Assessment of treatment responses in children and adolescents with Ewing sarcoma with metabolic tumor parameters derived from 18F-FDG-PET/CT and circulating tumor DNA
Assessment of treatment responses in children and adolescents with Ewing sarcoma with metabolic tumor parameters derived from 18F-FDG-PET/CT and circulating tumor DNA
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DOI：
10.1007/s00259-019-04649-1
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发表时间：
2019-12-18
影响因子：
9.1
通讯作者：
Metzler, Markus
中科院分区：
文献类型：
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作者：
Schmidkonz, Christian;Krumbholz, Manuela;Metzler, Markus
目的本研究的目的是进行一项前瞻性综合分析F-18-氟脱氧葡萄糖（F-18-FDG）-正电子发射断层扫描（PET）/计算机断层扫描（CT）和循环肿瘤DNA（ctDNA），以评估尤文肉瘤（EwS）儿童和青少年对多模式化疗的反应。方法对20例经病理证实的EwS患者在首次确诊时、第2次和第5次诱导化疗阻断后进行了多次F-18-FDG-PET/CT检查（EWING 2008治疗方案，NCT 00987636）。根据临床指征对某些患者进行额外的PET检查，例如，在怀疑患有进行性或复发性疾病的患者中。对视野内所有263个提示肿瘤组织的F-18-FDG阳性病灶进行定量评估，以计算PET衍生参数，包括全身代谢肿瘤体积（wb-MTV）和全身总病灶糖酵解（wb-TLG），以及以下数据：标准化摄取值（SUV）max和SUV mean。使用数字液滴PCR（ddPCR）定量患者血浆样品中的肿瘤特异性ctDNA，并分析ctDNA水平与PET衍生参数之间的相关性。将用PET参数评估的对多模式化疗的代谢应答与用ctDNA水平变化评估的生化应答进行比较。结果20例患者共进行了87次F-18-FDG-PET/CT扫描，检出263个FDG阳性肿瘤病灶。观察到SUVmax、SUVmean、wb-MTV和wb-TLG值与ctDNA水平之间的显著相关性（所有p < 0.0001）。所有患有EwS的患者，以组织学作为金标准，在开始治疗前也表现出阳性的相应ctDNA样品和阳性的18F-FDG-PET/CT检查。无假阴性结果。诱导化疗第5次阻断后的治疗反应评价显示，代谢反应和生化反应之间的一致性为90%，具有统计学显著性（Cohen kappa = 0.62; p < 0.05）。在16/17例患者（94%）中，第二次诱导化疗后未检测到ctDNA与第五次诱导化疗后的完全生化和代谢反应相关。在36个月（范围：8-104个月）的中位随访期内，4名患者出现肿瘤复发，所有病例均伴有血浆ctDNA水平升高和F-18-FDG-PET/CT阳性。在研究队列中未观察到假阴性结果。第五次诱导化疗阻断后的完全生化和代谢反应对随访期间的疾病缓解具有较高的阳性预测值;具体而言，阳性预测值为88%。结论F-18-FDG-PET/CT和ctDNA定量的结合是一种非常有前途的非侵入性工具，可用于评估接受多模式化疗的EwS儿童和青少年的治疗反应和检测肿瘤复发。
Purpose The purpose of this study was to perform a prospective integrated analysis of F-18-fluorodeoxyglucose (F-18-FDG)-positron emission tomography (PET)/computed tomography (CT) and circulating tumor DNA (ctDNA) to assess responses to multimodal chemotherapy in children and adolescents suffering from Ewing sarcoma (EwS). Methods A total of 20 patients with histologically confirmed EwS underwent multiple F-18-FDG-PET/CT, performed at the time of each patient's initial diagnosis and after the second and fifth induction chemotherapy block (EWING2008 treatment protocol, NCT00987636). Additional PET examinations were performed as clinically indicated in some patients, e.g., in patients suspected of having progressive or relapsing disease. All 263 F-18-FDG-positive lesions in the field of view suggestive of tumor tissue were assessed quantitatively to calculate PET-derived parameters, including whole-body metabolic tumor volume (wb-MTV) and whole-body total lesion glycolysis (wb-TLG), as well as the following data: standardized uptake value (SUV)max and SUVmean. Tumor-specific ctDNA in patient plasma samples was quantified using digital droplet PCR (ddPCR), and the correlations between ctDNA levels and PET-derived parameters were analyzed. Metabolic responses to multimodal chemotherapy as assessed with PET-parameters were compared to biochemical responses as assessed with changes in ctDNA levels. Results Twenty patients underwent a total of 87 F-18-FDG-PET/CT scans, which detected 263 FDG-positive tumor lesions. Significant correlations between SUVmax, SUVmean, wb-MTV and wb-TLG values, and ctDNA levels were observed (all p < 0.0001). All patients suffering from EwS, with histology serving as gold standard, also presented with a positive corresponding ctDNA sample and a positive 18F-FDG-PET/CT examination before initiation of therapy. There were no false-negative results. Evaluation of treatment response after the fifth block of induction chemotherapy showed that the agreement between the metabolic response and biochemical response was 90%, which was statistically significant (Cohen kappa = 0.62; p < 0.05). Non-detectable ctDNA after the second block of induction chemotherapy was associated with complete biochemical and metabolic responses after the fifth block of induction chemotherapy in 16/17 patients (94%). During a median follow-up period of 36 months (range: 8-104 months), four patients had tumor relapses, which, in all cases, were accompanied by an increase in plasma ctDNA levels and a positive F-18-FDG-PET/CT. No false-negative results were observed in the study cohort. Complete biochemical and metabolic responses after the fifth block of induction chemotherapy had a high positive predictive value for disease remission during the follow-up period; specifically, the positive predictive value was 88%. Conclusion The combination of F-18-FDG-PET/CT and ctDNA quantification is a very promising noninvasive tool for assessing treatment responses and detecting tumor relapses in children and young adolescents suffering from EwS who are undergoing multimodal chemotherapy.