The Research Of The Clinical Application Of ¹⁸F-AlF-NOTA-Octreotide PET/CT In Neuroendocrine Neoplasms

Background:Neuroendocrine neoplasms（NENs）are relatively rare tumors originating from neuroendocrine cells with high heterogeneity.With imaging methods renovating,the detection rate of NENs is increasing.Somatostatin receptor imaging,the functional imaging technology of nuclear medicine,plays a very important role in the diagnosis,localization,staging,and response evaluation of NENs.⁶⁸Ga-DOTA-somatostatin analog（SSA）PET/CT has been considered as a gold standard for the diagnosis of NENs.However,the short half-life of ⁶⁸Ga and the annual replacement of ⁶⁸Ge/⁶⁸Ga generator required for ⁶⁸Ga production,which hinder its application in most hospitals.In contrast,¹⁸F is an ideal choice for a PET imaging agent because of its mass production,long half-life,low positron energy and better image resolution.¹⁸F-AlF-NOTA-octreotide is a polypeptide radiotracer binding to somatostatin receptor type 2（SSTR2）.Because it can be synthesized rapidly and shows good tumor uptake in vivo,it has the potential to become an ideal imaging agent for NENs.This study aims to explore the clinical value of ¹⁸F-AlF-NOTA-octreotide in NENs from three aspects—1)to determine the uptake range of ¹⁸F-AlF-NOTA-octreotide in normal organs and tumor lesions,and determine the uptake value of non-NENs as well as the uptake differences between lesions of different grades;2)to evaluate the diagnostic efficacy of ¹⁸F-AlF-NOTA-octreotide PET/CT compared with ⁶⁸Ga-DOTATATE;3)to evaluate the predictive value of PET/CT series parameters combined with ¹⁸F-FDG and ¹⁸F-AlF-NOTA-octreotide for PFS in GEP-NETs patients.The purpose of this study is to provide a new way to improve the efficiency of lesion localization diagnosis and predict the prognosis of patients with NENs.Method:162 patients who underwent ¹⁸F-AlF-NOTA-octreotide PET/CT in our hospital were included.The uptake values of normal tissues and organs or different lesions were collected,and the physiological uptake range of21 tissues or organs was established.The uptake of tumor lesions of different grades and the ratio of tumor to background（T/B）in primary and metastatic lesions were calculated.The uptake range of non-NENs was recorded,and the difference of SUV value between NENs and benign lesions was compared.At the same time,19 patients with NENs diagnosed by pathology were prospectively collected for ¹⁸F-AlF-NOTA-octreotide and ⁶⁸Ga-DOTATATE PET/CT.The biodistribution of two imaging agents in normal organs was compared.The detection rates of NEN lesions and the differences of SUVmax,TLR and TSR in different parts of ¹⁸F-AlF-NOTA-octreotide and ⁶⁸Ga-DOTATATE PET/CT imaging were compared to clarify the application scope of ¹⁸F-AlF-NOTA-octreotide.Univariate and multivariate cox analysis were used to evaluate the predictive value of¹⁸F-AlF-NOTA-octreotide and ¹⁸F-FDG PET/CT series parameters and clinical indexes for PFS in patients with GEP-NETs.A nomogram containing PET parameters was constructed and the efficiency was evaluated.Results:（1）The high physiological uptake of ¹⁸F-AlF-NOTA-octreotide was mainly in the spleen,adrenal gland,renal parenchyma,pituitary,and liver（SUVmax>6.77）;Moderate uptake（SUVmax 3.0-6.77）in the uncinate process of pancreas,prostate,thyroid,and uterus;Slight uptake can be seen in the small intestine,gallbladder,pancreas,and colon（SUVmax 1.34-3.00）.There were significant differences between benign lesions and NENs in bone（P<0.01）,lymph nodes（P<0.01）and other parts（P=0.014）,but there was no significant difference between them in lung lesions（P=0.29）.At the same time,SUVmax was calculated as 5.18 to distinguish benign lesions from NENs lesions with its sensitivity and specificity of 88.2%and62.2%,respectively.There was significant correlation between tumor uptake and grade in primary tumors,lymph node,bone and lung metastases.（2）Compared with ⁶⁸Ga-DOTATATE,there was no significant difference in the biodistribution of ¹⁸F-AlF-NOTA-octreotide in most organs,but the uptake of ¹⁸F-AlF-NOTA-octreotide in salivary gland and liver decreased significantly（P<0.05）.¹⁸F-AlF-NOTA-octreotide detected more lesions than ⁶⁸Ga-DOTATATE（172 vs 146）,especially liver lesions（114 vs 91）.The SUVmax of ¹⁸F-AlF-NOTA-octreotide in different parts of tumors was higher,but there was no significant difference between them.However,the TLR of ¹⁸F-AlF-NOTA-octreotide was higher than that of⁶⁸Ga-DOTATATE（P<0.05）.（3）Univariate analysis showed that pathological grade,presence of bone metastases,T stage,parameters of ¹⁸F-FDG and ¹⁸F-AlF-NOTA-octreotide,combined PET imaging grade were correlated with PFS.In multivariate analysis,SUVmax and SSTRTV of ¹⁸F-AlF-NOTA-octreotide and T stage,PET imaging grade and pathological grade were independent predictors of PFS in patients with GEP-NETs.The above indicators were included in the nomogram of prognostic evaluation.The C-index of the nomogram was 0.766±0.04,the AUC was 0.803（95%CI:0.699-0.908）,and the AUC of AJCC stage was 0.646（95%CI:0.533-0.759）.Conclusion:（1）The reference range of biodistribution of ¹⁸F-AlF-NOTA-octreotide in different tissues or organs was based on a large sample data.Although some benign lesions show varying uptake,they are still different from NENs lesions.There were also differences in the uptake of different grades of NENs lesions in different parts.（2）Compared with ⁶⁸Ga-DOTATATE,¹⁸F-AlF-NOTA-octreotide has a similar image quality and similar detection rate of NEN lesions.It is worth noting that ¹⁸F-AlF-NOTA-octreotide is more effective in detecting liver lesions.（3）The series parameters of combining ¹⁸F-AlF-NOTA-octreotide and ¹⁸F-FDG can be used to evaluate the prognosis of GEP-NETs.The nomogram based on pathological grade,PET grading system,T stage,SUVmax of ¹⁸F-AlF-NOTA-octreotide and SSTRTV can be used for personalized prognosis prediction of GEP-NETs patients.In a word,¹⁸F-AlF-NOTA-octreotide is a PET imaging agent that can be used in the diagnosis of NENs and has the potential to be used in the evaluation of clinical prognosis.