Impact of fasting on 18F-fluorocholine gastrointestinal uptake and detection of lymph node metastases in patients with prostate cancer

Background 18F-fluorocholine PET/CT is used to detect lymph node metastases in prostate cancer patients. Physiological 18F-fluorocholine in the gastrointestinal tract, especially in the intestines, may interfere with the detection of malignant lymph nodes. Fasting is frequently proposed in literature; however, scientific support is lacking. This study aims to determine the impact of fasting on 18F-fluorocholine uptake in the gastrointestinal tract. Methods Eighty patients were studied, 40 fasted for at least 6 h prior to 18F-fluorocholine administration while the other 40 did not fast. 18F-fluorocholine uptake pattern and intensity were evaluated in the intestine near the abdominal aorta and four regions near the iliac arteries. 18F-fluorocholine intensity was also measured in the liver, pancreas, stomach and spleen. Findings No statistically significant differences were found in 18F-fluorocholine uptake in the gastrointestinal tract between the fasting and non-fasting group. Conclusions Fasting for 6 h has no effect on 18F-fluorocholine uptake in the gastrointestinal tract. Therefore, no effects on the detection of malignant lymph nodes are expected, and fasting is not recommended in our opinion.


Introduction
Choline-PET/CT is widely used in patients with prostate cancer. Clinically, the imaging technique is used mainly for restaging of patients with a biochemical relapse and less frequently for initial staging. One of the strengths of choline-PET/CT is the detection and localisation of prostate cancer metastases in patients with slightly elevated PSA. Lymph node metastases can be detected in lymph nodes, which do not show malignant characteristics on conventional imaging such as CT and MRI. Patients with limited lymph node metastases may be selected for procedures with curative intent, while patients with more extensive disease can be protected from the morbidity of senseless aggressive therapies.
Detection of lymph node metastases may be hampered by high physiological choline uptake in the gastrointestinal tract commonly seen on choline-PET/CT. In the literature, fasting is frequently proposed before 18 F-fluorocholine PET/CT, as can be found in a summary of literature by Chondrogiannis et al. [1]. Four hours of fasting before administration of 11 C-choline is suggested in a document of the Society of Nuclear Medicine and Molecular Imaging [2]; however, both the Society of Nuclear Medicine and Molecular Imaging and the European Association of Nuclear Medicine have no specific guidelines for 18 F-or 11 C-choline PET/CT. To the best of our knowledge, there is no evidence that supports fasting prior to choline-PET/CT in order to suppress physiological choline uptake in the gastrointestinal tract. In a small animal study, fasting was not found to affect tracer uptake in the liver for both 11 C-choline and 18 F-fluorocholine [3]. This study aims to determine the impact of fasting, for at least 6 h, on 18 F-fluorocholine uptake in the gastrointestinal tract.

Methods
From May 2013 data of all 18 F-fluorocholine-PET/CTs at our department were prospectively entered in a database. All patients gave written consent for the use of their anonymous data. Initially, all patients were scanned without prior fasting. Due to the observed high physiological 18 F-fluorocholine uptake in the intestine, the patient preparation protocol for prostate cancer patients was changed after the first 40 patients had been scanned. In the revised patient preparation protocol, patients were asked to fast for at least 6 h prior to administration of 18 F-fluorocholine. All scans were evaluated after a second cohort of 40 patients was scanned that had properly followed the revised patient preparation protocol.
LIST-mode data of the prostatic region were acquired for 10 min directly after 18 F-fluorocholine administration (190 MBq, mean), followed by late images from the inguinal region to the base of the skull approximately 45 min later (Siemens Biograph-16 TruePoint PET/CT, Siemens Healthcare, Knoxville, USA).
For each patient, the LIST-mode data was used to determine the choline time-activity pattern in the intestine during the first 10 min after 18 F-fluorocholine administration (software: Siemens syngo.via, Siemens Healthcare, Knoxville, USA). The Kolmogorov-Smirnov test was used to check for a normal distribution in the data. A T test or the Mann-Whitney U test was used to check for the differences between the groups at each time point after injection. A T test was used when the data in both groups showed a normal distribution; otherwise, the Mann-Witney U test was used.
Late data was used to determine the 18 F-fluorocholine uptake in the liver, spleen, stomach, pancreas and intestine. In five different regions: 1 cm or less in the proximity of the aorta, both the left and right common iliac arteries, and both the left and right external iliac arteries, intestinal activity were measured. A T test or the Mann-Whitney U test was used to check for the differences between the groups in measured SUV max and SUV peak , for each evaluated organ/region.

