High-uptake Features Of ¹⁸F-FDG And ¹⁸F-FLT In Non-small Cell Lung Cancer And Guiding Biological Target Boost

BackgroundThe morbidity and mortality of lung cancer are increasing during recent years.Non-small cell lung cancer(NSCLC)accounts for about 80-85%of all lung cancer patients.Squamous cell carcinoma and adenocarcinoma are the most common pathological types.The majority of newly diagnosed NSCLC patients have lost the chance of surgery.Radiotherapy,chemotherapy,molecular targeted therapy and biological therapy are the main treatment modalities.NSCLC is associated with short survival and poor quality of life,has become a hot topic in oncology worldwide.Radiotherapy,one of important modalities to treat tumors,has been estimated to be applied in 70%of cancer patients.Radiotherapy plays an important role in the treatment of NSCLC,and almost all of the NSCLC patients experience one or more radiation therapy,as a cure,or play a palliative role.Radiotherapy alone or in combination with chemotherapy can be applied for local control of the primary tumor and regional lymph node metastasis,and can also be used to control bone,liver,brain and other distant metastases,also can be used to reduce the clinical symptoms of local compression and pain caused by NSCLC primary tumor and metastases.Standard radiotherapy of NSCLC with 60-70 Gy is associated with a local recurrence rate of estimated 50%.Great efforts have been made to facilitate higher radiation dose under modern radiation techniques based on the clear existed association between total dose,local control and survival of NSCLC patients.However,the result of the Radiation Therapy Oncology Group(RTOG)0617 protocol was contrary to the expectation.A total of 185 institutions in the United States and Canada participated in this study.464 cases of non-resectable stage III NSCLC patients in the study were randomized to receive high-dose irradiation(74 Gy)or standard dose(60 Gy),combined with concurrent paclitaxel and carboplatin chemotherapy.The final results showed that overall survival of the high dose group was shorter than the standard dose group(20.3 months vs 28.7 months,P=0.004).The progression-free survival(PFS)of the high dose group and the standard dose group were 9.8 months and 11.8 months respectively(P=0.12).The 2-year local recurrence rate were 38.6%and 30.7%respectively(P=0.13),and the 2-year distant metastasis rate were 51.0%and 46.6%respectively(P=0.48).The incidences of grade 3 or worse toxic effects were similar in the two groups,with 79%in the high dose group and 76%in the standard dose group.It is worth noting that 8 patients in the high dose group occurred treatment related deaths,while only 3 cases in the standard dose group occurred.Compared with standard dose irradiation,increased mortality may be associated with normal lung tissue and heart injury by high dose irradiation.In addition,at 3 months of treatment,45%of the high dose group and 30%of the standard dose group(P=0.02)had clinically meaningful decline in quality of life."This is a critical study in the field of radiation oncology," commented 2013 American Society of Clinical Oncology(ASCO)President Sandra M.Swain,"After a decade of research,we can finally close the chapter on the high dose vs standard dose therapy debate in lung cancer therapy,using evidence-based data to improve care for our patients."Under the situation of higher radiation dose not performing better,radiation boost to biological target volumes(BTV)non-uniformly to improve local control,may likely bring about new hope for dose escalation to radiation-resistant sub-regions.Heterogeneity is the inherent feature of the tumor,mainly in the cells and molecular biology characteristics within the tumor,including the heterogeneity of the glucose metabolism,cell proliferation,hypoxia,epidermal growth factor receptor expression,and choline metabolism,et al.Ideal biological target delineation enables visualization of subvolumes exhibiting heterogeneous biological characteristics of pathophysiological processes within tumor volume.Functional molecular imaging technology is the common techniques to detect tumor heterogeneity.Positron emission tomography/computed tomography(PET/CT)technology is the most widely applied.Molecular probes are used as imaging tracers,which combined with specific targets inside or outside of tumor cells,and then can be detected by PET/CT imaging.Considering its high specificity and sensitivity,high image resolution,it is widely used in tumor diagnosis,staging,response evaluation,prognosis prediction and follow-up.The most commonly used PET tracer in oncology is 18F-Fluorodeoxvglucose(18F-FDG)for