In this study, among four 18F-FDG PET/CT metabolic parameters, TLG showed a significant correlation with lymph node metastasis and the longest tumor diameter. Univariate analysis showed MTV, TLG, radiotherapy dose, and chemotherapy as significant prognostic factors for OS and PFS. However, lymph node metastasis and the longest diameter of the tumor were prognostic factors only for OS. In the Multivariate analysis, for LAPC patients treated with SBRT by Cyberknife, TLG, radiotherapy dose and chemotherapy were demonstrated as the independent prognostic factors for OS and PFS.
Although current research on the LAPC potential prognostic markers has reached the molecular level, such as tissue biomarkers, epigenetic markers and blood markers, including circulating tumors, few of them have been clinically recognized [12,13,14]. PET/CT is a technique integrating functional imaging together with anatomy imaging, which has been widely applied in the prognosis of various malignant tumors. SUVmax, as the most commonly used semi-quantitative index in FDG PET/CT, is still controversial in LAPC prognosis assessment. Several previous studies confirmed the prognostic role of SUVmax in LAPC and suggested that the higher the pre-treatment SUVmax value of the primary lesions, the poorer the prognosis [8, 15]. Schellenberg et al.8 also found in a univariate analysis that the metabolic burden of the primary pancreatic tumor (similar conception to MTV) was prognostically related, but only SUVmax was an independent prognostic factor. However, SUVmax only represents the highest metabolic activity within tumor lesions and is easily affected by noise. At the same time, SUVmean is calculated from the average SUV value of the entire tumor, normally varies between different operators. Moreover, SUVmean can not reflect the internal metabolic characteristics of tumor. A recent study carried out by Dholakia et al. [16] found that SUVmax was not an independent prognostic factor for LAPC, while MTV and TLG were proved to be independent factors in LAPC prognostic value. LAPC patients with higher MTV or TLG led to poor prognosis. Similar to our study, in which SUVmax and SUVmean were found not significantly associated with PFS or OS.
MTV refers to the volume of tumor tissue, whose FDG uptake exceeds a certain threshold (40% of SUVmax in this study). TLG represents the metabolic activity and metabolic volume of the tumor tissue. Compared to SUV, MTV and TLG have advantages in reflecting the tumor metabolic burden. Thus, MTV and TLG could provide a more accurate prognostic value. In recent stuides, TLG was considered as a much better indicator than MTV in prognosis evaluation [17]. It is conceptual understandable that TLG gained favour. As the product of SUVmean and MTV, TLG not only reflects the tumor volume [18], but also shows the abnormal level of metabolism inside the tumor tissue. Furthermore, TLG was proved to be strongly correlated with clinical factors, which was not showed in other metabolic parameters. Chong et al. [19] reported TLG was significantly correlated with CA19–9 level in patients with resected pancereatic cancer. Further proved the advanced oncologic prognostic value of TLG. Choi et al. [20] retrospectively analyzed 60 patients with LAPC and found the pre-treatment MTV value was an independent prognostic factor for both PFS and OS. At the same time, TLG was an independent prognostic indicator for PFS. In addition, the disease control rate (DCR) was significantly higher among LAPC patients with low MTV or TLG value. Similar results were found by our previously published work [11], in which 23 LAPC patients received chemo-SBRT combined therapy were included. And MTV was proven to be an independent prognostic factor for OS. In the current study, with a wider inclusion criterion and a larger group of research samples, both MTV and TLG are proved to be associated with PFS and OS by univariate analysis. Further tested by multivariate analysis, only TLG was an independent prognostic factor for OS and PFS. We divided TLG into 4 groups based on its quartile, and further analyzed the relationship between TLG and OS with Cox proportional hazards model. Although all the p values were > 0.05, the trend of higher TLG value lead to poorer prognosis could also be indicated from the analysis. The insignificant result might be related to the limited patients included in the study. Compared to our last study, the difference in analytical results may be caused by inclusion criteria. Not only LAPC patients received chemo-SBRT combined therapy were included, but also LAPC patients treated with SBRT only were enrolled in this research. Additionally, only 23 patients were analyzed in the previous study, the number was broadened to 73 patients in this study. And the difference in patient numbers may be another reason leading to the discrepant results.
