The Cell Proliferation Correlates with 18F-Fluorothymidine Uptake on Positron Emission Tomography in Patients with Lung Cancer: a Meta-Analysis

Objectives Positron emission tomography (PET) imaging using the radiotracer 18F-Fluorothymidine (FLT) has been proposed as an imaging biomarker of tumor proliferation. If FLT-PET can be established as such, it will provide a non-invasive, quantitative measurement of tumour proliferation across the entire tumor. Results from validation studies have so far been conflicting with some studies confirming a good correlation between FLT uptake and Ki-67 score and others presenting negative results. We aimed to explore the correlation of FLT uptake with the Ki-67 labeling index in patients with lung cancer.

Methods The MEDLINE, EMBASE, Cochrane Library and China National Knowledge Infrastructure (CNKI) databases were systematically searched for all relevant literature about the relationship of FLT uptake/Ki-67 expression in patients with lung cancer. The publishing language was limited to English and Chinese. Retrieved articles were screened carefully based on the selection criteria: (a) focusing on patients with malignant pulmonary tumors, or the vast majority of included tumors were malignant (b) investigated the correlation between Ki-67 measured by immunohistochemistry and FLT uptake measured with PET scanning, and (c) published as a full paper. Then the quality of included studies was evaluated according to the Quality Assessment of Diagnostic Accuracy Studies (QUADAS-2) tool, which consists of two parts of contents “risk of bias” and “applicability concerns”. To ensure the application of QUADAS-2 in our analysis, the PET scan was designated as the “index test” and the Ki-67 immunohistochemistry as the “reference test”. The correlation coefficient (r) and its 95% confidence interval (CI) of individual studies were meta-analyzed using a random-effects model. The 95% CIs were calculated by applying Fisher’s z transformation and inverse Fisher transformation. Higher values indicated stronger correlation. Begg’s test was performed to assess the publication bias, and the stability of pooled results was evaluated by the sensitivity analysis. The sources of heterogeneity were explored by subgroup analysis based on scanning modality (PET vs. PET/CT) and sample method (surgery vs. surgery+biopsy).

Results Eleven studies involving 304 patients eventually met the inclusion criteria. Most studies enrolled patients prospectively while only one was designed retrospectively. For scanning modality, four studies used the integrated PET/CT while 6 used PET alone, 1 used both. As for the sample method, seven studies used surgery while other 4 used both surgery and biopsy. The results of QUADAS-2 showed the common weakness was concentrated in the interpretation of index test and reference standard without blindness. In addition, due to lack of information about the appropriate interval between index test and reference standard, the risk of bias about flow and timing was high or unclear in two studies. The pooled r for the correlation of 18F-FLT uptake with Ki-67 expression was 0.64 (95% CI, 0.57-0.71), meaning a significant level in spite of high heterogeneity (I2=90.5%, p<0.001) (Figure 1a). Sensitivity analysis revealed that a single study contributed no significant influence to the overall estimate. The funnel plot showed that there was no notable publication bias (p=0.21) (Figure 1b). Compared with PET subgroup, the PET/CT subgroup displayed a lower heterogeneity, providing an r=0.51 (95% CI, 0.40-0.63; I2=58.8%). Based on the subgroup analysis, the scanner and sample method were potential sources of heterogeneity (p<0.05) (Table 1).

Conclusions The correlation between FLT uptake on PET/CT and Ki-67 index was significant; however, larger and prospective studies with improved study design are warranted to validate the findings. This study was supported by National Natural Science Foundation of China (Grant No. 81471692).

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