The traditional method divides malignant tumors into local or locally advanced diseases and metastatic diseases. The former is suitable for local treatment and possibly curable while the latter is appropriate for the combined management of systemic and local treatment . Primary liver cancer has one of the highest incidences of malignancies and is the third leading cause of death worldwide . Since the liver receives a dual blood supply from the hepatic artery and portal vein, its blood flow is abnormally rich, making it a likely site for the growth of metastatic tumors. In addition to regional lymph node metastases, the liver is the second most prone to metastatic disease, often from primary colorectal, breast, lung, kidney, and skin cancers (melanoma) . Malignant tumors in any part of the human body can metastasize to the liver through the portal vein, hepatic artery and lymphatic pathway, or they can directly invade the liver. There were nine patients with metastatic liver cancer, most of whom had metastases from colorectal cancer, only one from lung cancer, and three with primary liver cancer in our study. For patients with inoperable primary liver cancer or metastatic liver cancer, radiotherapy, especially SBRT, has emerged as an effective, noninvasive alternative therapy . The current NCCN guidelines for colon and rectal cancer support aggressive local treatment of metastatic sites.
At present, there is no consensus on the role of PET/MRI in delineating the target area in tumors, though various methods have been proposed and used to determine the contouring of 18F-FDG-positive tissue, which has led clinician to reach different conclusions when using these methods. The visual contour method we chose with lower technical requirements is highly dependent on the observer. Therefore, three doctors with the qualification of attending physician or above were employed to identify the image, define the target area, and delineate the target volume. The average value was used as the final data. We assessed the differences and similarities between target volumes delineated on MRI, PET, and PET/MRI. Our results showed that GTV-PET/MRI was larger than GTV-MRI and GTV-PET, and GTV-PET/MRI (p = 0.021) diverged statistically significantly from the referenced GTV-MRI. The reason may be that hybrid PET/MRI integrates the anatomical-, functional-, and molecular-level information of biological tissues, which can provide more clinical correlative information and higher accuracy. A larger GTV may avoid situation in which some lesions are not contoured in the target area and, therefore, are not irradiated, which may affect the efficacy of treatment. The radiotherapy effects of target profiling based on PET/MRI are unknown. However, considering the statistically significant difference in the target volume, we have reason to suspect that this method has an impact on the therapeutic effect, which is of major importance for patients. All these findings inspire us to conduct some prospective research on the implementation of radiotherapy planning in the future studies.
Studies of other tumor locations (e.g., esophagus, lung, pancreas, head and neck) have shown that the additional biological information of PET has an effect on the variation in the GTV during radiation therapy, can reduce the risk of positioning error and influence the normal tissue dose-volume histogram and the calculation of probability values in corresponding normal tissue [15, 16, 17]. Ma, J. T. et al.  showed that GTV contouring based on hybrid PET/MRI for head and neck cancers is feasible and may provide improved accuracy. In their study, GTVVIS and GTVFUS were larger than GTVMRI with the use of hybrid PET/MRI images, which was similar to our findings, but tumor site determinations were different. While Wang, K. et al.  demonstrated that hybrid PET/MRI- and CT-generated GTVs were similar overall and supplied similar radiation doses to the head and neck. Zhang, Shaomin. et al.  reported that there were tumor volume discrepancies between GTV-MRI and GTV-PET for cervical cancer. With the increase in tumor volume, the difference between GTV-MRI and GTV-PET increased. Samolyk-Kogaczewska, N. et al.  pointed out that the primary tumor volumes with manual delineation methods from MRI, PET and CT differed slightly from each other, but the differences were statistically irrelevant. Similarly, in our study, GTV-PET (p = 0.266) was not statistically significant different from GTV-MRI. We consider that this may be related to the imaging limitations of 18F-FDG PET in liver cancer. Unlike in lung cancer patients, 18F-FDG PET has already been established to play a role in the application of target volume contouring . In addition, the artifacts caused by tumor location, anatomical boundaries, clinical situations, and patient cooperation during examination have a great impact on the quality of the contouring [22, 23].
18F-FDG, a marker of glycolysis in cells, has a short half-life, high imaging spatial resolution, and excellent nuclear and chemical features , which make it the most widely used radioactive tracer for PET. After 18F-FDG is transported across the cell membrane by glucose transporters (GLUTs), it is subsequently phosphorylated by hexokinase subsequently, which is the same as what occurs during glucose metabolism. As cancer cells exhibit high glycolysis rates, the uptake of 18F-FDG in cancer tissues is increased . Thus, 18F-FDG reflects the glucose metabolism of tumor tissue, and has demonstrated enhanced value in the diagnosis, staging, appraisal of prognosis and efficacy evaluation of malignant diseases .
