treat lung cancer with bone metastases. The authors perform this meta-analysis to better evaluate the clinical outcome of ZA and strontium-89 for non–small cell lung cancer (NSCLC) patients.

Methods

We carried out standard meta-analysis and network meta-analysis based on a comprehensive data retrieval of EMBASE, PubMed, and Cochrane Library databases (up to March 2019). Random and fixed effects models were used where indicated and between-study heterogeneity was assessed. The primary endpoints were overall survival (OS) and skeletal-related events (SREs). The second endpoints were progression-free survival (PFS) and overall response rate (ORR).

Results

Seven randomized clinical trials, including 1426 NSCLC patients with seven studies of zoledronic acid and two studies of strontium-89, met the inclusion criteria. Compared with the control group, ZA is associated with a OS benefit (1-year survival rate: RR = 1.76, 95% CI 1.36–2.27; and 24-month survival rate: RR = 2.38, 95% CI 1.35–4.19) and a reduction of SREs (RR = 0.57, 95% CI 0.40–0.84) for the patients with bone metastases. No statistical differences were found in PFS and ORR. Network meta-analysis for the patients with bone metastases showed that ZA + strontium-89 and ZA harbored significantly clinical benefits than strontium-89 and placebo in terms of 1-year survival rate and SREs. Both head-to-head study and network meta-analysis showed that strontium-89 had no statistical impact on OS and SREs compared with placebo.

Conclusion

Our analysis demonstrates that ZA +strontium-89 can be considered a priority for NSCLC patients with bone metastases, followed by ZA.

Keywords

Zoledronic acid (ZA) Non small cell lung cancer Bone metastases Strontium-89 

Abbreviations

NSCLC

Non–small cell lung cancer

NTX

N-Telopeptide of type I collagen

ORR

Overall response rate

PFS

Progression-free survival

RR

Relative risk

SREs

Skeletal-related events

ZA

Zoledronic acid

Notes

Author contributions

Z.G.H. and W.X.L. conceived the study and participated in the design. Y.S.R and Y.F T. collected the data. F.J.Z. performed statistical analyses. Z.G.H. drafted the manuscript. W.X.L. and Y.S.R helped to draft the manuscript. F.J.Z. revised the manuscript critically for important intellectual content. All authors read and approved the final manuscript.

Compliance with ethical standards

Competing interests

The authors declare that they have no conflict of interest.

