Use of benzodiazepines before (18)F-FDG-PET/CT dual-phase imaging does not decrease the efficacy of the study.

PURPOSE: We aimed to investigate whether administration of benzodiazepines decreases the efficacy of fluorine-18 fluorodeoxyglucose positron emission tomography/computed tomography PET/CT) ((18)F-FDG-PET/CT) dual-phase imaging.
MATERIALS AND METHODS: Eighteen patients with malignant tumors who were administered 0.5 mg alprazolam before undergoing (18)F-FDG-PET/CT scan (group A) and 21 patients with malignant tumors who were not administered alprazolam before (18)F-FDG-PET/CT scan (group B) were included in this study. Forty lesions from the 18 patients in group A and 66 lesions from the 21 patients in group B were evaluated. Initial "early" whole-body imaging commenced 60 ± 5 minutes after injection of (18)F-FDG and delayed scan was obtained 120 ± 10 minutes after the injection. Maximum standardized uptake values (SUVs) were obtained by drawing three-dimensional regions of interest (ROIs) around each lesion on the early study and the corresponding lesion on the delayed study.
RESULTS: The average SUVmax in lesions in group A (mean ± S.D.) was 10.2 ± 6.4 on early examination (SUVmax E) and 12.6 ± 7.6 on delayed examination (SUVmax D). There was a significant difference between these two time points (P < 0.05). Similarly, for the lesions in group B, the average uptake values were 9.3 ± 5.2 (SUVmax E) and 11.2 ± 6.5 (SUVmax D). The increase in these values was significant as it was in group A (P < 0.05). Differences between groups A and B for the variables SUVmax E, SUVmax D were not significant statistically (P > 0.05).
CONCLUSION: Benzodiazepines do not adversely affect the efficacy of the dual-phase FDG-PET imaging technique.

INTRODUCTION

There have been many reports indicating that 18F-FDG PET is an effective method in the diagnosis, differential diagnosis, staging, follow-up, therapy planning, and predicting the prognosis of malignancies.[1-3] Tumor cells, generally, exhibit increased glucose utilization,[4] probably due to their high glucose transporter protein content[5] and increased enzyme levels of hexokinase and phosphofructokinase promoting glycolysis.[6] Consequently, FDG uptake, which reflects glucose metabolic rate, is increased in tumor cells. However, a significant overlap of the SUVmax among some of the benign and malignant tumors has been demonstrated. Some malignant tumors with low FDG affinity like bronchoalveolar carcinomas and carcinoid tumors may not show increased FDG uptake.[78] FDG has been also demonstrated to accumulate in inflammatory lesions and infections which results in low specificity for 18F-FDG PET in the differentiation of malignant tumors from benign lesions.[9-11] Some studies have shown that delayed PET (2 to 3 h post injection) might help in differentiating malignant lesions from benign ones.[12-17] In these studies it has been shown that the uptake of 18F-FDG continues to increase in tumors for several hours after injection, while the FDG uptake in inflammatory cells decline.

Benzodiazepines are frequently used for their muscle relaxant activity before intravenous administration of FDG to prevent the unwanted increased physiological muscle uptake. It was also reported that brown adipose tissue uptake of 18F-FDG could be supressed by oral diazepam.[18]

It has been postulated that the routine use of benzodiazepines before intravenous administration of FDG might decrease the hexokinase/glucose-6-phosphatase ratio and render the dual-phase study ineffective since the efficacy of dual-phase or delayed imaging is thought to be related to the elevated ratio of hexokinase to glucose-6-phosphatase in tumor cells.[19] In this study we aimed to investigate whether administration of benzodiazepines before intravenous injection of FDG renders the study ineffective or not.

MATERIALS AND METHODS

Patients

Eighteen patients with malignant tumors (14 male and 4 female; mean age 49.6 ± 12.3 years; age range 28-71 years) who were administered 0.5 mg alprazolam before undergoing 18F-FDG PET/CT scan (group A) and 21 patients with malignant tumors (12 male and 9 female; mean age 52 ± 11.8 years; age range 31-71 years) who were not administered alprazolam before 18F-FDG PET/CT scan (group B) were included in this study. Forty lesions from the 18 patients in group A and 66 lesions from the 21 patients in group B were evaluated. Only the lesions which were proved to be malignant were included in the study and the final diagnosis was based on the histopathology and/or follow-up information like resolving of the lesion on follow-up PET after therapy or progression on follow-up PET or other imaging (Ultrasonography, Computerized Tomography, Bone Scintigraphy or Magnetic Resonance Imaging) for a period of 6 months. In group A, 14 patients had lymphoma (12 non-Hodgkin's lymphoma, 2 Hodgkin's lymphoma), 4 patients had head and neck cancer (3 larynx cancer, 1 nasopharynx cancer), and in group B 12 patients had lymphoma (4 Hodgkin's lymphoma, 8 non-Hodgkin's lymphoma), 9 patients had head and neck cancer (5 nasopharynx cancer, 2 larynx cancer, 1 lip cancer, 1 oropharynx cancer). The study was approved by the ethics committee for clinical research of our hospital, and written informed consent was obtained from all subjects.