As mentioned above, although a number of previous studies have discussed the prognostic value of MTV and TLG in LAPC patients, all came up with various results [16, 20]. This could be caused by different inclusion criteria, especially variable treatment options. Research carried out by Dholakia et al. [16] included 32 LAPC cases underwent SBRT, among which 27 of 32 cases were pre-treated with 1 cycle of gemcitabine-based inducing chemotherapy. In another study performed by Choi et al. [20], all 60 LAPC patients were treated with gemcitabine-based chemotherapy combined with SBRT. In our study, 73 cases of LAPC were treated with SBRT, 23 cases of which were combined with chemotherapy. Additionally, the disprepant results might also arise from unstandardized MTV delineation. The commonly used methods for MTV delineation are relative threshold method, multiple SUV absolute threshold method and gradient threshold method. A phantom study suggested that 40–50% of SUVmax could maximally delineate the actual tumor lesion [21]. Currently, the mainstream measurement methods of MTV include fixed SUV value, based on threshold and algorithm-based. MTV measured based on thresholds performed well in prognosis evaluation in several studies [22,23,24], and the method is simpler than algorithm-based. Because of tumor heterogeneity, the metabolic level of pancreatic cancer can be varied individually. When the metabolism level of pancreatic cancer is low, the fixed SUV thresholds may have a larger risk of underestimating the actual tumor volume, which will bias the results with false negative errors. Therefore, the method of MTV measurement based on threshold was applied in this study. However, if the threshold of MTV is too low, it is easy to cause an over-high background. If the threshold of MTV is too high, it may underestimate the tumor volume, and even cause partial volume effects. According to the research carried out by Dholakia et al. [25], MTV was calculated at 40% of the SUVmax value. In addition, our previous study [11] also found that MTV assessed based on a threshold of 40% was an independent prognostic factor for LAPC. For the later researches, the standardization of SUV threshold should be improved to widen the application of FDG PET/CT volume parameters in disease prognosis.
Despite the value of TLG in the prognostic assessment of SBRT treated LAPC patients, our study also showed that chemotherapy was an independent prognostic factor for PFS and OS. With chemotherapy, the survival duration of PFS and OS could be improved, which reconfirmed the role of chemotherapy in LAPC treatment [26, 27]. To date, the CRT remains to be a recommended treatment plan for LAPC patients, though the role of traditional radiotherapy was controversial. In order to offer a better treatment option, several clinical trials tried to compare the survival rates between single chemotherapy and CRT in LAPC patients, ending up with contradictory results [26, 27]. In recent years, Cyberknife therapy has been recognized by the American Society of Clinical Oncology to have a role in LAPC treatment [3]. As a newly improved SBRT equipment, the Cyberknife has been applied for LAPC treatment, and the value has been verified by several studies, as well as in our study [4, 5, 28]. It was found that the PFS and OS of LAPC patients received a higher radiotherapy dose (> 64.4 Gy) was significantly longer than those receiving a therapeutic dose (≤64.4 Gy). Similar results were found by Gurka et al. [29]. Therefore, for LAPC patients with high pre-treatment TLG, if the basic conditions and chemo-tolerance allowed, we suggested a combination treatment of chemotherapy and high radiotherapy dose improve prognosis.
There are limitations to this study. First, Considering of the defects of retrospective study, the follow-up plan was not highly standardized, which limited the robustness of PFS. In addition of censored data and selection bias. The confidence intervals in this study were not ideal, which may due to the limited number of patients limited. To get a more precised result, a randomized controlled prospective with a large sample size needs to be performed in the future work. Secondly, some images presented with diffuse uptake because of obstructive pancreatitis, it was difficult to clearly contour the tumor lesions, which might affect the measurement of MTV. Thus, ceCT and MRI images were used to help define tumor tissue. However, as ceCT and MRI and PET/CT scans were performed by different machines, there may be some deviation in the image matching. More effort will be paid and Co-scans could be performed in future work to improve the accuracy of tumor delineation. All patients underwent a ceCT scan or a MRI scan before radiotherapy, and the images were used to help differentiate pancreatic inflammatory from tumor.