Medical Oncology

, 32:405 | Cite as

Protective effect of ulinastatin in patients with non-small cell lung cancer after radiation therapy: a randomized, placebo-controlled study

  • Pengtao Bao
  • Weiguo Zhao
  • Yun Li
  • Yu Liu
  • Yi Zhou
  • Changting Liu
Original Paper
First Online:
Received:
Accepted:

Abstract

Radiation-induced lung injury (RILI) is a frequent, sometimes life-threatening complication of radiation therapy for the treatment of lung cancer. The anti-inflammatory role of ulinastatin has been well documented, and the potential application of ulinastatin in management of acute lung injury has been suggested in multiple animal studies. In this article, we described a double-blind, randomized, placebo-controlled study in patients with non-small cell lung cancer. A total of 120 patients were randomized into two groups: the trial group was treated with ulinastatin for 3 days prior to and for the first 7 days of radiation therapy and the control group was treated with placebo for 10 days following the same schedule. The results from follow-up studies showed that the incidence and grade of RILI were significantly lower in the trial group than in the control group. Reduction in pulmonary function from baseline was significantly smaller in the trial group than that in the control group. Production of serum TGF-β1, TNF-α and IL-6 decreased significantly in the trial group promptly following radiation therapy. However, no difference in survival or tumour response rate was found between the two groups. The results indicated that ulinastatin exerted a protective effect on radiation-induced lung injury. Treatment with ulinastatin could be an effective management strategy and greatly improve the clinical efficacy of radiation therapy for patients with lung cancer.

Keywords

Ulinastatin Non-small cell lung cancer Radiation-induced lung injury Inflammatory cytokines 

Abbreviations

NSCLC

Non-small cell lung cancer

RILI

Radiation-induced lung injury

BALF

Bronchoalveolar lavage fluid

UTI

Urinary trypsin inhibitor

PF

Pulmonary function

IMRT

Intensity-modulated radiotherapy

FVC

Forced vital capacity

FEV1

Forced expiratory volume at 1s

DLCO

Diffusion capacity for carbon monoxide

ELISA

Enzyme-linked immunosorbent assay

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

Notes

Conflict of interest

The authors declare that they have no competing interests.

