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

Purpose Tc-99m-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 Tc-99m-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 Tc-99m-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 Tc-99m-annexin A5 uptake were performed at baseline and after the start of treatment. Various quantitative parameters have been used for the calculation of Tc-99m-annexin A5 tumor uptake and delta (Delta) tumor changes post-treatment compared to baseline including: tumor-to-background ratio (TBR), Delta TBR, tumor-to-noise ratio, relative tumor ratio (TR), Delta TR, standardized tumor uptake ratio (STU), Delta STU, maximum count per pixel within the tumor volume (Cmax), C-max%, absolute Delta U and percentage (Delta U%), maximum Delta U counts, semiquantitative visual scoring, percent injected dose (%ID) and %ID/cm(3). 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 Tc-99m-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 Tc-99m-annexin A5 tumor uptake were found to be reproducible (mean difference