Supplementary material

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References

  1. 1.
    Tsuya A, Kurata T, Tamura K, Fukuoka M (2007) Skeletal metastases in non-small cell lung cancer: a retrospective study. Lung Cancer 57(2):229–232CrossRefGoogle Scholar
  2. 2.
    Aft RL, Naughton M, Trinkaus K, Weilbaecher K (2012) Effect of (neo) adjuvant ZA on disease-free and overall survival in clinical stage II/III breast cancer. Br J Cancer 107(1):7–11CrossRefGoogle Scholar
  3. 3.
    Mohamed SZ, Rimoun B, Hisham E et al (2010) A prospective, randomized, placebo-controlled trial of ZA in bony metastatic bladder cancer. Int J Clin Oncol 15(4):382–389CrossRefGoogle Scholar
  4. 4.
    Pan Y, Jin H, Chen W, Yu Z, Ye T, Zheng Y, Weng Z, Wang F (2014) Docetaxel with or without ZA for castration-resistant prostate cancer. Int Urol Nephrol 46(12):2319–2326CrossRefGoogle Scholar
  5. 5.
    Uemura H, Yanagisawa M, Ikeda I, Fujinami K, Iwasaki A, Noguchi S, Noguchi K, Kubota Y, Yokohama Bone Metastasis Study Group (2013) Possible anti-tumor activity of initial treatment with ZA with hormonal therapy for bone-metastatic prostate cancer in multicenter clinical trial. Int J Clin Oncol 18(3):472–477CrossRefGoogle Scholar
  6. 6.
    Schulman KL, Kohles J (2017) Economic burden of metastatic bone disease in the U.S. Cancer 109(11):2334–2342CrossRefGoogle Scholar
  7. 7.
    Delea T, Langer C, McKiernan J, Liss M, Edelsberg J, Brandman J, Sung J, Raut M, Oster G (2004) The cost of treatment of skeletal-related events in patients with bone metastases from lung cancer. Oncology 67(5–6):390–396CrossRefGoogle Scholar
  8. 8.
    Ozturk OH, Bozcuk H, Burgucu D, Ekinci D, Ozdogan M, Akca S, Yildiz M (2007) Cisplatin cytotoxicity is enhanced with ZA in A549 lung cancer cell line: preliminary results of an in vitro study. Cell Biol Int 31(9):1069–1071CrossRefGoogle Scholar
  9. 9.
    Chang JW, Hsieh JJ, Shen YC, Yeh KY, Wang CH, Li YY, Hsu T (2009) Bisphosphonate ZA enhances the inhibitory effects of gefitinib on EGFR-mutated non-small cell lung carcinoma cells. Cancer Lett 278(1):17–26CrossRefGoogle Scholar
  10. 10.
    Zarogoulidis K, Boutsikou E, Zarogoulidis P, Eleftheriadou E, Kontakiotis T, Lithoxopoulou H, Tzanakakis G, Kanakis I, Karamanos NK (2009) The impact of ZA therapy in survival of lung cancer patients with bone metastasis. Int J Cancer 125(7):1705–1709CrossRefGoogle Scholar
  11. 11.
    Wang Y, Tao H, Yu X et al (2013) Clinical significance of ZA and strontium-89 in patients with asymptomatic bone metastases from non small cell lung cancer. Clin Lung Cancer 14(3):254–260CrossRefGoogle Scholar
  12. 12.
    Scagliotti GV, Kosmidis P, de Marinis F et al (2012) ZA in patients with stage IIIA/B NSCLC: results of a randomized, phase III study. Ann Oncol 23(8):2082–2087CrossRefGoogle Scholar
  13. 13.
    Ogawa K, Washiyama K (2012) Bone target radiotracers for palliative therapy of bone metastases. Curr Med Chem 19(20):3290–3300CrossRefGoogle Scholar
  14. 14.
    Ye X, Sun D, Lou C (2018) Comparison of the efficacy of strontium-89 chloride in treating bone metastasis of lung, breast, and prostate cancers. J Cancer Res Ther 14(Supplement):S36–S40PubMedGoogle Scholar
  15. 15.
    Sierko E, Hempel D, Zuzda K et al (2019) Personalized radiation therapy in cancer pain management. Cancers 11(3):E390CrossRefGoogle Scholar
  16. 16.
    Silberstein EB (2005) Teletherapy and radiopharmaceutical therapy of painful bone metastases. Semin Nucl Med 35(2):152–158CrossRefGoogle Scholar
  17. 17.
    Li N, Yang Z, Chai H et al (2018) Clinical research of zoledronic acid and strontium-89in treatment of patients with asymptomatic bone metastases from non-small cell lung cancer. Chin J Cancer Prevent Treatment 25(13):962–967Google Scholar
  18. 18.
    Liberati A, Altman DG, Tetzlaff J et al (2009) The PRISMA statement for reporting systematic reviews and meta-analyses of studies that evaluate health care interventions: explanation and elaboration. PLoS Med 6:e1000100CrossRefGoogle Scholar
  19. 19.
    Higgins JPT, Altman DG, Sterne JAC (2011) Chapter 8: Assessing risk of bias in included studies. In: Higgins JPT, Green S, editors. Cochrane handbook for systematic reviews of interventions version 5.1.0 (updated March 2011). The cochrane collaboration. Available: https://www.cochranehandbook.org. Accessed 10 Oct 2012
  20. 20.
    White IR, Barrett JK, Jackson D et al (2012) Consistency and inconsistency in network meta-analysis: model estimation using multivariate meta-regression. Res Synth Methods 3(1):111–125CrossRefGoogle Scholar
  21. 21.
    Hirsh V, Major PP, Lipton A et al (2008) Zoledronic acid and survival in patients with metastatic bone disease from lung cancer and elevated markers of osteoclast activity. J Thorac Oncol 3(8):228–236CrossRefGoogle Scholar
  22. 22.