Image acquisition

PET/CT studies were carried out using an integrated PET/CT scanner, which consisted of a full-ring HI-REZ LSO PET and a six-slice Computerized Tomography (CT) (Siemens Biograph 6; Siemens, Chicago, USA). Patients were instructed to fast for at least 6 hours before 18 F -FDG injection. Blood glucose levels were measured before study and 18F-FDG injections were given only when the blood glucose levels were below 11.11 mmol/l. The patients were injected with 296-555MBq 18F-FDG according to body weight. Initial “early” whole body imaging commenced 60 ± 5 minutes after injection of 18F-FDG and “delayed” scan was obtained 120 ± 10 minutes after the injection. The CT portion of the study was done without an intravenous contrast medium, just for defining anatomical landmarks and making attenuation correction on PET images. CT was acquired first with the following parameters: 50 mAs, 140 kV, and 5 mm section thickness. Whole-body CT was performed in a craniocaudal direction. PET images were acquired in a three-dimensional mode, from the base of the skull to the mid-thigh, with five to seven bed positions of 3 minutes each and PET data were collected in a caudocranial direction. The CT data were matched and fused with the PET data.

Data analysis

Early and delayed images were interpreted on the Siemens workstation in the axial, coronal, and sagittal planes along with maximum intensity projection images. All images were evaluated visually on a computer display with knowledge of the clinical data by consensus of two experienced nuclear medicine physicians (T.Ö., F.Ö.) Maximum standardized uptake values (SUVs) were obtained by drawing three-dimensional regions of interest (ROIs) around each lesion on the early study and the corresponding lesion on the delayed study. For the assessment of FDG-avid lesions, lesions with the visually most intensive FDG uptake on early scan were chosen from different sites in patients with multiple metastases. The maximum SUV (SUVmax) was calculated using the following formula: SUV = cdc/(d/w), where cdc is the decay-corrected tracer tissue concentration (in Bq/g); d, the injected dose (in Bq); and w, the patient's body weight (in grams). We named the SUVmax of early image as SUVmax E and the SUVmax of delayed image as SUVmax D. The retention index (RI) of the lesions were obtained by calculating the percent change in SUVmax between SUVmax E and SUVmax D using the formula: (SUVmax D − SUVmax E) ×100/SUVmax E. ROIs were also placed over normal liver parenchyme to obtain SUVs of the background normal liver parenchyme and the tumor to normal parenchyme ratio (T/N ratio) was then calculated as a contrast value for each lesion identified on the early and delayed studies using the following formulas:

Statistical analysis

All semi-quantitative data were expressed as mean ± S.D. Differences in 18F-FDG uptake between the early and delayed images in both group A and B, as reflected by SUV levels, were examined for statistical significance using the Wilcoxon signed rank test. Differences between groups A and B for the variables SUVmax E, SUVmax D, T/N early, T/N delayed and RI were analyzed with Mann-Whitney U test. Significance was assumed if the probability of a first-degree error was less than 0.05 for all analyses.

RESULTS

The patient characteristics and examination results for malignant tumors are listed in Tables 1 and 2. The average SUVmax in lesions in group A (mean ± S.D.) was 10.2 ± 6.4 on early examination (SUVmax E) and 12.6 ± 7.6 on delayed examination (SUVmax D). There was a significant difference between these two time points (P < 0.05). In 36 of 40 lesions (90%) an increase in uptake values were detected. In 4 lesions uptake values decreased in delayed images (10%). In 34 of 40 lesions (85%) there was an increase in the T/N delayed values when compared to T/N early values. The calculated RI representing the change for the SUVmax was 24.5 ± 22 (range, −16.3 to 85.7), indicating a significant increase in SUVmax between the two time points for this group. The average values for T/N early and T/N delayed was 3.5 ± 1.9 and 4.7 ± 2.9 respectively. The increase in the T/N ratio was also statistically significant (P < 0.05).

