Baseline clinical characteristics of two cohorts’ patients after cases selection
From April 2011 to December 2015, a total of 185 patients with unresectable CRLM were enrolled in our study, including 101 patients receiving first line chemotherapy plus bevacizumab (beva cohort), 84 patients receiving first-line CMT (CMT cohort). Their age range was 24–81 years and their median age was 59 years. The medians for size, CEA (carcinoembryonic antigen), CA199 (Carbohydrate antigen 199), primary SUVmax and metastatic SUVmax were 4.1 cm, 28.0 ng/L, 91.4 ng/L, 11.6 and 9.9, respectively. Details of other clinical data were demonstrated in Table 1. Table 1 also showed that there is no difference between two groups for gender, age, primary site, ECOG score, number of metastatic site and distribution of liver metastasis.
Correlation between SUV and clinical characteristics
11.6 of primary lesion SUV, 9.9 of liver metastatic lesion were regarded as the cut-off value of primary and metastatic SUV (median value), respectively. Besides, metastatic SUV which is larger than primary lesion SUV was regarded as elevation of SUV. Table 2 demonstrated Chi-square test of clinical correlation between SUV and clinical characteristics. Higher primary SUV was significantly correlated with larger primary tumor size (P=0.000), while metastatic SUV was related with the status of number of metastases and metastatic tumor size (P=0.000). No statistical difference was observed among different Age level, gender group, primary sites, CEA, CA199 level, distribution of liver metastasis (P>0.05).
SUV was clinically correlated with treatment response
Details of treatment response were listed in Table S2, overall objective response rate (ORR) and optimal response rate was 41.6% and 25.9%, respectively. For different treatment protocol cohorts, CMT patients demonstrated a higher rate of progressive disease (PD) rate than beva cohort patients (P=0.014); there is no difference between two cohorts for partial response (PR) and stable disease (SD). Furthermore, to evaluate next efficacy of RECIST and morphologic status on prognosis, among the 185 patients, those with optimal response by morphologic criteria had better overall survival than patients with incomplete or no response in beva cohort, with median overall survival of 37 months (95% CI, 28.8-39.2 months) and 25 months (95%CI, 21.4-28.6 months), respectively (P<0.001, Figure S2 (A)). In contrast, response by RECIST was not associated with an improvement in survival in this group (Figure S2 (C)). In addition, Figure S2 (D) also demonstrated that there is no statistically significant difference for duration of OS between optimal group and no optimal group in CMT cohort (P>0.05), while RECIST criteria was more suitable for evaluating response in CMT cohort (P<0.05, Figure S2(B)). To analyze correlation between SUV and treatment response, details of different treatment cohort have been constructed to demonstrate the statistical correlation of separately primary lesion SUV, metastatic lesion SUV and SUV gap between metastatic and primary lesion (Table 3). Compared to primary and metastatic lesions SUV, the gap was determined to have a significant relation with treatment response in both cohorts through different evaluation criteria.
PET-CT SUV were significantly related with PFS and OS
Totally, primary SUV was not a significant prognostic marker for PFS (median survival months: 7.0 months versus 6.0 months, P=0.38, hazard ratio [HR]=1.142, 95%CI: 0.846-1.604). In contrast, higher metastatic lesion SUV (P=0.01) and elevation of SUV (P=0.008) were regarded as a significant factor for PFS. In terms of OS, patients with higher primary lesion SUV had worse survival outcome than patients with lower primary SUV (median survival months: 33.0 months versus 21.0 months, P=0.01, HR=1.799, 95% CI: 1.150-2.816), while metastatic lesion SUV was also regarded as a prognostic factor for OS (median survival months: 35.0 months versus 19.0 months, P<0.001, HR=2.512, 95%CI: 1.605-3.932). Besides, elevation of SUV between metastatic and primary lesion was demonstrated to be a significant OS-related factor with higher HR (P<0.001, HR=3.330, 95%CI: 2.126-5.213). To further determine the prognostic efficacy of primary, metastatic SUV and SUV elevation, C-index of three OS-related prognostic models were evaluated. The performance of elevated SUV model was statistically better than primary SUV (C-index: 0.688 versus 0.638, P<0.001) and metastatic SUV level (C-index: 0.688 versus 0.568, P<0.001). Details were shown in Figure 2.
Furthermore, data of all patients were included in univariate and multivariate analysis, which was demonstrated in Table 4. From multivariable analysis of OS, CEA level (P=0.031, hazard ratio [HR]= 1.461; 95% confidential interval [CI]: 1.063-1.795), CA199 level (P=0.029, HR=1.806; 95%CI: 1.062-3.072), SUV elevation status (P=0.000, HR=2.863; 95%CI=1.645-4.981) and metastatic tumor size (P=0.012, HR=1.631; 95%CI=1.211-2.087) were regarded as independent risk indicators for tumor OS.
PET-CT SUV as a predictive factor for bevacizumab therapy in CRLM
As the PET SUVmax value was often a reflection of metabolic ability on the hepatic and primary lesions, an elevated metastatic SUV may reflect a more progressive tumor metabolic ability. To confirm this hypothesis, we created another two internal controlled groups: high risk group (with elevated SUV) and low risk group (without elevated SUV). Among high risk group, our data showed that patients receiving the CMT plus bevacizumab has reached a longer duration of PFS (median survival months: 7.0 months versus 5.4 months) and OS (median survival months: 25.0 months versus 18.0 months) than patients receiving CMT only (P<0.05); similar results cannot be reached in the low risk cohort, demonstrating that patients with an elevated SUV should receive a combination treatment of CMT and bevacizumab. Details were shown in Figure 3.