    Pandya KJ, Gajra A, Warsi GM, Argonza-Aviles E, Ericson SG, Wozniak AJ (2010) Multicenter, randomized, phase 2 study of Zoledronic acid in combination with docetaxel and carboplatin in patients with unresectable stage IIIB or stage IV non-small cell lung cancer. Lung Cancer 67(3):330–338CrossRefGoogle Scholar
  23. 23.
    Murakami H, Yamanaka T, Seto T et al (2010) Phase II study of zoledronic acid combined with docetaxel for non-small-cell lung cancer: West Japan Oncology Group. Cancer Sci 105(8):989–995CrossRefGoogle Scholar
  24. 24.
    Kritikos K, Heras P, Hatzopoulos A et al (2008) Efficacy and safety of intravenous zoledronic acid (ZA) 4 MG infused over 15 minutes: results from a 2-year study of lung cancer patients (LCP) with metastatic bone disease. Ann Oncol 19(S8):viii286–viii287Google Scholar
  25. 25.
    Tamiya M, Tokunaga S, Okada H, Suzuki H, Kobayashi M, Sasada S, Okamoto N, Morishita N, Matsuura Y, Miyamoto N, Hattori M, Taira K, Daga H, Takeda K, Hirashima T (2013) Prospective study of urinary and serum cross-linked N-telopeptide of type I collagen (NTx) for diagnosis of bone metastasis in patients with lung cancer. Clin Lung Cancer 14(4):364–369CrossRefGoogle Scholar
  26. 26.
    Tamiya M, Kobayashi M, Morimura O, Yasue T, Nakasuji T, Satomu M, Kohei O, Takayuki S, Morishita N, Suzuki H, Sasada S, Okamoto N, Hirashima T, Kawase I (2013) Clinical significance of the serum crosslinked N-telopeptide of type I collagen as a prognostic marker for non-small-cell lung cancer. Clin Lung Cancer 14(1):50–54CrossRefGoogle Scholar
  27. 27.
    Lipton A, Cook R, Saad F, Major P, Garnero P, Terpos E, Brown JE, Coleman RE (2008) Normalization of bone markers is associated with improved survival in patients with bone metastases from solid tumors and elevated bone resorption receiving Zoledronic acid. Cancer 113(1):193–201CrossRefGoogle Scholar
  28. 28.
    Stathopoulos GT, Moschos C, Loutrari H et al (2008) Zoledronic acid is effective against experimental malignant pleural effusion. Am J Respir Crit Care Med 178(1):50–59CrossRefGoogle Scholar
  29. 29.
    Song Z, Zhang Y (2014) Zoledronic acid treatment in advanced non-small cell lung cancer patients with bone metastases. Med Oncol 31(4):898CrossRefGoogle Scholar
  30. 30.
    Yoshimura M, Saito K, Park J, Akata S, Koizumi K, Tokuue K, Kakizaki D (2011) Tumoricidal effect of strontium-89. Clin Nucl Med 36(4):296–299CrossRefGoogle Scholar
  31. 31.
    Kuroda I (2014) Strontium-89 for prostate cancer with bone metastases: the potential of cancer control and improvement of overall survival. Ann Nucl Med 28(1):11–16CrossRefGoogle Scholar
  32. 32.
    Heianna J, Miyauchi T, Endo W et al (2014) Tumor regression of multiple bone metastases from breast cancer after administration of strontium-89 chloride (Metastron). Acta Radiol Short Rep 10(4):2047981613493412Google Scholar
  33. 33.
    Baba K, Kaida H, Hattori C, Muraki K, Kugiyama T, Fujita H, Ishibashi M (2018) Tumoricidal effect and pain relief after concurrent therapy by strontium-89 chloride and zoledronic acid for bone metastases. Hell J Nucl Med 21(1):15–23PubMedGoogle Scholar
  34. 34.
    Lopez-Olivo MA, Shah NA, Pratt G, Risser JM, Symanski E, Suarez-Almazor ME (2012) Bisphosphonates in the treatment of patients with lung cancer and metastatic bone disease: a systematic review and meta-analysis. Support Care Cancer 20(11):2985–2998CrossRefGoogle Scholar
  35. 35.
    LeVasseur N, Clemons M, Hutton B, Shorr R, Jacobs C (2016) Bone-targeted therapy use in patients with bone metastases from lung cancer: a systematic review of randomized controlled trials. Cancer Treat Rev 50:183–193CrossRefGoogle Scholar
  36. 36.
    Mhaskar R, Redzepovic J, Wheatley K et al (2012) Bisphosphonates in multiple myeloma: a network meta-analysis. Cochrane Database Syst Rev 16:CD003188Google Scholar
  37. 37.
    Zhou J, Ma X, Wang T, Zhai S (2016) Comparative efficacy of bisphosphonates in short-term fracture prevention for primary osteoporosis: a systematic review with network meta-analyses. Osteoporos Int 27(11):3289–3300CrossRefGoogle Scholar
  38. 38.
    Zuradelli M, Masci G, Biancofiore G, Gullo G, Scorsetti M, Navarria P, Tancioni F, Berlusconi M, Giordano L, Santoro A (2009) High incidence of hypocalcemia and serum creatinine increase in patients with bone metastases treated with zoledronic acid. Oncologist 14(5):548–556CrossRefGoogle Scholar

Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2019

Authors and Affiliations

  1. 1.Department of Respiratory Medicine, The First College of Clinical Medicine ScienceThree Gorges UniversityYichangPeople’s Republic of China
  2. 2.Department of Respiratory MedicineYichang Central People’s HospitalYichangChina
  3. 3.Clinical Research CenterThree Gorges UniversityYichangPeople’s Republic of China

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