Skip to main content

Advertisement

Log in

Intratumoral heterogeneity of 18F-FLT uptake predicts proliferation and survival in patients with newly diagnosed gliomas

  • Original Article
  • Published:
Annals of Nuclear Medicine Aims and scope Submit manuscript

Abstract

Background

The nucleoside analog 3′-deoxy-3′-18F-fluorothymidine (FLT) has been investigated for evaluating tumor proliferating activity in brain tumors. We evaluated FLT uptake heterogeneity using textural features from the histogram analysis in patients with newly diagnosed gliomas and examined correlation of the results with proliferative activity and patient prognosis, in comparison with the conventional PET parameters.

Methods

FLT PET was investigated in 37 patients with newly diagnosed gliomas. The conventional parameters [tumor-to-contralateral normal brain tissue (T/N) ratio and metabolic tumor volume (MTV)] and textural parameters (standard deviation, skewness, kurtosis, entropy, and uniformity) were derived from FLT PET images. Linear regression analysis was used to compare PET parameters and the proliferative activity as indicated by the Ki-67 index. The associations between parameters and overall survival (OS) were tested by Cox regression analysis.

Results

Median OS was 662 days. For the conventional parameters, linear regression analysis indicated a significant correlation between T/N ratio and Ki-67 index (p = 0.02) and MTV and Ki-67 index (p = 0.02). Among textural parameters, linear regression analysis indicated a significant correlation for kurtosis (p = 0.003), entropy (p < 0.001), and uniformity (p < 0.001) as compared to Ki-67 index, exceeding those of the conventional parameters. The results of univariate analysis suggested that skewness and kurtosis were associated with OS (p = 0.03 and 0.02, respectively). Mean survival for patients with skewness values less than 0.65 was 1462 days, compared with 917 days for those with values greater than 0.65 (p = 0.02). Mean survival for patients with kurtosis values less than 6.16 was 1616 days, compared with 882 days for those with values greater than 6.16 (p = 0.006).

Conclusions

Based on the results of this preliminary study in a small patient population, textural features reflecting heterogeneity on FLT PET images seem to be useful for the assessment of proliferation and for the potential prediction of survival in newly diagnosed gliomas.

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

Access this article

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Fig. 1
Fig. 2

Similar content being viewed by others

References

  1. Davnall F, Yip CS, Ljungqvist G, Selmi M, Ng F, Sanghera B, et al. Assessment of tumor heterogeneity: an emerging imaging tool for clinical practice? Insights Imaging. 2012;3:573–89.

    Article  PubMed  PubMed Central  Google Scholar 

  2. Höckel M, Knoop C, Schlenger K, Vorndran B, Baussmann E, Mitze M, et al. Intratumoral pO2 predicts survival in advanced cancer of the uterine cervix. Radiother Oncol. 1993;26:45–50.

    Article  PubMed  Google Scholar 

  3. Yang Z, Tang LH, Klimstra DS. Effect of tumor heterogeneity on the assessment of Ki67 labeling index in well-differentiated neuroendocrine tumors metastatic to the liver: implications for prognostic stratification. Am J Surg Pathol. 2011;35:853–60.

    Article  PubMed  Google Scholar 

  4. Höckel M, Schlenger K, Aral B, Mitze M, Schaffer U, Vaupel P. Association between tumor hypoxia and malignant progression in advanced cancer of the uterine cervix. Cancer Res. 1996;56:4509–15.

    PubMed  Google Scholar 

  5. Goh V, Ganeshan B, Nathan P, Juttla JK, Vinayan A, Miles KA. Assessment of response to tyrosine kinase inhibitors in metastatic renal cell cancer: CT texture as a predictive biomarker. Radiology. 2011;261:165–71.

    Article  PubMed  Google Scholar 

  6. Ganeshan B, Skogen K, Pressney I, Coutroubis D, Miles K. Tumour heterogeneity in oesophageal cancer assessed by CT texture analysis: preliminary evidence of an association with tumour metabolism, stage, and survival. Clin Radiol. 2012;67:157–64.

    Article  CAS  PubMed  Google Scholar 

  7. Tixier F, Le Rest CC, Hatt M, Albarghach N, Pradier O, Metges JP, et al. Intratumor heterogeneity characterized by textural features on baseline 18F-FDG PET images predicts response to concomitant radiochemotherapy in esophageal cancer. J Nucl Med. 2011;52:369–78.

