Increased 18F-FDG uptake occurs not only in tumor cells with upregulated glucose transporter but also in the inflammatory process of normal tissue with cellular hypermetabolism (25). In recent years, several studies used 18F-FDG PET/CT to assess and quantify the inflammation of lung tissue after RT for thoracic cancers (19, 26). Our study successfully assessed lung inflammation between HD and LD regions by integrating 18F-FDG PET/CT with VBA in EC patients undergoing dynamic arc-based RT. We found that the SUVmax, SUVmean, and GLG increased significantly in the HD regions of RP lungs between pre- and post-RT. The present study indicated that post-RT SUVmax > 2.28 and the lung V5 > 47.14% could be a predictor for RP.
Several studies demonstrated that 18F-FDG PET/CT could be used to evaluate RP after RT (2, 27, 28). Yue et al. (22) found that the changes of SUVmax, SUVmean, and GLG in lungs could detect the severity of RP during the first 6 months after treatment. Abdulla et al. (11) indicated that SUVmean and GLG in lung parenchyma could be the potential biomarkers to quantify RP after thoracic RT in lung cancer. De Ruysscher et al. (29) found that the SUVmax highly correlated with clinical radiation-induced lung toxicity during the first week of thoracic RT. In the abovementioned studies, the analysis of VOIs was divided into the affected lung, the non-affected lung, or the global lung volume to measure the metabolic response. However, the non-affected lung would still receive low-dose radiation ≧ 5 Gy during RT for lung cancer and EC. Numerous studies reported that the lung V5 might reach as high as 40 to 60% in EC, which indicated that 40 to 60% of the lung volume might receive absorbed doses ≧ 5 Gy. Low-dose radiation could be a significant predictor of RP (14, 15, 30). Based on the VBA (17), the present study used the 5 Gy isodose curve to distinguish HD (≧ 5 Gy) and LD (< 5 Gy) regions in the lung volume to assess the relationship between metabolic response and absorbed dose. There were statistically significant increases in the SUVmax, SUVmean, and GLG of HD regions between pre- and post-RT. Furthermore, we found that there were no statistically significant increases in the SUVmax, SUVmean, and GLG of LD regions between pre- and post-RT.
Researchers have found that radiation-induced lung inflammation after the lungs received higher radiation doses (13, 31). Radiographically evident changes are uncommon when the total radiation dose delivered is less than 30 Gy, but they are almost always seen with doses higher than 40 Gy (32, 33). Furthermore, Zhang et al. (34) showed that there was a significant difference in the SUVmean of the lungs between with or without RP group received more than 35 Gy for non-small cell lung cancer patients. It should be noted that several studies had evaluated patients with symptomatic RP (≥ grade 2) and asymptomatic RP by using volume-based 18F-FDG PET (22, 34). Yue et al. (22) found the cut-off value of SUVmax, SUVmean, and GLG were 4.54, 0.78, and 2295 after RT predicted later development of symptomatic RP (≥ grade 2). The present study found that there were significant differences between pre- and post-RT SUVmax, SUVmean, and GLG of the HD regions in the RP lungs. We found the optimal cut-off value of post-RT SUVmax, post-RT SUVmean, and post-RT GLG were 2.28, 0.56, and 287.65 for prediction of RP, respectively. The cut-off value of this study was lower than those of Yue et al. The main reason was probably that we aimed to detect asymptomatic RP (≥ grade 1) while they detected symptomatic RP (≥ grade 2). Therefore, the cut-off value might be more sensitive to detect asymptomatic RP. Our study showed that post-RT SUVmax with the highest AUC has a sensitivity of 80% and a specificity of 86.36%. The post-RT SUVmax > 2.28 could be used as an early predictor for RP with grade ≥ 1.
It is common to assess the relation between radiation absorbed dose and the risk of symptomatic RP. Graham et al. (35) indicated that the incidence of ≥ grade 2 RP was associated with the V20. Tonison et al. (36) found that the lung V20 should be kept below 23% to decrease the incidence of symptomatic RP. Wang et al. (15) demonstrated that the lung V5 was highly related to the risk of RP, and the risks of V5 < 42% and V5 > 42% causing RP within 1 year were 3% and 38%, respectively. Pinnix et al. (14) noted that a lung V5 exceeding 55% was associated with the maximum likelihood ratio for RP. Jo et al. (37) showed a statistically significant association between the development of grade 2-3 RP and pulmonary dosimetric parameters, including lung V5, V10, V15, V20, V25 and MLD. The AUC value was highest for V5. However, we evaluated changes of lung dose and metabolic response in patients with ≥ grade 1 RP versus nRP to detect the presence of RP at the earlier stage. The results of the present study revealed that there were significant differences between RP and nRP in the MLD, lung V5, and lung V10. However, there were no significant differences for lung V15, V20, and V25. The lung V5 has the highest AUC, with a sensitivity of 60.00% and specificity of 81.82% similar to the results of the previous study. We recommend limiting the V5 to ≦ 47.14% to decrease the incidence of the ≥ grade 1 RP. Additionally, it was feasible to distinguish the HD and LD regions to assess RP by the 5 Gy isodose in our study.
There were some limitations in this study. First, this study was a retrospective pilot study, and we only analyzed the existing clinical data. Most EC patients did not regularly have 18F-FDG PET/CT scans within 3 months after RT, which resulted in the relatively small sample size in this study. Second, the interval time between completion of RT and post-RT PET/CT scan ranged from 21 days to 89 days. The degree of metabolism may present in different stages of the inflammatory process. Third, the two PET/CT scans were performed before and after the RT treatment. Therefore, the lung volume might change in different PET/CT scans, somehow leading GLG to change. Last, the fusion and registration of simulation CT images and PET/CT images were based on the experience of the operators in this study. There might be some discordances in the manual operation. Therefore, further prospective studies with more patients are needed to verify our results.