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99mTc-Annexin A5 quantification of apoptotic tumor response: a systematic review and meta-analysis of clinical imaging trials

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Abstract

Purpose

99mTc-Annexin A5 has been used as a molecular imaging probe for the visualization, characterization and measurement of apoptosis. In an effort to define the quantitative 99mTc-annexin A5 uptake criteria that best predict tumor response to treatment, we performed a systematic review and meta-analysis of the results of all clinical imaging trials found in the literature or publicly available databases.

Methods

Included in this review were 17 clinical trials investigating quantitative 99mTc-annexin A5 (qAnx5) imaging using different parameters in cancer patients before and after the first course of chemotherapy and/or radiation therapy. Qualitative assessment of the clinical studies for diagnostic accuracy was performed using the QUADAS-2 criteria. Of these studies, five prospective single-center clinical trials (92 patients in total) were included in the meta-analysis after exclusion of one multicenter clinical trial due to heterogeneity. Pooled positive predictive values (PPV) and pooled negative predictive values (NPV) (with 95 % CI) were calculated using Meta-Disc software version 1.4.

Results

Absolute quantification and/or relative quantification of 99mTc-annexin A5 uptake were performed at baseline and after the start of treatment. Various quantitative parameters have been used for the calculation of 99mTc-annexin A5 tumor uptake and delta (Δ) tumor changes post-treatment compared to baseline including: tumor-to-background ratio (TBR), ΔTBR, tumor-to-noise ratio, relative tumor ratio (TR), ΔTR, standardized tumor uptake ratio (STU), ΔSTU, maximum count per pixel within the tumor volume (Cmax), Cmax%, absolute ΔU and percentage (ΔU%), maximum ΔU counts, semiquantitative visual scoring, percent injected dose (%ID) and %ID/cm3. Clinical trials investigating qAnx5 imaging have included patients with lung cancer, lymphoma, breast cancer, head and neck cancer and other less common tumor types. In two phase I/II single-center clinical trials, an increase of ≥25 % in uptake following treatment was considered a significant threshold for an apoptotic tumor response (partial response, complete response). In three other phase I/II clinical trials, increases of ≥28 %, ≥42 % and ≥47 % in uptake following treatment were found to be the mean cut-off levels in responders. In a phase II/III multicenter clinical trial, an increase of ≥23 % in uptake following treatment was found to be the minimum cut-off level for a tumor response. In one clinical trial, no significant difference in 99mTc-annexin A5 uptake in terms of %ID was found in healthy tissues after chemotherapy compared to baseline. In two other clinical trials, intraobserver and interobserver measurements of 99mTc-annexin A5 tumor uptake were found to be reproducible (mean difference <5 %, kappa =  0.90 and 0.82, respectively) and to be highly correlated with treatment outcome (Spearman r = 0.99, p < 0.0001). The meta-analysis demonstrated a pooled positive PPV of 100 % (95 % CI 92 – 100 %) and a pooled NPV of 70 % (95 % CI 55 – 82 %) for prediction of a tumor response after the first course of chemotherapy and/or radiotherapy in terms of ΔU%. In a symmetric sROC analysis, the AUC was 0.919 and the Q* index was 85.21 %.

Conclusion

Quantitative 99mTc-annexin A5 imaging has been investigated in clinical trials for the assessment of apoptotic tumor responses. This meta-analysis showed a high pooled PPV and a moderate pooled NPV with ΔU cut-off values ranging between 20 % and 30 %. Standardization of quantification and harmonization of results are required for high-quality clinical research. A standardized uptake value score (SUV, ΔSUV) using quantitative SPECT/CT imaging may be a promising approach to the simple, reproducible and semiquantitative assessment of apoptotic tumor changes.

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Acknowledgments

The authors acknowledge the invaluable scientific contribution of Dr. Allan Green as a previous President and CEO of Theseus Imaging Corporation Inc. (Boston, MA, USA) for the single-center and multicenter clinical trials on 99mTc-annexin A5 imaging of apoptosis in cancer patients. The authors thank Dr. Neil Steinmetz as a previous Vice-President and Medical Monitor of Theseus Imaging Corporation Inc. for providing his unique data on the quantitative results from the European multicenter phase II/III 99mTc-Hynic-rh-annexin A5 clinical trial (NAS-2020). The authors also thank Dr. Rick L.M. Haas of The Netherlands Cancer Institute/Antoni van Leeuwenhoek Hospital, Department of Radiotherapy (Amsterdam, The Netherlands) for providing detailed data on the 99mTc-annexin A5 clinical trial he conducted.

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Conflict of Interest

None.

Ethical approval

All procedures performed in studies involving human participants in the single-center and multicenter clinical trials included in this systematic review and meta-analysis of quantitative 99mTc-annexin A5 imaging of apoptosis were in accordance with the ethical standards of the institutional and/or national research committee and with the principles of the 1964 Declaration of Helsinki and its later amendments or comparable ethical standards. This article does not describe any studies with animals performed by any of the authors.

Informed consent

Informed consent was obtained from all individual participants included in the studies described.

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Authors and Affiliations

  1. Biomedical Imaging Research Centre (BIRC), Western University, London, Ontario, Canada

    Tarik Z. Belhocine

  2. Division of Pediatric Radiology, Department of Radiology, Lucile Salter Packard Children’s Hospital, Stanford, Palo Alto, CA, USA

    Francis G. Blankenberg

  3. Department of Nuclear Medicine, Medical Center Alkmaar, Alkmaar, The Netherlands

    Marina S. Kartachova

  4. LW Stitt Statistical Services, London, Ontario, Canada

    Larry W. Stitt

  5. JLVMI Consulting LLC, Waukesha, WI, USA

    Jean-Luc Vanderheyden

  6. Department of Radiation Oncology (MAASTRO Clinic), GROW School for Oncology and Developmental Biology, Maastricht University Medical Centre, Maastricht, The Netherlands

    Frank J. P. Hoebers

  7. Department of Nuclear Medicine and Radiology, University Hospital Ghent, Ghent, Belgium

    Christophe Van de Wiele

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  1. Tarik Z. Belhocine
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Correspondence to Tarik Z. Belhocine.

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Belhocine, T.Z., Blankenberg, F.G., Kartachova, M.S. et al. 99mTc-Annexin A5 quantification of apoptotic tumor response: a systematic review and meta-analysis of clinical imaging trials. Eur J Nucl Med Mol Imaging 42, 2083–2097 (2015). https://doi.org/10.1007/s00259-015-3152-0

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  • DOI: https://doi.org/10.1007/s00259-015-3152-0

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