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A pilot study imaging integrin αvβ3 with RGD PET/CT in suspected lung cancer patients

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European Journal of Nuclear Medicine and Molecular Imaging Aims and scope Submit manuscript

Abstract

Purpose

Angiogenesis is an essential step in tumour development and metastasis. Integrin αvβ3 plays a major role in angiogenesis, tumour growth and progression. A new tracer, 18F-AL-NOTA-PRGD2, denoted as 18F-alfatide, has been developed for positron emission tomography (PET) imaging of integrin αvβ3. This is a pilot study to test the safety and diagnostic value of 18F- arginine-glycine-aspartic acid (RGD) PET/computed tomography (CT) in suspected lung cancer patients.

Methods

Twenty-six patients with suspected lung cancer on enhanced CT underwent 18F-alfatide RGD PET/CT examination before surgery and puncture biopsy. Standard uptake values (SUVs) and the tumour-to-blood ratios were measured, and diagnoses were pathologically confirmed.

Results

RGD PET/CT with 18F-alfatide was performed successfully in all patients and no clinically significant adverse events were observed. The 18F-alfatide RGD PET/CT analysis correctly recognized 17 patients with lung cancer, 4 patients (hamartoma) as true negative, and 5 patients (4 chronic inflammation and 1 inflammatory pseudotumour) as false positive. The sensitivity, specificity, accuracy, positive predictive value (PPV) and negative predictive value (NPV) of 18F-alfatide RGD PET/CT for the diagnosis of suspected lung cancer patients was 100, 44.44, 80.77, 77.27, and 100 %, respectively. The area under a receiver operating characteristic (ROC) curve was 0.75 (P = 0.038), and ROC analysis suggested an SUVmax cut-off value of 2.65 to differentiate between malignant lesions and benign lesions. The SUV for malignant lesions was 5.37 ± 2.17, significantly higher than that for hamartomas (1.60 ± 0.11; P < 0.001). The difference between the tumour-to-blood ratio for malignant lesions (4.13 ± 0.91) and tissue of interest-to-blood ratio for hamartomas (1.56 ± 0.24) was also statistically significant (P < 0.001). Neither the SUVmax nor the tumour-to-blood ratio was significantly different between malignant lesions and inflammatory lesions or inflammatory pseudotumours (P > 0.05). Sixteen of 26 patients later underwent successful surgery, and pathologic examination confirmed nodes positive for metastasis in 14 of 152 lymph nodes. The sensitivity, specificity, accuracy, PPV, and NPV of PET/CT for lymph nodes was 92.86, 95.65, 95.40, 61.90, and 99.25 %, respectively.

Conclusion

Our results suggest that RGD PET/CT with the new tracer 18F-alfatide is safe and potentially effective in the diagnosis of non-small cell lung cancer. It may be used in the diagnosis of lung cancer, successfully distinguishing malignant lesions from hamartoma. However, it is difficult to clearly differentiate inflammatory or inflammatory pseudotumours from malignant lesions. Additional studies with a larger number of patients are needed to validate our findings.

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References

  1. Jain RK. Normalization of tumor vasculature: an emerging concept in antiangiogenic therapy. Science. 2005;307:58–62.

    Article  CAS  PubMed  Google Scholar 

  2. Folkman J. Tumor angiogenesis: therapeutic implications. N Engl J Med. 1971;285:1182–6.

    Article  CAS  PubMed  Google Scholar 

  3. Botrel TE, Clark O, Clark L, Paladini L, Faleiros E, Pegoretti B. Efficacy of bevacizumab (Bev) plus chemotherapy (CT) compared to CT alone in previously untreated locally advanced or metastatic non-small cell lung cancer (NSCLC): systematic review and meta-analysis. Lung Cancer. 2011;74:89–97.

    Article  PubMed  Google Scholar 

  4. Niu G, Chen X. Why integrin as a primary target for imaging and therapy. Theranostics. 2011;1:30–47.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  5. Liu S. Radiolabeled cyclic RGD peptides as integrin alpha(v)beta(3)-targeted radiotracers: maximizing binding affinity via bivalency. Bioconjug Chem. 2009;20:2199–213.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  6. Danhier F, Le BA, Preat V. RGD-based strategies to target alpha(v) beta(3) integrin in cancer therapy and diagnosis. Mol Pharm. 2012;9:2961–73.

    Article  CAS  PubMed  Google Scholar 

  7. Beer AJ, Kessler H, Wester HJ, Schwaiger M. PET imaging of integrin alphaVbeta3 expression. Theranostics. 2011;1:48–57.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  8. Battle MR, Goggi JL, Allen L, Barnett J, Morrison MS. Monitoring tumor response to antiangiogenic sunitinib therapy with 18F-fluciclatide, an 18F-labeled alphaVbeta3-integrin and alphaV beta5-integrin imaging agent. J Nucl Med. 2011;52:424–30.