References

  1. 1.
    Coggle JE, Lambert BE, Moores SR. Radiation effects in the lung. Environ Health Perspect. 1986;70:261–91.PubMedCentralPubMedCrossRefGoogle Scholar
  2. 2.
    Spiro SG, Douse J, Read C, Janes S. Complications of lung cancer treatment. Semin Respir Crit Care Med. 2008;29(3):302–17.PubMedCrossRefGoogle Scholar
  3. 3.
    Yamashita H, Nakagawa K, Nakamura N, Koyanagi H, Tago M, Igaki H, et al. Exceptionally high incidence of symptomatic grade 2–5 radiation pneumonitis after stereotactic radiation therapy for lung tumors. Radiat Oncol. 2007;2:21.PubMedCentralPubMedCrossRefGoogle Scholar
  4. 4.
    Westbury CB, Yarnold JR. Radiation fibrosis–current clinical and therapeutic perspectives. Clin Oncol. 2012;24(10):657–72.CrossRefGoogle Scholar
  5. 5.
    McDonald S, Rubin P, Phillips TL, Marks LB. Injury to the lung from cancer therapy: clinical syndromes, measurable endpoints, and potential scoring systems. Int J Radiat Oncol Biol Phys. 1995;31(5):1187–203.PubMedCrossRefGoogle Scholar
  6. 6.
    Abratt RP, Morgan GW. Lung toxicity following chest irradiation in patients with lung cancer. Lung Cancer. 2002;35(2):103–9.PubMedCrossRefGoogle Scholar
  7. 7.
    Fan M, Marks LB, Hollis D, Bentel GG, Anscher MS, Sibley G, et al. Can we predict radiation-induced changes in pulmonary function based on the sum of predicted regional dysfunction? J Clin Oncol. 2001;19(2):543–50.PubMedGoogle Scholar
  8. 8.
    Marks LB, Fan M, Clough R, Munley M, Bentel G, Coleman RE, et al. Radiation-induced pulmonary injury: symptomatic versus subclinical endpoints. Int J Radiat Biol. 2000;76(4):469–75.PubMedCrossRefGoogle Scholar
  9. 9.
    Ding NH, Li JJ, Sun LQ. Molecular mechanisms and treatment of radiation-induced lung fibrosis. Curr Drug Targets. 2013;14(11):1347–56.PubMedCentralPubMedCrossRefGoogle Scholar
  10. 10.
    Otani K, Nishiyama K, Ito Y, Kawaguchi Y, Inaji H. Steroid treatment increases the recurrence of radiation-induced organizing pneumonia after breast-conserving therapy. Cancer Med. 2014;3(4):947–53.Google Scholar
  11. 11.
    Wynn TA. Cellular and molecular mechanisms of fibrosis. J Pathol. 2008;214(2):199–210.PubMedCentralPubMedCrossRefGoogle Scholar
  12. 12.
    Chen Y, Williams J, Ding I, Hernady E, Liu W, Smudzin T, et al. Radiation pneumonitis and early circulatory cytokine markers. Semin Radiat Oncol. 2002;12(1 Suppl. 1):26–33.PubMedCrossRefGoogle Scholar
  13. 13.
    Jackson IL, Zhang X, Hadley C, Rabbani ZN, Zhang Y, Marks S, et al. Temporal expression of hypoxia-regulated genes is associated with early changes in redox status in irradiated lung. Free Radic Biol Med. 2012;53(2):337–46.PubMedCentralPubMedCrossRefGoogle Scholar
  14. 14.
    Yuan ST, Ellingrod VL, Schipper M, Stringer KA, Cai X, Hayman JA, et al. Genetic variations in TGFbeta1, tPA, and ACE and radiation-induced thoracic toxicities in patients with non-small-cell lung cancer. J Thorac Oncol. 2013;8(2):208–13.PubMedCrossRefGoogle Scholar
  15. 15.
    Minami-Shimmyo Y, Ohe Y, Yamamoto S, Sumi M, Nokihara H, Horinouchi H, et al. Risk factors for treatment-related death associated with chemotherapy and thoracic radiotherapy for lung cancer. J Thorac Oncol. 2012;7(1):177–82.PubMedCrossRefGoogle Scholar
  16. 16.
    Kim JY, Kim YS, Kim YK, Park HJ, Kim SJ, Kang JH, et al. The TGF-beta1 dynamics during radiation therapy and its correlation to symptomatic radiation pneumonitis in lung cancer patients. Radiat Oncol. 2009;4:59.PubMedCentralPubMedCrossRefGoogle Scholar
  17. 17.
    Yang HJ, Youn H, Seong KM, Yun YJ, Kim W, Kim YH, et al. Psoralidin, a dual inhibitor of COX-2 and 5-LOX, regulates ionizing radiation (IR)-induced pulmonary inflammation. Biochem Pharmacol. 2011;82(5):524–34.PubMedCrossRefGoogle Scholar
  18. 18.
    Ogata T, Yamazaki H, Teshima T, Kihara A, Suzumoto Y, Inoue T, et al. Early administration of IL-6RA does not prevent radiation-induced lung injury in mice. Radiat Oncol. 2010;5:26.PubMedCentralPubMedCrossRefGoogle Scholar
  19. 19.
    Redlich CA, Gao X, Rockwell S, Kelley M, Elias JA. IL-11 enhances survival and decreases TNF production after radiation-induced thoracic injury. J Immunol. 1996;157(4):1705–10.PubMedGoogle Scholar
  20. 20.
    Kanai T, Ishiwata T, Kobayashi T, Sato H, Takizawa M, Kawamura Y, et al. Ulinastatin, a urinary trypsin inhibitor, for the initial treatment of patients with Kawasaki disease: a retrospective study. Circulation. 2011;124(25):2822–8.PubMedCrossRefGoogle Scholar
  21. 21.
    Hiyama A, Takeda J, Kotake Y, Morisaki H, Fukushima K. A human urinary protease inhibitor (ulinastatin) inhibits neutrophil extracellular release of elastase during cardiopulmonary bypass. J Cardiothorac Vasc Anesth. 1997;11(5):580–4.PubMedCrossRefGoogle Scholar
  22. 22.
    Inoue K, Takano H. Urinary trypsin inhibitor as a therapeutic option for endotoxin-related inflammatory disorders. Expert Opin Investig Drugs. 2010;19(4):513–20.PubMedCrossRefGoogle Scholar
