Supplementary Material for: High Metabolic Tumour Volume on 18-Fluorodeoxyglucose Positron Emission Tomography Predicts Poor Survival from Neuroendocrine Neoplasms

<b><i>Introduction:</i></b> 18-Fluorodeoxyglucose (¹⁸F-FDG) positron emission tomography (PET) avidity in neuroendocrine neoplasms (NENs) has been associated with higher-grade disease. ¹⁸F-FDG avidity and high SUV_max have been demonstrated to predict poor outcome. Quantitative metrics of ¹⁸F-FDG PET, specifically metabolic tumour volume (MTV) and total lesion glycolysis (TLG), have been shown to be prognostic factors in other malignancies, but these have not been investigated to date in NENs. <b><i>Methods:</i></b> Patients with NEN undergoing ¹⁸F-FDG at Royal North Shore Hospital from 2012 to 2018 were included. Images were analysed with automated segmentation (SUV cut-off of 4) followed by contour verification by a nuclear medicine physician and manual segmentation where required. Variables collected included patient age, histological grade, MTV, TLG, and SUV_max/SUV_mean. The primary outcome was overall survival (OS), and the secondary outcome was progression-free survival (PFS). Univariate (UV) and multivariate (MV) analyses were performed for OS and PFS for MTV and TLG separately. For UV analysis, the median MTV and TLG were used to dichotomise the cohort. MTV/TLG for NENs of different histological grade were compared using ANOVA. <b><i>Results:</i></b> One hundred and ninety patients were included (median age 63.5, 49% female). Primary site: 42% small bowel, 32% pancreas, 15% other gastrointestinal, 6% lung, 6% other. Grade for gastroenteropancreatic NENs and bronchial NEN: G1/typical carcinoid 37%, G2/atypical carcinoid 40%, G3/large-cell/small-cell neuroendocrine carcinoma 16%, unknown 8%. Median MTV was 4.83 mL (range 0–3,161 mL) and median TLG was 29.22. Patients with high MTV had worse median OS compared to those with low MTV (29.7 months vs. not reached, HR 4.1, 95% CI 2.25–7.49, <i>p</i> &lt; 0.00001). Considered as a continuous variable, MTV predicted for poorer OS on UV (<i>p</i> &lt; 0.00001) and MV (<i>p</i> = 0.003) analyses. Whilst histological grade was significant on both UV and MV, SUV_max was significant on UV (<i>p</i> &lt; 0.00001) but not MV (<i>p</i> = 0.76). Tumours of higher grade had higher MTV (mean MTV – G1: 39.6 mL, G2: 107 mL, G3: 337 mL; <i>p</i> = 0.0001 by ANOVA). <b><i>Conclusions:</i></b> Quantitative analysis of ¹⁸F-FDG PET in NEN is feasible. High MTV/TLG are predictors of poor prognosis in NEN. Further analyses are underway to investigate a larger cohort of NEN patients.

<b><i>引言:</i></b> 神经内分泌肿瘤（NENs）的18-氟脱氧葡萄糖（¹⁸F-FDG）正电子发射断层显像（PET）摄取活性与高级别疾病相关。已有研究证实¹⁸F-FDG摄取活性及高最大标准化摄取值（SUVmax）可预测不良预后。¹⁸F-FDG PET的定量指标，尤其是代谢肿瘤体积（MTV）与总病灶糖酵解（TLG），已被证实为其他恶性肿瘤的预后因素，但目前尚未在神经内分泌肿瘤中开展相关研究。<b><i>方法:</i></b> 纳入2012年至2018年在皇家北岸医院接受¹⁸F-FDG PET检查的神经内分泌肿瘤患者。采用自动分割（SUV阈值为4）对图像进行分析，随后由核医学医师对轮廓进行验证，必要时采用手动分割。收集的变量包括患者年龄、组织学分级、代谢肿瘤体积（MTV）、总病灶糖酵解（TLG）以及最大标准化摄取值/平均标准化摄取值（SUVmax/SUVmean）。主要结局指标为总生存期（OS），次要结局指标为无进展生存期（PFS）。分别针对MTV与TLG，对总生存期和无进展生存期开展单因素（UV）与多因素（MV）分析。单因素分析中，以MTV与TLG的中位值将队列进行二分分组。采用方差分析（ANOVA）比较不同组织学分级的神经内分泌肿瘤的MTV与TLG。<b><i>结果:</i></b> 本研究共纳入190例患者（中位年龄63.5岁，女性占比49%）。原发部位分布：42%为小肠，32%为胰腺，15%为其他胃肠道部位，6%为肺部，6%为其他部位。胃肠胰神经内分泌肿瘤与支气管神经内分泌肿瘤的分级情况：G1/典型类癌占37%，G2/不典型类癌占40%，G3/大细胞/小细胞神经内分泌癌占16%，未知分级占8%。中位MTV为4.83 mL（范围0~3161 mL），中位TLG为29.22。高MTV组患者的中位总生存期劣于低MTV组（29.7个月 vs 未达到，风险比（HR）=4.1，95%置信区间（CI）：2.25~7.49，p<0.00001）。将MTV作为连续变量进行分析时，单因素与多因素分析均显示MTV可预测较差的总生存期（单因素分析p<0.00001，多因素分析p=0.003）。尽管组织学分级在单因素与多因素分析中均具有统计学意义，但SUVmax仅在单因素分析中具有统计学意义（p<0.00001），多因素分析中无统计学意义（p=0.76）。高级别肿瘤的MTV更高（平均MTV：G1组39.6 mL，G2组107 mL，G3组337 mL；方差分析ANOVA检验p=0.0001）。<b><i>结论:</i></b> 针对神经内分泌肿瘤的¹⁸F-FDG PET定量分析具备可行性。高MTV/TLG可作为神经内分泌肿瘤不良预后的预测指标。目前正在开展更大规模的神经内分泌肿瘤患者队列分析。