Measuring Tumor Cell Proliferation And Hypoxia And Predicting Clinical Response With ¹⁸F-FLT PET And ¹⁸F-FETNIM PET During Radiotherapy Of Esophageal Squamous Cell Carcinoma: A Pilot Clinical Study

Part IMeasuring Tumor Cell Proliferation and Predicting Clinical Response With 18F-FLT PET During Radiotherapy Of Esophageal Squamous Cell Carcinoma:A Pilot Clinical StudyPurpose: Radiation therapy (RT) plays an important role in the treatment of locally advanced esophageal cancer. Treatment effectiveness may be limited by accelerated repopulation of clonogenic tumor cells. The aim of the study are to measure tumor cell proliferation during radiotherapy (RT) of squamous cell carcinoma (SCC) of the esophagus with serial 18F-3’-deoxy-3’-fluoro-L-thymidine positron emission tomography(18F-FLT PET/CT) and evaluate whether 18F-FLT PET can predict clinical response to concurrent chemoradiotherapy(CCRT) as early as one week after the initial of treatment.Methods:Thirty-two patients with inoperable locally advanced SCC of esophagus underwent serial 18F-FLT PET/CT scans during RT. Each patient received a pretreatment scan, followed by 1-3 scans after delivery of 2Gy,6Gy,10Gy,20Gy, 30Gy,40Gy,50Gy or 60Gy to the tumor. Among them,19 cases received CCRT with pretreatment and after delivery of 10Gy and 20Gy scans. PET data were correlated with clinical response for the 19 cases.Results:Among the 29 patients who completed RT without interruption, parameters reflecting 18F-FLT uptake in tumor (e.g., Maximum tumor standardized uptake value [SUVmax], proliferation target volume [pTV]) decreased steadily with increasing doses. All patients demonstrated almost complete absence of proliferating esophageal tumor after 30Gy and complete absence after 40Gy. In the 2 patients whose RT courses were interrupted, 18F-FLT uptake in tumor increased compared to before the interruption after 2Gy and 46Gy respectively. Marked early reduction of 18F-FLT uptake in irradiated bone marrow was observed in all cases, even after only 2Gy. All demonstrated complete absence of proliferating marrow in irradiated regions after 10Gy. Both patients who underwent scans after completing the entire RT course showed no tumor uptake on 18F-FLT PET, but high uptake on 18F-fluoro-deoxy-glucose (18F-FDG) PET. Pathologic examination of these regions revealed inflammatory infiltrates but no residual tumor. For the 19 patients with CCRT, the decrease of pTV between pretreatment and after delivery of 10Gy and 20Gy scans showed significant correlation with clinical responsewith logic regression analysis (p=0.033 and 0.023 respectively) and demonstrated significant prediction for clinical response with ROC curve analysis (p=0.001 and 0.005 respectively)Conclusions:18F-FLT uptake can be used to monitor the biological response of esophageal SCC and normal tissue to RT. Increased uptake of F-FLT following treatment interruptions may reflect accelerated repopulation. F-FLT PET may have advantages compared to 18F-FDG PET at differentiating inflammation from tumor. 18F-FLT PET may help oncologists predict treatment response as early as one week after the beginning of treatment and estimate clonogenic repopulation during RT.PartⅡMeasuring tumor hypoxia with 18F-FETNIM PET in esophageal squamous cell carcinoma:a pilot clinical studyPurpose:Radiation therapy (RT) plays an important role in the treatment of locally advanced esophageal cancer. Treatment effectiveness may be limited by tumor hypoxia, which is associated with increased aggressiveness, enhanced metastatic potential and poor prognosis. Hypoxia imparts radioresistance among tumor cells and is believed to be an important cause of local failure following concurrent chemoradiotherapy (CCRT). The purpose of this study was to evaluate hypoxia in esophageal squamous cell carcinoma (SCC) with 18F-fluoroerythronitroimidazole positron emission tomography(18F-FETNIM PET). We determined an imaging threshold for hypoxia, quantified the spatiotemporal variability of hypoxia in untreated tumor, and evaluated the ability of 18F-FETNIM PET to predict clinical response following CCRT.Methods:Twenty-eight consecutive patients with inoperable SCC of the esophagus were consecutively accrued between April 2007 and June 2010. The first 10 patients received two pretreatment 18F-FETNIM-PET scans on separate days. The remaining 18 patients only underwent 18F-FETNIM-PET once before CCRT. The ratio of the maximum standardized uptake value (SUVmax) of 336 normal tissue regions (i.e., heart, lung, brain or muscle) to the mean standardized uptake value (SUVmean) of the respective patient’s spleen was calculated, and the imaging threshold for hypoxia defined as the level of uptake demonstrated by less than 5% of tissue regions. Among the patients with two pretreatment scans, each pair of scans was compared with respect to location and intensity of uptake to assess for baseline spatiotemporal variability. Logistic regression analysis was used to determine whether pretreatment imaging characteristics are predictive of clinical response.Results:The mean and median ratios of the SUVmax of tissue:SUVmean of spleen were nearly identical, and 95% of the ratios fell below 1.3. The mean Dice similarity coefficient for the hypoxic volumes on pretreatment PET scans acquired in the same patient on different days was 0.12 (range,0.05-0.21). Individuals’tumor SUVmax and SUVmean did not vary significantly, but on average, the geometric centers of hypoxic regions shifted 15 mm (range,8-20 mm) from the first pretreatment scan to the second. SUVmax was the imaging characteristic most predictive of treatment response (p=0.041), with high SUVmax associated with poor clinical response.Conclusions:18F-FETNIM PET can depict hypoxia in esophageal SCC. Prior to CCRT, tumor hypoxia demonstrates spatial variability on different days, though overall 18F-FETNIM uptake remains similar. Baseline SUVmax may be predictive of treatment response.