| Lung cancer is the leading cause of cancer death in both men and women worldwide. Every year, an estimated1,350,000patients are diagnosed and1,200,000died from this disease, with15%-20%of these patients expected to have small cell lung cancer (SCLC). Although non-small cell lung cancer (NSCLC) is the most common type of lung cancer, SCLC generally has a more rapid doubling time, a higher growth fraction, and earlier development of widespread metastases. SCLC is highly sensitive to initial chemotherapy and radiotherapy; however, most patients eventually die of recurrent disease. Better knowledge of the biological background of tumors and the availability of new drug and technologies offer oncologists the possibility to develop a more personalized treatment of cancer not only on an anatomical basis but on a molecular basis as well. However, everyday practice points out several clinical questions for many oncologists. For example, how to select patients who have a better prognosis could influence treatment decisions, how to potentially reduce therapeutic toxieity with the ultimate goal of improving survival, and so on. Considering all these clinical questions, molecular imaging may be a potential new tool for cancer patient’s care.Positron emission tomography (PET) is the most sensitive and specific technique for imaging molecular pathways in vivo. PET uses positron-emitting radionuclides to label molecules, which can then be imaged in man. The inherent sensitivity and specificity of PET methodology is the major strength of technique. PET can image molecular interactions and pathways, providing quantitative kinetic information down to the subpicomolar level. PET/CT, which is combined by PET and CT, now is becoming the most useful molecular technology and play an important role in tumor diagnosis, treatment monitoring and prognosis evaluation. Part One Metabolic Parameters Measured by F-Fluorodeoxyglucose Positron Emission Tomography/computed Tomography early predict response and prognosis in Patients with Small Cell Lung CancerCurrently, tumor stage is the most important prognostic factor of SCLC. The Veteran’s Administration Lung Group two-stage classification scheme is routinely used to define the extent of disease in patients with SCLC, which divides SCLC into limited disease (LD) and extensive disease (ED). Despite its practical usefulness and prognostic advantage, the two-stage system is not accurate enough to reflect tumor burden, and it is inadequate for predicting survival in some patients. Therefore, more reliable prognostic markers, which might more properly represent tumor burden, would be needed to further stratify risk groups with the goal of developing individualized therapy strategies.PET or fused PET/CT imaging using the tracer18F-fluorodeoxyglucose (18F-FDG) has emerged as an essential imaging tool for staging lung cancer. Recently, the degree of tumor uptake of’F-FDG on PET as measured by standardized uptake value (SUV) was shown to be an important prognostic factor in lung cancer. Metabolic tumor volume (MTV), defined as the volume of tumor tissues with increased F-FDG uptake, also has been reported is an important independent prognostic factor in esophageal carcinoma and head-and-neck cancer. Furthermore, La et al reported that the integrated SUV (iSUV), defined as the product of MTV and average SUV (SUVmean), was related to disease free survival (DFS) of patients with head-and-neck cancer. Xie et al observed the similar results using "metabolic index" to predict long term survival of patients with nasopharyngeal carcinoma.In this study, we evaluated the ability of MTV, iSUV, SUVmeanand SUVmax measured in pre-treatment18F-FDG PET/CT to predict survival in patients with SCLC treated by chemotherapy alone or with concurrent radiotherapy. Moreover, we conducted this study to determine whether the incorporation of some PET/CT parameters into the conventional two-stage classification system is more accurate for predicting survival than the tumor stage alone in patients with SCLC.Purpose3. To evaluate the prognostic significance of some metabolic parameters measured by 18F-FDG PET in patients with SCLC4. To determine whether F-FDG PET parameters can early predict chemo-radiation eificacyofSCLC.Methods1. We retrospectively reviewed the medical records of all127patients with histologically or cytologically proven SCLC who underwent pre-treatment18F-FDG PET/CT scanning at Shandong Cancer Hospital and Institute, Jinan, China, between October2002and February2009.98patients met inclusion criteria formed the cohort analyzed in the present study.2. Treatment of SCLC patients Patients with LD underwent