    Article  CAS  PubMed  Google Scholar 

  9. Ruoslahti E, Pierschbacher MD. New perspectives in cell adhesion: RGD and integrins. Science. 1987;238:491–7.

    Article  CAS  PubMed  Google Scholar 

  10. Haubner R, Wester HJ, Reuning U, Senekowitsch-Schmidtke R, Diefenbach B, Kessler H, et al. Radiolabeled alpha(v)beta3 integrin antagonists: a new class of tracers for tumor targeting. J Nucl Med. 1999;40:1061–71.

    CAS  PubMed  Google Scholar 

  11. Beer AJ, Schwaiger M. PET imaging of alphavbeta3 expression in cancer patients. Methods Mol Biol. 2011;680:183–200.

    Article  CAS  PubMed  Google Scholar 

  12. Chen X, Park R, Shahinian AH, Tohme M, Khankaldyyan V, Bozorgzadeh MH, et al. 18F-labeled RGD peptide: initial evaluation for imaging brain tumor angiogenesis. Nucl Med Biol. 2004;31:179–89.

    Article  CAS  PubMed  Google Scholar 

  13. Jeong JM, Hong MK, Chang YS, Lee YS, Kim YJ, Cheon GJ, et al. Preparation of a promising angiogenesis PET imaging agent: 68Ga-labeled c(RGDyK)-isothiocyanatobenzyl-1,4,7-triazacyclononane-1,4,7-triacetic acid and feasibility studies in mice. J Nucl Med. 2008;49:830–6.

    Article  CAS  PubMed  Google Scholar 

  14. Li ZB, Chen K, Chen X. (68)Ga-labeled multimeric RGD peptides for microPET imaging of integrin alpha(v)beta (3) expression. Eur J Nucl Med Mol Imaging. 2008;35:1100–8.

    Article  CAS  PubMed  Google Scholar 

  15. Chen X, Liu S, Hou Y, Tohme M, Park R, Bading JR, et al. MicroPET imaging of breast cancer alphav-integrin expression with 64Cu-labeled dimeric RGD peptides. Mol Imaging Biol. 2004;6:350–9.

    Article  PubMed  Google Scholar 

  16. Lang L, Li W, Jia HM, Fang DC, Zhang S, Sun X, et al. New methods for labeling RGD peptides with bromine-76. Theranostics. 2011;1:341–53.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  17. Jacobson O, Zhu L, Niu G, Weiss ID, Szajek LP, Ma Y, et al. MicroPET imaging of integrin alphavbeta3 expressing tumors using 89Zr-RGD peptides. Mol Imaging Biol. 2011;13:1224–33.

    Article  PubMed Central  PubMed  Google Scholar 

  18. Haubner R, Weber WA, Beer AJ, Vabuliene E, Reim D, Sarbia M, et al. Noninvasive visualization of the activated alphavbeta3 integrin in cancer patients by positron emission tomography and [18F]Galacto-RGD. PLoS Med. 2005;2:e70.

    Article  PubMed Central  PubMed  Google Scholar 

  19. Haubner R, Wester HJ, Weber WA, Mang C, Ziegler SI, Goodman SL, et al. Noninvasive imaging of alpha(v)beta3 integrin expression using 18F-labeled RGD-containing glycopeptide and positron emission tomography. Cancer Res. 2001;61:1781–5.

    CAS  PubMed  Google Scholar 

  20. Beer AJ, Haubner R, Goebel M, Luderschmidt S, Spilker ME, Wester HJ, et al. Biodistribution and pharmacokinetics of the alphavbeta3-selective tracer 18F-galacto-RGD in cancer patients. J Nucl Med. 2005;46:1333–41.

    CAS  PubMed  Google Scholar 

  21. Beer AJ, Haubner R, Sarbia M, Goebel M, Luderschmidt S, Grosu AL, et al. Positron emission tomography using [18F]Galacto-RGD identifies the level of integrin alpha(v)beta3 expression in man. Clin Cancer Res. 2006;12:3942–9.

    Article  CAS  PubMed  Google Scholar 

  22. McParland BJ, Miller MP, Spinks TJ, Kenny LM, Osman S, Khela MK, et al. The biodistribution and radiation dosimetry of the Arg-Gly-Asp peptide 18F-AH111585 in healthy volunteers. J Nucl Med. 2008;49:1664–7.

    Article  PubMed  Google Scholar 

  23. Kenny LM, Coombes RC, Oulie I, Contractor KB, Miller M, Spinks TJ, et al. Phase I trial of the positron-emitting Arg-Gly-Asp (RGD) peptide radioligand 18F-AH111585 in breast cancer patients. J Nucl Med. 2008;49:879–86.

    Article  PubMed  Google Scholar 

  24. Doss M, Kolb HC, Zhang JJ, Belanger MJ, Stubbs JB, Stabin MG, et al. Biodistribution and radiation dosimetry of the integrin marker 18F-RGD-K5 determined from whole-body PET/CT in monkeys and humans. J Nucl Med. 2012;53:787–95.