  23. 23.
    Chen CC, Wang SS, Lee FY. Action of antiproteases on the inflammatory response in acute pancreatitis. JOP. 2007;8(4 Suppl.):488–94.PubMedGoogle Scholar
  24. 24.
    Fang Y, Xu P, Gu C, Wang Y, Fu XJ, Yu WR, et al. Ulinastatin improves pulmonary function in severe burn-induced acute lung injury by attenuating inflammatory response. J Trauma. 2011;71(5):1297–304.PubMedCrossRefGoogle Scholar
  25. 25.
    Song Z, Chen G, Lin G, Jia C, Cao J, Ao G. The ultra-early protective effect of ulinastatin on rabbit acute lung injury induced by paraquat. BMC Emerg Med. 2013;13(Suppl. 1):S7.PubMedCentralPubMedGoogle Scholar
  26. 26.
    Wang N, Liu X, Zheng X, Cao H, Wei G, Zhu Y, et al. Ulinastatin is a novel candidate drug for sepsis and secondary acute lung injury, evidence from an optimized CLP rat model. Int Immunopharmacol. 2013;17(3):799–807.PubMedCrossRefGoogle Scholar
  27. 27.
    Katoh H, Ishikawa H, Hasegawa M, Yoshida Y, Suzuki Y, Ohno T, et al. Protective effect of urinary trypsin inhibitor on the development of radiation-induced lung fibrosis in mice. J Radiat Res. 2010;51(3):325–32.PubMedCrossRefGoogle Scholar
  28. 28.
    Shigetomi H, Onogi A, Kajiwara H, Yoshida S, Furukawa N, Haruta S, et al. Anti-inflammatory actions of serine protease inhibitors containing the Kunitz domain. Inflamm Res. 2010;59(9):679–87.PubMedCrossRefGoogle Scholar
  29. 29.
    Bao P, Gao W, Li S, Zhang L, Qu S, Wu C, et al. Effect of pretreatment with high-dose ulinastatin in preventing radiation-induced pulmonary injury in rats. Eur J Pharmacol. 2009;603(1–3):114–9.PubMedCrossRefGoogle Scholar
  30. 30.
    Suresh K, Chandrashekara S. Sample size estimation and power analysis for clinical research studies. J Hum Reprod Sci. 2012;5(1):7–13.PubMedCentralPubMedCrossRefGoogle Scholar
  31. 31.
    Bradley JD, Ieumwananonthachai N, Purdy JA, Wasserman TH, Lockett MA, Graham MV, et al. Gross tumor volume, critical prognostic factor in patients treated with three-dimensional conformal radiation therapy for non-small-cell lung carcinoma. Int J Radiat Oncol Biol Phys. 2002;52(1):49–57.PubMedCrossRefGoogle Scholar
  32. 32.
    Suntharalingam M, Paulus R, Edelman MJ, Krasna M, Burrows W, Gore E, et al. Radiation therapy oncology group protocol 02-29: a phase II trial of neoadjuvant therapy with concurrent chemotherapy and full-dose radiation therapy followed by surgical resection and consolidative therapy for locally advanced non-small cell carcinoma of the lung. Int J Radiat Oncol Biol Phys. 2012;84(2):456–63.PubMedCrossRefGoogle Scholar
  33. 33.
    Schuetze SM, Zhao L, Chugh R, Thomas DG, Lucas DR, Metko G, et al. Results of a phase II study of sirolimus and cyclophosphamide in patients with advanced sarcoma. Eur J Cancer. 2012;48(9):1347–53.PubMedCrossRefGoogle Scholar
  34. 34.
    Zhao W, Robbins ME. Inflammation and chronic oxidative stress in radiation-induced late normal tissue injury: therapeutic implications. Curr Med Chem. 2009;16(2):130–43.PubMedCrossRefGoogle Scholar
  35. 35.
    Kobayashi H, Gotoh J, Fujie M, Terao T. Characterization of the cellular binding site for the urinary trypsin inhibitor. J Biol Chem. 1994;269(32):20642–7.PubMedGoogle Scholar
  36. 36.
    Kobayashi H, Shinohara H, Takeuchi K, Itoh M, Fujie M, Saitoh M, et al. Inhibition of the soluble and the tumor cell receptor-bound plasmin by urinary trypsin inhibitor and subsequent effects on tumor cell invasion and metastasis. Cancer Res. 1994;54(3):844–9.PubMedGoogle Scholar
  37. 37.
    Hirano T, Manabe T. Human urinary trypsin inhibitor, urinastatin, prevents pancreatic injuries induced by pancreaticobiliary duct obstruction with cerulein stimulation and systemic hypotension in the rat. Arch Surg. 1993;128(12):1322–9; discussion 9.Google Scholar
  38. 38.
    Fujino N, Kubo H, Suzuki T, He M, Yamada M, Takahashi T, et al. Administration of a specific inhibitor of neutrophil elastase attenuates pulmonary fibrosis after acute lung injury in mice. Exp Lung Res. 2012;38(1):28–36.PubMedCrossRefGoogle Scholar
  39. 39.
    Kouvaris JR, Kouloulias VE, Vlahos LJ. Amifostine: the first selective-target and broad-spectrum radioprotector. Oncologist. 2007;12(6):738–47.PubMedCrossRefGoogle Scholar
  40. 40.
    Antonadou D, Petridis A, Synodinou M, Throuvalas N, Bolanos N, Veslemes M, et al. Amifostine reduces radiochemotherapy-induced toxicities in patients with locally advanced non-small cell lung cancer. Semin Oncol. 2003;30(6 Suppl 18):2–9.PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2014

Authors and Affiliations

  • Pengtao Bao
    • 1
    • 2
  • Weiguo Zhao
    • 2
  • Yun Li
    • 2
  • Yu Liu
    • 2
  • Yi Zhou
    • 2
  • Changting Liu
    • 1
  1. 1.Department of Nanlou Respiratory PulmonologyChinese PLA General HospitalBeijingPeople’s Republic of China
  2. 2.Department of Respiratory MedicineThe 309th Hospital of PLABeijingPeople’s Republic of China

Personalised recommendations