concurrent chemo-radiation, which consisted of4-6cycles of chemotherapy and thoracic radiotherapy. Both LD and ED patients underwent combined chemotherapy with EP or CE regimen as the first-line treatment.3.18F-FDG PET/CT imaging All patients fasted and rested for at least6h before undergoing PET/CT. To define the contouring margins around the target lesions, SUV2.5was used as previously reported, which means that the PET area was delineated by a circle encompassing regions equal or greater than SUV2.5. The MTV of each slice was then determined by multiplying the area within the threshold margin by CT interval. Finally, after all hypermetabolic tumor foci were segmented, we calculated the MTV of all malignant lesions by adding all MTVs of each slice manually. Of note, the cavity or non-avid area in tumors, when present, is excluded as part of the MTV. SUVmax and SUVmcan within the MTV of each malignant lesion are also calculated automatically. For further analysis, iSUV is also calculated by multiplying the MTV by the nicanSUVniean, defined as the average SUVmean values of all malignant lesions.4. Treatment response evaluation Response Evaluation Criteria in Solid Tumor1.1(RECIST1.1) was used to assess the treatment response with a CT scan every two cycles, and the responses were classified as complete response (CR), partial response (PR), progressive disease (PD) or stable disease (SD). 5. Follow-up of SCLC patientsAfter completion of treatment, patients were evaluated with CT scans every3months for3years, every6month in the following year, and yearly thereafter. Overall survival (OS) and progression free survival (PFS) were chosen as endpoints. OS was defined as the time interval from the date of18F-FDG PET/CT scanning to the date of death from any cause. PFS was defined as the time interval from the date of F-FDG PET/CT scanning to the date of first progression or death from any cause without previous progression.6. Statistical analysisWe used SPSS statistical software, version13.0, for statistical analyses. Probability values of<0.05were considered to be statistically significant.Results1. The estimated median OS for the entire cohort was16.7months (95%CI,12.8-20.6months), with1-year cumulative overall survival of67.3%. The estimated median PFS was9.8months (95%CI,8.3-11.3months), with1-year cumulative progression free survival of41.6%.2. PET metabolic parameters and survivalThe ability of MTV, iSUV and meanSUVmean of all malignant lesions and primary tumor SUVmax to predict prognosis were depicted by ROC curve. According to the optimal cut-off value of MTV, the patients were divided into two groups, the patients with larger MTV had significantly shorter median OS and PFS than the patients with smaller MTV. Likewise, when patients were divided into two groups according to the optimal cutoff value of iSUV, similar results can be found. On multivariate analysis, independent prognostic factors associated with OS only including MTV, iSUV, LDH and stage. We also analyzed the association between PFS and these factors, and similar results were obtained.5. Subgroup analysis by stageA strong association between MTV and OS was also found within each stage. Similar results were obtained for the analysis of PFS. It’s worth noting that the patients of LD with larger MTV and the patients of ED with smaller MTV had similar median OS. Similar results can be observed when iSUV was incorporated into the two-stage classification system.6. PET metabolic parameters and responseFor the responses to treatment, the smaller MTV group differed significantly from the larger MTV group (p<0.001), and the smaller iSUV group also differed significantly from the larger iSUV group (p=0.001). However, the significant association was not achieved between treatment response and SUVmax (p=0.466) and meanSUVmcan (p=0.444).Conclusions4. MTV and iSUV well predicted response of SCLC patients;5. MTV and iSUV can well predict prognosis of SCLC patients in addition to tumor stage;6. Incorporation of MTV or iSUV into a two-stage classification system is more accurate for predicting survival than the tumor stage alone.Part Two18F-FLT PET can early predict response and prognosis in patients with small cell lung cancer18F-FDG PUT has proven capable of prediction response to therapy. However, despite its many advantages.18F-FDG is not a highly selective tracer for imaging cancer, as it is also taken up by activated macrophages and other cells involved in inflammatory processes. Exploring the role of radiopharmaceuticals other than18F-FDG is therefore warranted. A comparatively novel tracer in oncology imaging is18F-fluoro-L-thymidine (18F-FLT).18F-FLT