Prognostic value of maximum standard uptake value, metabolic tumour volume, and total lesion glycolysis of 18F-FDG PET/CT in patients with malignant pleural mesothelioma: a systematic review and meta-analysis

Malignant pleural mesothelioma (MPM) is an uncommon and aggressive cancer derived from mesothelial cells.MPM is most commonly observed in menolder than 60 years, and its prognosis is poor [1‐3]. MPM occurrence is high among the mesothelioma subtypes and is a refractory disorder [4, 5]. MPM is usually diagnosed at advanced stages, and palliative systemic antitumor care is preferable to aggressive surgery [6]. Immune checkpoint inhibitors (ICIs) immune checkpoint molecules are expressed physiologically on immune cells and play a key role in maintaining immune homeostasis and ensuring self-tolerance by mediating signals to attenuate excessive immune activation [7]. Immune checkpoint inhibitors based immunotherapy has been investigated in several clinical studies [8, 9] and could be an extremely effective MPM treatment [10]. The diagnostic techniques and treatments for MPM have progressed substantially [11]. Although prognostic factors such as sarcomatous histological type, sex, and performance status have been described in MPM patients [12], the imaging tool to accurately assess MPM survival and the prognostic outcome is lacking [11]. The overall survival (OS) of MPM patients is as low as 12 months [13]. Additionally, the 5-year survival for patients with MPM is extremely low. Identification of biomarkers to predict MPM prognosis for improving the clinical effectiveness of treatments is therefore crucial. Many models have been constructed for predicting MPM prognosis, including the models established by Cancer and Leukaemia Group B (CALGB) and the European Organization for the Research and Treatment of Cancer (EORTC) [14‐16]. Many studies have supported that 18-fluorodeoxyglucose (18F-FDG) positron emission tomography (PET/CT) is a valuable tool for efficiently predicting and assessing cancer and the TNM stage. Mainly, FDG parameters like total lesional glycolysis (TLG), tumour volume/metabolism, metabolic tumour volume (MTV), and maximal standard uptake value (SUVmax) have been studied extensively, MTV represents the size of tumor tissue that actively ingests ¹⁸ F-FDG and TLG is the median SUV value in the region of interest of MTV [17‐21].

Nonetheless, MPM survival prediction using the 18F-FDG PET/CT parameters is debatable.Some reports suggest that the increased SUVmax is related to the dismal survival of MPM cases [22‐24], where as Doi et al. [25] did not observe such relationships. Hence, through the current meta-analysis, we aimed to evaluate the significance of SUVmax, TLG, and MTV in predicting MPM survival.

To our knowledge, the present meta-analysis is the first toelaborate on the significance of SUVmax, TLG, and MTV in predicting MPM prognosis.MPM is a refractory disorder with an increasing incidence worldwide [5, 37‐39]. Some recent meta-analyses have verified that FDG uptake can be applied in predicting the prognosis of cancers like soft tissue sarcoma, hepatocellular carcinoma, and head-and-neck cancer (HNC) [40‐45]. Prediction of OS using these parameters will certainly benefit MPM cases [46‐48]. The current meta-analysis has been performed on data pooled from 12 research articles. As a result, Despite the adoption of different methods for different types of MPM patients, the increased SUVmax and TLG values predicted an increased OS risk [95% CI 1.13–1.449, P = 0.000)] and low HRs (1.30) [1.81 (95% CI 1.25–2.61, P=0.089)]. The current study suggests that MTV did not significantly predict the OS (HR=1.14 [95% CI 0.87–2.1.50, P=0.18], (Fig 3B) due to smaller sample size(6 reports examined OS with MTV). More studies are required for investigating the influence of MTV in predicting OS in MPM patients.

