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

PURPOSE: (99m)Tc-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 (99m)Tc-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 (99m)Tc-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 (99m)Tc-annexin A5 uptake were performed at baseline and after the start of treatment. Various quantitative parameters have been used for the calculation of (99m)Tc-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/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 (99m)Tc-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 (99m)Tc-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 (99m)Tc-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.

99mTc-HYNIC-rh-annexin-V scintigraphy: visual and quantitative evaluation of early treatment-induced apoptosis to predict treatment outcome.

AIM: To determine the reliability of visual analysis of 99mTc-HYNIC-rh-annexin-V tumour uptake (ATU) compared to quantitative tracer uptake evaluation. METHODS: Thirty-eight patients (22 male, 16 female, mean age 57) with histologically proved lymphoma (n=31), non-small cell lung cancer (NSCLC) (n=4) and head and neck squamous cell carcinoma (H&NSCC) (n=3) were examined. 99mTc-HYNIC-rh-annexin-V scintigraphy (TAS) was acquired before and within 2 days after the start of anti-cancer treatment. Maximal counts per pixel in the tumour volume (Cmax) were calculated for every target lesion. To match the quantitative and visual ATU, both were expressed as a four-grade score. Cmax as percentages of baseline values: grade 1, decrease >25%; grade 0, 1-25% decrease; grade 1, 1-25% increase; grade 2, >25% increase. Visual analysis: 0=absent, 1=weak, 2=moderate, 3=intense. Intra-observer and inter-observer variability and methodological agreement between visual and quantitative evaluation of ATU was expressed by computing Cohen's kappa statistics. RESULTS: A statistically highly significant correlation was found between the changes in ATU and therapy outcome: r=0.97 (P<0.0001) and r=0.99 (P<0.0001) for visual and quantitative analysis, respectively. Good intra-observer reproducibility, with a high kappa of 0.82 for observer 1 and a kappa of 0.90 for observer 2, was determined. Inter-observer variability was 0.82. CONCLUSION: Visual evaluation of ATU after image co-registration appears to be a reliable and reproducible method for preliminary assessment of early treatment-induced apoptosis.

Mapping of treatment-induced apoptosis in normal structures: 99mTc-Hynic-rh-annexin V SPECT and CT image fusion.

PURPOSE: The purpose of this study was to map treatment-induced (99m)Tc-Hynic-rh-annexin V uptake in normal tissues using co-registration of SPECT and CT. METHODS: Nineteen patients (11 male, 8 female, mean age 57 years) with various malignant tumours (12 lymphomas, four non-small cell lung cancers and three head and neck squamous cell carcinomas) underwent (99m)Tc-Hynic-rh-annexin V scintigraphy and CT before and within 48 h after the start of anticancer therapy. SPECT and CT were performed separately, with the patient in a reproducible position. Volume-based automated and manual methods were used to match functional and anatomical data. SPECT/CT co-registration was used to evaluate treatment-induced changes in the normal structures. RESULTS: A significant radiation field-related increase in early post-treatment (99m)Tc-Hynic-rh-annexin V uptake in salivary glands and bone marrow was detected in eight of nine patients. Radiation field-related increase in bone marrow activity above the baseline value was detected in all 13 irradiated patients. A minimal, symmetrical increase in activity in the salivary glands was detected after the initial course of platinum-based chemotherapy, and a diffuse prominent increase in (99m)Tc-Hynic-rh-annexin V in the bone marrow was detected in all cases. Precise delineation between the tumour and normal tissue tracer accumulation was accomplished in all cases using SPECT/CT co-registered volumes, enhanced by the "colourwash" technique. CONCLUSION: Mapping of early treatment-related changes in annexin V uptake by SPECT/CT co-registration permits accurate evaluation of tracer distribution in normal structures and precise delineation from tumour uptake. The associations between tracer distribution in the normal tissues and treatment regimen found in this study may contribute to the evaluation of dose-effect relations in various treatment schedules.