Table 1

Patients who are given alprazolam before 18F-FDG PET/CT scan

Table 2

Patients who are not given alprazolam before 18F-FDG PET/CT scan

Similarly, for the lesions in group B, the average uptake values were 9.3 ± 5.2 (SUVmax E) and 11.2 ± 6.5 (SUVmax D). The increase in these values was significant as it was in group A (P < 0.05). In 60 of 66 lesions (90.9%) an increase in uptake values were detected. In four lesions (6%) uptake values decreased in delayed images and in one lesion remained unchanged. In 60 of 66 lesions (90.9%) there was an increase in the T/N delayed values when compared to T/N early values. The average RI calculated from these values was 19.6 ± 15.3 (range, −17.7 to 58.3), indicating an significant increase between the early and delayed uptake values of the patients who were not given alprazolam. The average values for T/N early and T/N delayed was 3.5 ± 2.0 and 4.7 ± 3.0 respectively. The increase in the T/N ratio was statistically significant (P< 0.05).

Differences between groups A and B for the variables SUVmax E, SUVmax D, T/N early, T/N delayed, and RI were not significant statistically (P > 0.05) [Table 3].

Table 3

Maximum standardized uptake values (SUVmax) measurements and changes in malignant tumors of patients in groups A and B

DISCUSSION

Conventionally, a SUVmax of 2.5 in the early images of [18] F-FDG PET/CT scan has been suggested as the optimal threshold for differentiating malignant from benign lung lesions.[2021] Afterwards, this threshold was applied to other malignancies in several studies. However, there is a considerable overlap between SUV results of malignant and benign lesions, which leads to a difficulty in correctly interpreting FDG PET findings.[2122] There are also other factors that can influence the exact determination of SUV.[23] For instance, extravasation of FDG, the patient's blood glucose levels, insulin levels, the time interval between FDG injection and image acquisition, and partial volume effects, can all significantly influence the accuracy of the SUV determination.[2425] For that reason, a diagnosis based on the SUV obtained at a single-time point may not always give accurate results. In order to increase the accuracy of this technique, it has been proposed that dual-time point FDG PET imaging can be performed, because FDG uptake by most benign lesions peaks much earlier than uptake by most malignant lesions and tumor uptake of FDG increases for hours while inflammatory lesions decreases gradually from 60 minutes after FDG injection.[122627]

There have been numerous studies reporting the advantages of delayed imaging with 18 F-FDG PET for the diagnosis and differential diagnosis of malignant and benign lesions.[28-34] Dual-time-point 18 F-FDG PET improves the sensitivity, specificity, accuracy and positive predictive value in the evaluation of locoregional lymph nodes in thoracic esophageal squamous cell cancer.[35] Lai, et al., showed that dual-phase FDG-PET is superior to CT/MRI in the restaging of recurrent cervical carcinoma.[36] In a study it has been shown that a delayed FDG-PET scan was useful for differentiating between malignant lesions and benign lesions in the pancreas.[37]

The increase in the SUV values over time in malignant cells was tried to be explained by tumor vascularity.[38] Glut-1 and hexokinase II (HK-II) which allows FDG to enter the cell, become phosphorylated, and then trapped intracellularly, are expressed mostly in the center of the tumors and delayed imaging allows more time for FDG to migrate to central hypoxic areas which have higher regional levels of Glut-1 and HK-II.[3839]

Benzodiazepines, which are routinely used in FDG-PET studies to circumvent the FDG uptake in muscles and brown fat, can cause glycemia and consequently change the biodistribution of FDG. It has been shown that even a single dose of diazepamin can lead to increased glycemia.[40] Aggravation of hyperglycemia has been reported during benzodiazepine treatment in diabetic patients.[41] In vitro experiments have shown that drugs acting specifically at peripheral benzodiazepine receptors inhibit glucose-induced insulin secretion[42] by reducing oxidative metabolism.[43] It has been reported that benzodiazepines, can alter the sensitivity of cells to insulin and reduce phosphorylation of glucose by inhibiting hexokinase activity.[44-46] After muscular activity insulin sensitivity and noninsulin-mediated glucose disposal have been shown to increase,[47] so probably the muscle relaxant action of the benzodiazepine also alter insulin sensitivity and glucose disposal. Zhuang et al., postulated that oral administration of diazepam before the injection of FDG would render dual-phase PET imaging ineffective since the dual-phase imaging technique depends on the elevated ratio of hexokinase to glucose-6-phosphatase in tumor cells.[19] In the present study, SUVmax values obtained from malignant lesions significantly increased in the delayed images in both patient groups. When an increase in the SUVmax in delayed imaging compared to early imaging was used as the diagnostic criterion, the sensitivities of dual-time point studies were found as 90% and 90.9% in groups A and B respectively. There was not any significant difference between patients who were given alprazolam before FDG-PET study and who were not administered any benzodiazepines, concerning the ratio of increase of SUVmax between early and delayed imaging studies. In our study we could not assess the specificity of the dual-phase imaging in detecting malignant lesions, as only the patients who were proved to have metastases were included in the study and this might be a limitation of the study.

In conclusion, for this patient population benzodiazepines do not adversely affect the efficacy of the dual-phase FDG-PET imaging technique.