    Article  PubMed  Google Scholar 

  25. Mittra ES, Goris ML, Iagaru AH, Kardan A, Burton L, Berganos R, et al. Pilot pharmacokinetic and dosimetric studies of (18)F-FPPRGD2: a PET radiopharmaceutical agent for imaging alpha(v)beta(3) integrin levels. Radiology. 2011;260:182–91.

    Article  PubMed Central  PubMed  Google Scholar 

  26. Beer AJ, Niemeyer M, Carlsen J, Sarbia M, Nahrig J, Watzlowik P, et al. Patterns of alphavbeta3 expression in primary and metastatic human breast cancer as shown by 18F-Galacto-RGD PET. J Nucl Med. 2008;49:255–9.

    Article  PubMed  Google Scholar 

  27. Schnell O, Krebs B, Carlsen J, Miederer I, Goetz C, Goldbrunner RH, et al. Imaging of integrin alpha(v)beta(3) expression in patients with malignant glioma by [18F] Galacto-RGD positron emission tomography. Neuro Oncol. 2009;11:861–70.

    Article  PubMed Central  PubMed  Google Scholar 

  28. Beer AJ, Grosu AL, Carlsen J, Kolk A, Sarbia M, Stangier I, et al. [18F]galacto-RGD positron emission tomography for imaging of alphavbeta3 expression on the neovasculature in patients with squamous cell carcinoma of the head and neck. Clin Cancer Res. 2007;13:6610–6.

    Article  CAS  PubMed  Google Scholar 

  29. McBride WJ, D’Souza CA, Sharkey RM, Goldenberg DM. The radiolabeling of proteins by the [18F]AlF method. Appl Radiat Isot. 2012;70:200–4.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  30. Lang L, Li W, Guo N, Ma Y, Zhu L, Kiesewetter DO, et al. Comparison study of [18F]FAl-NOTA-PRGD2, [18F]FPPRGD2, and [68Ga]Ga-NOTA-PRGD2 for PET imaging of U87MG tumors in mice. Bioconjug Chem. 2011;22:2415–22.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  31. Wan W, Guo N, Pan D, Yu C, Weng Y, Luo S, et al. First experience of 18F-alfatide in lung cancer patients using a new lyophilized kit for rapid radiofluorination. J Nucl Med. 2013;54:691–8.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  32. Shim SS, Lee KS, Kim BT, Chung MJ, Lee EJ, Han J, et al. Non-small cell lung cancer: prospective comparison of integrated FDG PET/CT and CT alone for preoperative staging. Radiology. 2005;236:1011–9.

    Article  PubMed  Google Scholar 

  33. Yang W, Fu Z, Yu J, Yuan S, Zhang B, Li D, et al. Value of PET/CT versus enhanced CT for locoregional lymph nodes in non-small cell lung cancer. Lung Cancer. 2008;61:35–43.

    Article  PubMed  Google Scholar 

  34. Yuan S, Yu Y, Chao KS, Fu Z, Yin Y, Liu T, et al. Additional value of PET/CT over PET in assessment of locoregional lymph nodes in thoracic esophageal squamous cell cancer. J Nucl Med. 2006;47:1255–9.

    PubMed  Google Scholar 

Download references

Compliance with Ethical Standards

Funding

This study was funded by the Natural Science Foundation of China (NSFC81172133, NSFC81372413), the special fund for Scientific Research in the Public Interest (201402011), the projects of medical and health technology development program in Shandong province (2014WS0058) and the Outstanding Youth Natural Science Foundation of Shandong Province (JQ201423). No other potential conflicts of interest relevant to this article are reported.

Conflict of interest

The authors declare that there are no conflicts of interests.

Ethical standards

Our investigation of 26 patients was approved by the Shandong Cancer Hospital & Institute Ethical Committee and has, therefore, been performed in accordance with the ethical standards laid down in the 1964 Declaration of Helsinki. All persons gave their informed consent prior to their inclusion in the study.

Author information

Authors and Affiliations

  1. Department of Radiation Oncology, Shandong Cancer Hospital & Institute, No 440 Jiyan Road, Jinan, Shandong, 250117, China

    Song Gao, Xudong Hu, Suzhen Wang, Jinming Yu & Shuanghu Yuan

  2. School of Medicine and Life Sciences, University of Jinan-Shandong Academy of Medical Sciences, Jinan, Shandong, China

    Song Gao

  3. Wuyi County People’s Hospital of Hengshui City, Hengshui, Hebei Province, China

    Honghu Wu

  4. Department of Radiology, Shandong Cancer Hospital & Institute, Jinan, Shandong, China

    Wenwu Li, Shuqiang Zhao, Xuepeng Teng & Hong Lu

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  1. Song Gao
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  2. Honghu Wu
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  10. Shuanghu Yuan
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Correspondence to Shuanghu Yuan.

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Gao, S., Wu, H., Li, W. et al. A pilot study imaging integrin αvβ3 with RGD PET/CT in suspected lung cancer patients. Eur J Nucl Med Mol Imaging 42, 2029–2037 (2015). https://doi.org/10.1007/s00259-015-3119-1

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  • DOI: https://doi.org/10.1007/s00259-015-3119-1

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