measuring tumor glucose metabolism 18F-FDG is a glucose analogue and is phosphorylated by hexokinase,but cannot undergo further metabolism in the glycolytic pathway.Hence,the degree of 18F-FDG uptake detected by the PET scanner reflects the level of glucose metabolism.18F-fluorodeoxythymidine(18F-FLT)has been introduced for imaging tumor cell proliferation.18F-FLT is monophosphorylated by thymidine kinase 1(TK1),which leads to intracellular trapping.The fact that overexpression of glucose transporter 1 is consistent with increased cellular proliferation,as well as increased glucose uptake and glycolytic metabolism of tumor cells laid a solid foundation for the tight linkage of glucose metabolic activity and cell proliferation,which were exhibited by PET tracers of 18F-FDG and 18F-FLT respectively.PET with single radiotracer,such as typically well-studied 18F-FDG,18F-FLT and 18F-fluoromisonidazole(18F-FMISO),have been investigated as possible dose-painting targets.Image presentation of tumor glucose metabolism and cellular proliferative activity provides relevant and complementary information for treatment choices made by radiation oncologists.Nevertheless,multi-tracer guided subvolume boost in radiotherapy is urgently in need of research. Based on the above background,we investigated the spatial distribution relationship of regional glucose metabolism and proliferation by comparing 18F-FLT and 18F-FDG uptake on PET/CT images to explore the spatial location-relation between high uptake regions determined by baseline dual PET tracers of 18F-FDG and 18F-FLT in NSCLC patients.Additionally,we planned non-uniform radiation dose boost to high 18F-FDG and 18F-FLT uptake areas with intensity-modulated radiation therapy(IMRT)as a preclinical study to explore the efficacy and feasibility of BTV boost in NSCLC patients.Part Ⅰ Overlap Ratio of High-Uptake Regions of Dual Tracer 18F-FDG and 18F-FLT in Non-small Cell Lung CancerPurposeTo investigate the spatial distribution relationship of regional glucose metabolism and proliferation by comparing 18F-FDG and 18F-FLT uptake on PET/CT images to explore the spatial location-relation between high uptake regions determined by baseline dual PET tracers of 18F-FDG and 18F-FLT in NSCLC patients.Methods1.Patient RecruitmentPatients in Shandong Cancer Hospital with histologically confirmed primary NSCLC were enrolled into the study.Patients should be anticancer treatment naive and not indicated to undergo surgery because of advanced disease or comorbidities,as well as patients’ decline.2.18F-FDG and 18F-FLT PET/CT Imaging18F-FDG and 18F-FLT were automatically synthesized by GE Minitracer Tracer Lab in Shandong Cancer Hospital.For each patient,18F-FDG PET/CT and 18F-FLT PET/CT scans were performed on separate and consecutive days.No antitumor treatment was allowed either between or before PET/CT scans.Patients lied flat within the body frame on the scanning bed.Marks were made on the body frame and the skin of patients to make sure the repeatability of 2 PET/CT scans.3.Image Fusion and AnalysisAnalysis was performed on a lesion-by-lesion basis.Maximum standardized uptake values(SUVmax)of 18F-FDG and 18F-FLT were calculated automatically in the Extended Brilliance Workspace(EBW).Fixed-percentage threshold segmentation method was performed,and 50%of the SUVmax was applied on the 18F-FDG PET/CT images.The metabolic volumes(MVs)were automatically calculated by adding up the automatic delineations on the 18F-FDG PET images in transverse section slice by slice and named MV50.On the 18F-FLT PET/CT images,50%,60%,70%,80%,and 90%of the SUVmax were used.Similarly,the proliferative volumes(PVs)(PV50,PV60,PV70,PV80,and PV90)were derived from the 18F-FLT PET images.Conventional images including contrast-enhanced CT were used to help define boundaries of MV and PV.Mean SUV(SUVmean)within MV50 and PV50 were then calculated and labeled as FDG-SUVmean50 and FLT-SUVmean50.The CT images from 18F-FDG PET/CT scanning was rigidly coregistered to the CT deriving from the 18F-FLT PET/CT scan on the same PET/CT scanner automatically,which allowed coregistration of 2 series of PET images.Overlap volume(OV)between MV and PV was delineated manually and calculated by adding up the manual delineations in fusion PET image slice by slice automatically.Overlap ratio(OR)was determined as OV/PV.OR50,OR60,OR70,OR80,and OR90 were derived from MV50 overlapping with PV50,PV60,PV70,PV80,and PV90 respectively.4.Statistical MethodsAnalysis was performed using SPSS(version 19.0;SPSS Inc,Chicago,IL).ResultsTotally 23 NSCLC patients were prospectively included and 23 primary tumors,41 metastatic lymph nodes and 15 distant