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  • To date the biological behavior aggressiveness of tumor as


    To date, the biological behavior/aggressiveness of tumor as measured by cfDNA levels and metabolic tumor burden measured by PET/CT scan correlate with survival in advanced NSCLC patients [16,17]. However, the significance of the levels of cfDNA and the metabolic tumor burden in identifying patients who need more aggressive treatment is still poorly understood. The objective of this prospective trial was to evaluate these clinical implications to assess prognosis in advanced NSCLC patients.
    Materials and methods
    Discussion Since circulating cfDNA is postulated to be released from tumor lysis and necrosis in the tumor microenvironment, measurement of cfDNA levels is a promising method for assessing the biological behavior/aggressiveness of the tumor [21,22]. To date, high cfDNA levels have been associated with poor prognosis in NSCLC patients [8,23,24]. Numerous studies, including the recent meta-analysis (17 studies with 1723 patients), have shown poor survival outcome in patients with high-cfDNA compared to those with low-cfDNA levels [13]. The utilization of MTV and TLG levels from FDG PET/CT scanning offers a precise estimation of the metabolic tumor burden, theoretically [25,26]. Previously, an MTV risk POM 1 system was reported to have prognostic value independent of the clinical stage and other prognostic variables in NSCLC [27]. However, the clinical importance of the biological behavior/aggressiveness of the tumor as measured by quantifying cfDNA and metabolic tumor burden has not been well established. In the present study, we observed that the cfDNA levels were correlated with metabolic tumor burden as assessed by MTV and TLG in NSCLC patients. In other words, patients with a higher metabolic tumor burden were likely to have higher cfDNA concentration. To date, only two studies have evaluated the relationship between cfDNA levels and metabolic tumor burden in NSCLC. Nygaard et al. demonstrated the relationship between cfDNA levels and MTV or TLG in 53 stage III-IV NSCLC patients [16]. They reported that the level of cfDNA did not correlate with MTV and TLG levels. Morbelli et al. also reported similar results in 37 stage III-IV NSCLC patients [17]. Quantitative analysis was used in a recent study to show that increased cfDNA correlated with the number of metastatic sites and lesions, and the sum of measurable lesion diameters in 64 NSCLC patients with EGFR mutations [28]. Although both MTV and TLG are concordant with cfDNA levels, their clinical implications on NSCLC prognosis are quite different. Our study indicated poor OS in high-MTV or -TLG patients. Consistently, previous studies have reported that high baseline metabolic tumor parameters were independently associated with survival in NSCLC [[29], [30], [31]]. Chen et al. (105 stage I-IV NSCLC patients) and Zaizen et al. (68 stage III/IV NSCLC patients) reported that high TLG was associated with poor OS [29,30]. Liao et al. also showed that the highest tertile-MTV and -TLG patients had poorer OS than those of the lowest tertile in 169 stage I-IV NSCLC patients [31]. In summary, the results of Centrosomes study provide initial support for the clinical implications of tumor biological behavior/aggressiveness, measured by cfDNA quantification and metabolic tumor burden according to MTV/TLG using FDG-PET/CT scans, for the survival of patients with advanced NSCLC. We recommend that metabolic tumor burden should be initially considered for the therapeutic strategy for advanced NSCLC patients. High-MTV or high-TLG were associated with poor prognosis, and these patients would need more aggressive treatments, regardless of the biological behavior/aggressiveness of the tumor. The next consideration is tumor biologic aggressiveness/behavior. We identified that low-cfDNA and low-MTV or low-TLG showed a better prognosis than low-cfDNA and high-MTV or high-TLG. (Fig. 4) Therefore, our results suggest that monitoring cfDNA quantification as an early, accessible biomarker to identify patients with low metabolic tumor burden and who need more aggressive treatment strategies may be effective in informing treatment regimens.