    Article  PubMed  PubMed Central  Google Scholar 

  8. Cook GJ, Yip C, Siddique M, Goh V, Chicklore S, Roy A, et al. Are pretreatment 18F-FDG PET tumor textural features in non-small cell lung cancer associated with response and survival after chemoradiotherapy? J Nucl Med. 2013;54:19–26.

    Article  PubMed  Google Scholar 

  9. Tixier F, Hatt M, Valla C, Fleury V, Lamour C, Ezzouhri S, et al. Visual versus quantitative assessment of intratumor 18F-FDG PET uptake heterogeneity: prognostic value in non-small cell lung cancer. J Nucl Med. 2014;55:1235–41.

    Article  CAS  PubMed  Google Scholar 

  10. Eary JF, O’Sullivan F, O’Sullivan J, Conrad EU. Spatial heterogeneity in sarcoma 18F-FDG uptake as a predictor of patient outcome. J Nucl Med. 2008;49:1973–9.

    Article  PubMed  PubMed Central  Google Scholar 

  11. Kidd EA, Grigsby PW. Intratumoral metabolic heterogeneity of cervical cancer. Clin Cancer Res. 2008;14:5236–41.

    Article  CAS  PubMed  Google Scholar 

  12. Colavolpe C, Metellus P, Mancini J, Barrie M, Béquet-Boucard C, Figarella-Branger D, et al. Independent prognostic value of pre-treatment 18-FDG-PET in high-grade gliomas. J Neurooncol. 2012;107:527–35.

    Article  PubMed  Google Scholar 

  13. Kim S, Chung JK, Im SH, Jeong JM, Lee DS, Kim DG, et al. 11C-methionine PET as a prognostic marker in patients with glioma: comparison with 18F-FDG PET. Eur J Nucl Med Mol Imaging. 2005;32:52–9.

    Article  CAS  PubMed  Google Scholar 

  14. Hatakeyama T, Kawai N, Nishiyama Y, Yamamoto Y, Sasakawa Y, Ichikawa T, et al. 11C-methionine (MET) and 18F-fluorothymidine (FLT) PET in patients with newly diagnosed glioma. Eur J Nucl Med Mol Imaging. 2008;35:2009–17.

    Article  CAS  PubMed  Google Scholar 

  15. Chen W, Cloughesy T, Kamdar N, Satyamurthy N, Bergsneider M, Liau L, et al. Imaging proliferation in brain tumors with 18F-FLT PET: comparison with 18F-FDG. J Nucl Med. 2005;46:945–52.

    CAS  PubMed  Google Scholar 

  16. Choi SJ, Kim JS, Kim JH, Oh SJ, Lee JG, Kim CJ, et al. [18F]3′-deoxy-3′-fluorothymidine PET for the diagnosis and grading of brain tumors. Eur J Nucl Med Mol Imaging. 2005;32:653–9.

    Article  PubMed  Google Scholar 

  17. Spence AM, Muzi M, Link JM, O’Sullivan F, Eary JF, Hoffman JM, et al. NCI-sponsored trial for evaluation of safety and preliminary efficacy of 3′-Deoxy-3′-[F-18]fluorothymidine (FLT) as a marker of proliferation in patients with recurrent gliomas: preliminary efficacy studies. Mol Imaging Biol. 2009;11:343–55.

    Article  PubMed  PubMed Central  Google Scholar 

  18. Chen W, Dalaloye S, Silverman DH, Geist C, Czernin J, Sayre J, et al. Predicting treatment response of malignant gliomas to bevacizumab and irinotecan by imaging proliferation with [18F]fluorothymidine positron emission tomography: a pilot study. J Clin Oncol. 2007;25:4714–21.

    Article  CAS  PubMed  Google Scholar 

  19. Zhao F, Cui Y, Li M, Fu Z, Chen Z, Kong L, et al. Prognostic value of 3′-deoxy-3′-18F-fluorothymidine ([18F] FLT PET) in patients with recurrent malignant gliomas. Nucl Med Biol. 2014;41:710–5.