lesions were included for final analysis.For a single lesion,FDG-SUVmax was larger than FLT-SUVmax,FDG-SUVmean50 was greater than FLT-SUVmean50,and MV50 was greater than PV50.The differences were statistically significant with P values of<0.001,<0.001 and 0.047 respectively.The median values of PV50,PV60,PV70,PV80 and PV90 were 4085 mm3,2355 mm3,1353 mm3,746 mm3 and 332 mm3,respectively.The median values of OR50,OR60,OR70,OR80 and OR90 were 58.61%,69.02%,79.71%,91.64%and 93.12%respectively.The differences between two adjacent groups were statistically significant(P<0.001,<0.001,<0.001 and 0.002),showing that as the threshold for PV delineating increasing;the proportion of PV contained within MV50 region was gradually increasing.Conclusions18F-FLT PET/CT may be optional during boost sub-volumes delineation because of well encompassment of high 18F-FLT uptake region within 18F-FDG-based sub-volume and little information provided for dose escalation and subsequent local control benefit.Part Ⅱ Guiding Biological Target Boost by Dual Tracer 18F-FDG and 18F-FLT in Non-small Cell Lung CancerPurposeTo explore the feasibility of BTV boost guided by dual tracer 18F-FDG and 18F-FLT PET/CT in NSCLC patients by comparing the dosimetric characteristics of conventional IMRT and simultaneous BTV boost IMRT plans.Methods1.Patient RecruitmentPatients in this part were required to meet the requirements of the first part of the study and have completed the first part of the study.The 18F-FDG PET/CT and 18F-FLT PET/CT scan images should be of good quality and high registration accuracy.2.Target DelineationThe dual series of PET/CT images of NSCLC patients were loaded into the Philips Pinnacle3 radiotherapy treatment planning software.The target delineation was performed by radiologist and clinical radiation oncologist.Definitions of conventional gross tumor volume(GTV)-CT,clinical target volume(CTV)-CT,and planning target volume(PTV)-CT followed the recommendations of the ICRU Report No.83.Four-dimensional CT was applied to define internal target volume.We defined the regions with union of MV50 and PV80 as BTV,and PTV-boost was defined by BTV along with the same individualized margin used in PTV-CT.The following organs at risk(OAR)were contoured:lungs,spinal cord,esophagus,and heart.3.IMRT PlansWe made 2 IMRT plans for each patient:conventional radiotherapy plan delineated on CT images;and simultaneous BTV boost planning with a base dose as in conventional plan and boosted dose in sub-targets that delineated on PET/CT images.4.Dose LimitationsThe prescription dose for each patient was offered individually according to the tumor stage,differentiation,combined therapy and tolerance,et al.During the planning optimization.99%of PTV-boost was required to be covered by the 95%isodose area of the boost and 95%of the PTV-CT to be covered by the 95%isodose area of the conventional radiation.Parameters and corresponding dose-limiting constraints included the following:mean lung dose≤20 Gy.lung volume receiving 20 Gy or more(V20)≤35%,lung volume receiving 5 Gy or more(V5)≤65%;maximal irradiated dose(Dmax)of spinal cord<50 Gy;mean esophagus dose ≤34 Gy,Dmax of esophagus≤105%of prescribed dose;and mean heart dose≤35 Gy,heart volume receiving 40 Gy or more(V40)≤80%,heart volume receiving 60 Gy or more(V60)≤30%.5.Evaluation of IMRT PlansThe dose volume histogram(DVH)was used to evaluate dose distribution of BTV,PTV and OARs.Tumor control probability(TCP)and normal tissue complication probability(NTCP)were calculated for both treatment plans using the LQ-Poisson-based model and relative seriality model.6.Statistical MethodsAnalysis was performed using SPSS(version 19.0;SPSS Inc,Chicago,IL).ResultsFive NSCLC patients with typical lesions were selected for dosimetric analysis.Dose per fractionation was 1.8 to 2.0 Gy for conventional PTV-CT,whereas increased to 2.5 to 2.75 Gy for PTV-boost with simultaneous integrated boost technique.Median total dose were 83.2 Gy for PTV-boost and 60.0 Gy for conventional PTV-CT,respectively.V20 of lung,Dmax of spinal cord,mean dose of lung,esophagus,and heart derived from DVH were comparable between IMRT plans.All TCP values calculated were>70%,with higher TCP values of in BTV boost plan in each patient(P=0.04).BTV-boost plan resulted in slightly higher NTCP values in comparison with conventional IMRT plans from esophagus,heart,and lung.Conclusions18F-FDG and 18F-FLT dual tracer PET/CT applied for guiding biological sub-target delineation and simultaneous boost by IMRT in NSCLC patients was feasible,with improved tumor control probabilities and without increased normal tissue complication probabilities.