We detected heterogeneity in SUVmax for the prediction of OS (I² = 69.2%; P = 0.000). Based on the ¹⁸F-FDG PET imaging protocols and guidelines, the PET/CT parameters (duration of fasting, preinjection blood glucose test, post-injection interval, and dose of ¹⁸ F-FDG) involved in the current work were acceptable as the values were within normal range [3, 38, 39] (Table 3). To investigate heterogeneity's potential source, subgroup analyses stratified by study design, threshold, and cut-off methods were performed on OS. First, prospective studies provide high-level evidence by evaluating the clinical endpoints and using the most efficient and reliable method. In subgroup analyses performed according to study design, the OS (1.05) (95% CI = 1.03–1.08, I ² = 0.0%, P = 0.487) of the Pro group showed statistical significance, and no statistical heterogeneity existed between studies. In contrast, retrospective studies provide relatively low-level clinical evidence due to a potential selection bias. In subgroup analyses performed according to study design, the OS (1.69) (95% CI = 1.39–2.07, I² = 26.9%, P = 0.205) of the retro group also showed statistical significance, and no statistical heterogeneity existed between studies. Thus, data from both prospective and retrospective subgroups support our results. Second, data were further classified using cut-off method as 2 subgroups, where ROC group exhibited homogeneity (I² = 35.8%, P = 0.212). Third, different optimal thresholds were observed in the enrolled reports; as a result, studies were classified as 2 groups, and the median was 8.1. Later, subgroup that had the threshold less than 8.1 was considered homogeneous (I² = 0.0%, P = 0.619). Therefore, the study design, cut-off method, and threshold were considered sources of OS heterogeneity. The subgroup with a threshold above 8.1 revealed the existence of a statistically significant heterogeneity (I² = 69.9%, P = 0.005).The current study failed to determine the threshold for prognostic SUVmax. The articles applied different cut-off values, which possibly affected the prediction of survival and occurrence of the disease. Further research is required for determining standard thresholds for prognosis prediction based on SUVmax.

Heterogeneity in TLG for OS prediction was observed (I² = 50.5%, P = 0.089). Seven articles verified that TLG was related to OS. In addition, TLG was significantly correlated with the OS, as revealed by the random-effects model. Because of the few studies enrolled, subgroup analysis was not conducted; however, the Begg’s (P = 0.902) and Egger’s (P = 0.382) tests suggested the absence of publication bias. The stability of our results was supported by sensitivity analysis.

MTV and TLG are both affected by SUV [49]. However, SUV is influenced by several patient-dependent and technical parameters, such as blood glucose levels, fasting duration and uptake duration which must be strictly controlled [3, 38, 47]. SUV and other confounders possibly influence the relation of TLG with survival, and the increased TLG were related to patient survival. However, Owing to the lack of statistical data on TLG in relation to survival, systematic analysis was not possible, this study failed to establish the best threshold for TLG. Future high-quality study design and methods could find the best threshold for TLG. Similarly, SUVs and other confounders may affect the relationship between MTV and survival. The current study suggests that MTV did not significantly predict the OS (HR = 1.14 [95% CI 0.87–2.1.50], More studies are required for investigating the influence of MTV in predicting OS in MPM patients.

The current meta-analysis has some limitations. First, our enrolled articles were assessed by the Cochrane risk bias tool, and most of them were of high quality. In addition, some of the reports did not provide adequate details about 18F-FDG PET scanning data and patients. Moreover, further investigations involving PET parameters and MPM survival data are required for more conclusive analyses. Second, the sample sizes of the enrolled reports were small (n = 1307). Third, because of MPM heterogeneity, the present meta-analysis included cases at diverse stages, histological grades or those receiving various treatments, which might have a specific influence on survival and the occurrence of events over time. Fourth, the current work did not include studies published in languages other than English, which might affect possible language bias. Fifth, we used articles published only in electronic databases, which might result in possible publication bias. Nonetheless, our result reliability was verified by evaluating the publication bias.

Despite the adoption of different methods for different types of MPM patients, the present work discovered the significance of PET/CT in predicting the prognosis of MPM cases. We discovered that MPM cases exhibiting increased SUVmax and TLG had an increased risk of mortality. However, the current work failed to illustrate the significance of MTV in predicting patients’ deaths. Further large-scale prospective studies are warranted to confirm the prognostic value of PET/CT parameters in MPM patients.