    Article  CAS  PubMed  Google Scholar 

  20. Schwarzenberg J, Czernin J, Cloughesy TF, Ellingson BM, Pope WB, Geist C, et al. 3′-deoxy-3′-18F-fluorothymidine PET and MRI for early survival predictions in patients with recurrent malignant glioma treated with bevacizumab. J Nucl Med. 2012;53:29–36.

    Article  CAS  PubMed  Google Scholar 

  21. Rasey JS, Grierson JR, Wiens LW, Kolb PD, Schwartz JL. Validation of FLT uptake as a measure of thymidine kinase-1 activity in A549 carcinoma cells. J Nucl Med. 2002;43:1210–7.

    CAS  PubMed  Google Scholar 

  22. Pyka T, Gempt J, Hiob D, Ringel F, Schlegel J, Bette S, et al. Textural analysis of pre-therapeutic [18F]-FET-PET and its correlation with tumor grade and patient survival in high-grade gliomas. Eur J Nucl Med Mol Imaging. 2016;43:133–41.

    Article  PubMed  Google Scholar 

  23. Louis DN, Ohgaki H, Wiestler OD, Cavenee WK, Burger PC, Jouvet A, et al. The 2007 WHO classification of tumours of the central nervous system. Acta Neuropathol. 2007;114:97–109.

    Article  PubMed  PubMed Central  Google Scholar 

  24. Machulla HJ, Blocher A, Kuntzsch M, Piert M, Wei R, Grierson JR. Simplified labeling approach for synthesizing 3′-deoxy-3′-[18F]fluorothymidine ([18F]FLT). J Radioanal Nucl Chem. 2000;243:843–6.

    Article  CAS  Google Scholar 

  25. Amadasun M, King R. Textural features corresponding to textural properties. IEEE Trans Syst Man Cybern. 1989;19:1264–74.

    Article  Google Scholar 

  26. Radulescu E, Ganeshan B, Minati L, Beacher FDCC, Gray MA, Chatwin C, et al. Gray matter textural heterogeneity as a potential in vivo biomarker of fine structural abnormalities in Asperger syndrome. Pharmacogenomics J. 2013;13:70–9.

    Article  CAS  PubMed  Google Scholar 

  27. Chicklore S, Goh V, Siddique M, Roy A, Marsden PK, Cook GJ. Quantifying tumour heterogeneity in 18F-FDG PET/CT imaging by texture analysis. Eur J Nucl Med Mol Imaging. 2013;40:133–40.

    Article  PubMed  Google Scholar 

  28. la Fougère C, Suchorska B, Bartenstein P, Kreth FW, Tonn JC. Molecular imaging of gliomas with PET: opportunities and limitations. Neuro Oncol. 2011;13:806–19.

    Article  PubMed  PubMed Central  Google Scholar 

  29. Barwick T, Bencherif B, Mountz JM, Avril N. Molecular PET and PET/CT imaging tumour cell proliferation using F-18 fluoro-l-thymidine: a comprehensive evaluation. Nucl Med Commun. 2009;30:908–17.

    Article  CAS  PubMed  Google Scholar 

  30. Van de Wiele C, Kruse V, Smeets P, Sathekge M, Maes A. Predictive and prognostic value of metabolic tumour volume and total lesion glycolysis in solid tumours. Eur J Nucl Med Mol Imaging. 2013;40:290–301.

    Article  CAS  PubMed  Google Scholar 

  31. Brooks FJ, Grigsby PW. The effect of small tumor volumes on studies of intratumoral heterogeneity of tracer uptake. J Nucl Med. 2014;55:37–42.

    Article  CAS  PubMed  Google Scholar 

  32. Yu H, Caldwell C, Mah K, Mozeg D. Coregistered FDG PET/CT-based textural characterization of head and neck cancer for radiation treatment planning. IEEE Trans Med Imaging. 2009;28:374–83.

    Article  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Yuka Yamamoto.

Ethics declarations

Conflict of interest

No potential conflict of interest relevant to this article was reported.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Mitamura, K., Yamamoto, Y., Kudomi, N. et al. Intratumoral heterogeneity of 18F-FLT uptake predicts proliferation and survival in patients with newly diagnosed gliomas. Ann Nucl Med 31, 46–52 (2017). https://doi.org/10.1007/s12149-016-1129-0

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s12149-016-1129-0

Keywords

Navigation