In moderately and well-differentiated hepatocellular carcinoma (HCC), studies have confirmed that high FDG-6-phosphatase activity, high expression of p-glycoprotein, and low expression of GLUT1 or GLUT2 lead to low uptake of 18F-FDG. High levels of FDG-6-phosphatase hydrolyze intracellular FDG-6-phosphate into FDG, which is then transported outside the cells. P-glycoprotein acts as an efflux, and its high expression of it also transports more FDG out of the cells. GLUT1, GLUT3, and GLUT12 are involved in the transport of 18F-FDG into cancer cells , and their low expression reduces the uptake of FDG. All these factors contribute to a lower accumulation of FDG in HCC.
In cholangiocellular carcinoma (CCC) tumor cells, glucose uptake and metabolic mechanisms are different from those in HCC, although both are glucose energy sources. The low glucose-6-phosphatase (close to zero) and significantly higher expression of GLUT1 than that in normal liver tissues were related to 18F-FDG metabolic concentration foci in CCC [27, 28].
In liver metastatic tumor cells, due to the low level of dephosphorylation in cancer cells, the metabolism of 18F-FDG in liver metastases was significantly higher than that in surrounding normal liver cells, and the sensitivity of PET scanning for metastases was higher . The pathological types of liver cancer we included varied, and these may be factors affecting the results.
The range of DSC is 0–1. The value is 0 when there is no spatial overlap between imaging methodologies, while it is 1 when they completely overlap. Higher the DSC values indicate better coincidence degrees. Some scholars have noted that a DSC value ≥ 0.7 indicates a better degree of overlap , suggesting that DSC may be highly correlated with the change in volume but less correlated with the change in target shape. Our results show that the DICE index between GTV-MRI and GTV-PET/MRI—0.76—is higher, and the average DSC values were above 0.7. The the DSC value between GTV-PET and GTV-MRI was 0.45, lower than 0.7, which may be related to the low spatial resolution of PET data.
Future studies on tumor volume delineation based on PET/MRI may benefit from more advanced technology such as MR-linac, novel radioactive tracers and 4D-PET. For example, studies are ongoing to investigate the impact of MR-linac on liver SBRT planning [31, 32, 33]. On conventional linacs, based on X-ray-based image guidance, liver lesions are often poor or invisible in this pattern of images; thus, the injection of contrast material, or the implantation of markers is needed address this issue. An advanced treatment device, the Unity MR-linac, with the excellent soft-tissue contrast offered by the integrated MRI, may lead to margin reductions, better organ-at risk (OAR) sparing or dose escalation, and it can enable the use of liver SBRT without invasive fiducial markers.
Moreover, with the deepening of research, recent PET tracers such as 11C-acetate and 11C/18F-choline have attracted much attention from researchers in recent years. As a metabolic precursor of phospholipid synthesis, both of them have been used as a supplement to 18F-FDG PET imaging of well-differentiated HCC with improved values of sensitivity and specificity compared with those of other tracers[34, 35, 36].
Furthermore, during the process of PET/MRI image acquisition, images will be affected by motion artifacts due to breath-hold, which may lead to the underestimation of lesion uptake and to the possibility of missing small lesions . During normal respiratory movement, organs can undergo displacements of up to 2 cm [18, 19], and the liver is particularly vulnerable to respiratory motion. Considering that liver SBRT is a very precise treatment technique in regard to the tissue exposed to radiation toxicity, any procedure designed to make radiotherapy planning more precise is of particular interest. Respiratory-gated PET (4D–PET) has been proposed as one of the approaches to address these issues . Compared with non-gated PET, respiratory-gated PET can improve the image quality and lesion detectability of liver targets and assess the target volumes with increased accuracy . More appropriate irradiation of the liver volume may improve the safety and effectiveness of SBRT. Therefore, it will become a valuable tool to improve SBRT planning for liver cancer in the future.
This study had a certain limitation. We included a relatively small number of patients. For a more specific and accurate investigation of the advantages of PET/MR, a larger sample size is required.
Taking into consideration our experience in liver cancer and studies of other cancers, we believe that delineation based on hybrid PET/MRI for liver cancer radiation therapy is worth considering. Further prospective studies in this and other settings are needed to assess the optimal use of PET/MRI for target volume contouring.