Application Of ¹⁸F-FLT PET/CT In Guiding Delineation Of Biological Target Volume Of Head And Neck Cancer

Objective:To evaluate the correlation of the uptake of ¹⁸F-FLT PET/CT with TNM Staging and ki-67 index in patients with squamous cell carcinoma of head and neck,and to restage combined with ¹⁸F-FLT PET/CT,comparing with the TNM Staging based by anatomical images,and to evaluate the role of ¹⁸F-FLT PET/CT in the staging system.To determine the optimal threshold of ¹⁸F-FLT PET/CTfor evaluating the primary tumor volume based by CT in patients with squamous cell carcinoma of head and neck.To expect for guiding delineation of biological target volume,then to adjust and optimize the IMRT plan.To monitor the correlation between change of ¹⁸F-FLT uptake and therapeutic response.To explore the correlation between uptake of ¹⁸F-FLT PET/CT and tumor regression based by CT in patients with squamous cell carcinoma of head and neck.To expect to identify the biological target volume,then to guide BIMRT.Materials and methods:30 patients with newly diagnosed histologically proven primary squamous cell carcinoma of head and neck referred for radiotherapy were enrolled in this study.The exclusion criteria were as follows:with distant metastasis proven by clinical or radiologic evidence;with history of surgery or radiotherapy;with any other primary malignant tumor previously diagnosed,or combined concurrently.All enrolled patients took physical examination,MRI/CT scans of pharynx and neck,chest x-ray,electrocardiogram,abdominal ultrasound,emission computed tomography bone scan,blood type,complete blood count,hepatic and renal function,blood glucose,virus serological examination,electronic laryngoscope,biopsy and histopathology,then were staged according to the 7^th edition of AJCC TNM classification criteria.The biopsy specimens were innunohistochemically stained with anti-Ki-67 antibody.All enrolled patients underwent ¹⁸F-FLT PET/CT before the radiotherapy.¹⁸F-FLT PET/CT scanning method were:Intravenous injection 3.7MBq/Kg（0.lmci/Kg）radionuclide,rest for 60 minutes,perform the scanning.Standard uptake value（SUV）including Mean SUV(SUV_mean),maximum SUV(SUV_max)of ¹⁸F-FLT PET were evaluated by a nuclear medicine physician who were blinded to clinical and pathologic results.All data were analyzed by SPSS19.0Statistics software package.The Spearman correlation was used to evaluate the correlation of SUV_max,SUV_mean for ¹⁸F-FLT with T stage,TNM staging and Ki-67index.P value<0.05 were considered statistically significant.All patients were restaged with the information of ¹⁸F-FLT PET/CT by the oncologist together with the nuclear medicine physician.All enrolled patients underwent a CT simulation after preparing thermoplastic mask lied down in supine position on device table for CT imaging.A radiation oncologist delineated GTV for the primary tumor,named as GTV_TPS.Both the CT images with structures of GTV and the images of ¹⁸F-FLT PET/CT were imported to MIMvista software.The volume of different SUV threshold were autosegmented by MIMvista software and modified by the oncologist together with the nuclear medicine physician,the threshold were set as follows:30%SUV_max,40%SUV_max,50%SUV_max,60%SUV_max,70%SUV_max,SUV=1.3,SUV=1.4,SUV=1.5.All data were analyzed by SPSS19.0 Statistics software package.The volume of each group were compared with GTV_TPS,analyzing by paired t-test.All enrolled patients underwent MRI/CT after delivery of 50-56Gy during radiotherapy,and evaluated the clinical response for primary tumor using RECIST 1.1.They underwent serial ¹⁸F-FLT PET/CT before and after delivery of 10Gy,20Gy,30Gy,40Gy,50Gy,70Gy during radiotherapy.To monitor the change of ¹⁸F-FLT uptake,and to explore the relationship with clinical response.Each enrolled patients underwent a repeat CT simulation for CT imaging after delivery of 56Gy during radiotherapy.A radiation oncologist delineated GTV2 for the primary tumor,named as GTV_TPS2.GTV_TPS2 were imported to MIMvista software.All data were analyzed by SPSS19.0 Statistics software package.The volume of 60%SUV_max,70%SUV_max,SUV=1.5 were compared with GTV_TPS2,analyzing by paired t-test.Results:This prospective study was approved by the institutional review board of Shandong Cancer Institute.From October 2010 until July 2014,30 patients with newly diagnosed primary squamous cell carcinoma of head and neck（22nasopharyngeal cancer,8 hypopharyngeal cancer）referred for radiotherapy were enrolled in this study after giving written informed consent.The range of SUV_max in primary tumor for ¹⁸F-FLT was 3.53-8.29,median 4.91,SUV_mean was 1.05-3.53,median 2.56.Spearman correlation analysis showed there were correlation between SUV_max,SUV_mean and T Stage;meanwhile there were no correlation between SUV_max,SUV_mean and TNM Staging.There were no correlation between SUV_max,SUV_mean and Ki-67 index.The TNM staging of the enrolled patients according to 7^th edition of AJCC TNM classification criteria based by CT/MRI was performed,there were 2 patients for II stage;14 patients for III stage;14 patients for IV stage.The findings from ¹⁸ F-FLT PET/CT led in 11 patients to a change of category“T”or“N”:4 patients for category“T”,8 patients for category“N”.And it led to the change of TNM staging in 9patients,5 patients showed downstaging,4 patients showed upstaging.The results of paired t-test showed there were significant difference betweenstatistically significant difference between V_SUV1.3、V_SUV1.4 and GTV_TPS,p=0.610,p=0.226,respectively.There were no significant difference compared with V_SUV1.3、V_SUV1.4 and GTV_TPS analyzed by Kurskai-Wallis H independent samples nonparametric tests,p=0.713.The results showed ¹⁸F-FLT uptake decreased steadily with increasing doses.There is no correlation between the baseline ¹⁸F-FLT SUV_max and clinical reponse,r=0.236,p=0.209.21 patients underwent ¹⁸F-FLT after delivery of 20Gy,SUV_max significantly decreased,and 48.59%was the optimal threshold for evaluating clinical response.The results of paired t-test showed there were no statistically significant difference between V_70%SUV and GTV_TPS2.Conclusion:All primary tumors of squamous cell carcinoma of head and neck had intense uptake of ¹⁸F-FLT.There were significant correlation between SUV_max,SUV_mean in primary tumor and T Stage,meanwhile there were no correlation between SUV_max,SUV_mean and TNM Staging.No significant correlation was observed with Ki-67 index for either.¹⁸F-FLT PET/CT can provide tumor cell proliferational information lacking in anatomical images for the clinical staging,then lead to precise staging,then to give some advice for choosing and optimizing the thereupic strategy.No significant difference between V_SUV1.3、V_SUV1.4 and GTV_TPS.The results need to be verify by radiation biology and histopathology,then can be used to guide the BIMRT.Repetitive ¹⁸F-FLT uptake can be used to monitor the response for SCCHN.No significant difference between V_70%SUV of baseline ¹⁸F-FLT and GTV_TPS2.Further study can be used to explore the feasibility for dose escalating of the high proliferation subvolume.