is phosphorylated by the enzyme thymidine kinase-1(TK-1), which leads to intracellular trapping. Because TK-1concentration increases almost10-fold during the S phase of the cell cycle at the time of DNA synthesis, FFLT uptake reflects the proliferation rate of malignant cells. In malignancies of the lung, breast, head and neck. digestive tract, brain, and other organs, quantitative assessment of18F-FLT targeting has been shown to correlate with the proliferation marker Ki-67and with clinical outcome measures such as lime to progression (TTP) and overall survival (OS). Idema et al assessed various PET segmentation methods to estimate the proliferative volume (PV) and their prognostic value for OS in patients with suspected high-grade glioma, and drew a conclusion that the PV as determined by (18)F-FLT PET is associated with OS in high-grade malignant gliomas.This study intends to verify whether some metabolic parameters measured by F-FLT PET could early predict response and survival in patients with SCLC, and provide the basis for individualized treatment of SCLC.Purpose1. To determine whether the metabolic parameters and metabolic remission of F-FLT PET could early predict the survival in patients with SCLC.2. To judge the values of the metabolic parameters and metabolic remission of18F-FLT PET to early predict the chemo-radiation efficacy.Methods1. Recruitment of previously untreated SCLC patients with a total of39cases,1week before the first-line treatment,6weeks after the start of treatment underwent18F-FLT PET/CT scan.2. Obtain the corresponding the primary tumor SUVmax and SUVmean, using the original accumulation algorithm to calculate the PV.3. Radiotherapy and chemotherapy efficacy evaluation in patients with SCLC We judged the efficacy of CT-based response according to the response evaluation criteria solid tumors (RESICT), and assessed the efficacy of PET-based response according to the PET response criteria in solid tumors (PERCIST).4. Follow-up After completion of treatment, patients were evaluated with CT scans every3months for3years, every6month in the following years, and yearly thereafter.5. Statistical analysis We used SPSS statistical software, version16.0, for statistical analyses. Probability values of<0.05were considered to be statistically significant.Results1. The diagnostic value of’8F-FLT PET Patients enrolled in this study,5patients with multiple liver metastases,9patients with bone metastases, but due to the high uptake of F-FLT in the physiology of the liver and bone marrow tissue,18F-FLT PET diagnostic value is limited. However, due to the low uptake of F-FLT in the physiology of the brain tissue, F-FLT PET can well diagnose the3patients associated with brain metastases.2. The relationship between18F-FLT PET metabolic parameters and survival in patients with SCLC. The ability of PV, SUVmax, and SUVmean to predict prognosis were depicted by ROC curve. AUC of PV, SUVmax and SUVmean are0.824(P=0.004),0.796(P=0.008) and0.746(P=0.027), respectively. PV is the most valuable factor, with the optimal cut-off values of46.6cm*. According to the optimal cut-off value of PV, the patients were divided into two groups, the patients with larger PV had significantly shorter median OS and PFS than the patients with smaller PV. The results of Cox proportional hazards model univariate analysis showed that PV, SUVmax, SUVnican, stage, PS and gender but18F-FLT PET metabolic remission are the prognostic factors of OS and PFS. On multivariate analysis, independent prognostic factors associated with OS and PFS only including PV, SUVmeanand stage.3. The relationship between18F-FLT PET metabolic parameters and metabolic remission and response based on CT. The smaller PV group differed significantly from the larger PV group (P=0.012), however, the significant association was not achieved between treatment response and SUVmax (P=0.821) and SUVmean (P=0.426). Pearson correlation analysis showed that18F-FLT PET metabolic remission was positively correlated with response based on CT (correlation coefficient=0.535,p=0.04).Conclusions1.18F-FLT PET should not be used for the diagnosis of liver mctaslases and bone metastases, but can well diagnose brain metastases.2. As the independent prognostic factor, PV can early predict the survival time of patients with SCLC.3. The PV and chemo-radiotherapy efficacy significantly related, while The SUVmax and SUVmean cannot effectively predict the SCLC radiotherapy and chemotherapy efficacy.4.18F-FLT PET metabolic remission was positively correlated with response based on CT, but had no prognostic significance. |
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