Patient population
In both the fasting and non-fasting group, 40 patients were included. Mean age was 71.9 years (range 59-83) and 69.1 (range 51-83) for the fasting and non-fasting Early dynamic phase 18 F-fluorocholine PET/CT shows a rapid uptake of the 18 F-fluorocholine in the intestine in the first 2 min followed by a more or less stable concentration. No statistical differences were found between the fasting and non-fasting groups at any time-point (Fig. 1).

Late phase
In all patients' intestinal activity, which possibly interfered with lymph node metastases detection, was found near the aorta, especially in the duodenum. Possible interfering activity was found near the right common iliac artery in 65 and 80 % of the patients for the nonfasting and fasting group, respectively, right external iliac artery (93 and 98 %) and left external iliac artery (68 and 80 %). Activity near the left common iliac artery was found less frequently (37 and 45 %). The intensity of 18 F-fluorocholine uptake in these regions was not significantly different between the fasting and non-fasting groups ( Table 1, Fig. 2). In general, the intestinal activity near the aorta is higher than in the other regions, 0.003 ≥ p ≥ 0.000 for SUV max and 0.002 ≥ p ≥ 0.000 for SUV mean (ANOVA with post hoc Scheffe's test). No significant differences were found between the activities in the other regions.
No significant differences were found in the 18 Ffluorocholine activity uptake in the liver, spleen, stomach and pancreas between the fasting and the non-fasting groups (Table 2).

Discussion
The data of our study shows that physiological intestine activity in the vicinity of the abdominal aorta and iliac arteries, regions in which lymph node metastases of prostate cancer are frequently found, is present in all prostate cancer patients receiving 18 F-fluorocholine PET/CT, especially near the abdominal aorta. In earlier  data from our group, we found in 100 patients that the activity (SUV max ) in malignant lymph nodes and physiological intestine activity does not significantly differ at both early and late data acquisition time points (Fig. 3,  unpublished). Therefore, interference of physiological activity in the intestine with detection of lymph node metastases is realistic. Most papers on acquisition protocols of 18 F-fluorocholine deal with the time-point of acquisition and with the effects of voiding and hydration on detection of lesions in the prostate. Fasting is regularly proposed in acquisition protocols without scientific support [1]. Our data show that the nutritional status has no impact on the uptake of 18 F-fluorocholine in the gastrointestinal tract and, more specifically, in regions in the gastrointestinal tract that may interfere with the detection of lymph node metastases.
The CT part of the PET/CT is important to detect lymph nodes in areas with high intestinal activity. To distinguish lymph nodes in these areas, acquisition of CT images of diagnostic quality with administration of intravenous iodinated contrast is necessary. Once lymph nodes are detected on CT, the combination of PET and CT may distinguish malignant lymph nodes from physiological lymph nodes, however, especially in small lymph nodes, characterisation may remain difficult.  The statistical power may be a shortcoming of the study. In all regions, the observed differences in the mean SUV max and SUV peak are relatively small in comparison to the observed standard deviation. One could suggest that the large study populations would be needed to exclude the presence of statistically significant differences. However, in our opinion, the clinical value of such findings would still be irrelevant. Regarding the overlap of found 18 F-fluorocholine intensity in all intestine regions in both groups with the intensity in malignant lymph nodes, no effects on the detection of lymph node metastases are expected.

Conclusion
Intestinal activity that possibly interferes with the detection of lymph node metastases is encountered in all prostate cancer patients receiving 18 F-fluorocholine PET/CT. Fasting for at least 6 h before administration of 18 F-fluorocholine does not influence the uptake of 18 F-fluorocholine in the gastrointestinal tract in these patients. Therefore, fasting is not recommended in our opinion.

Ethical approval
All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards.

Informed consent
Informed consent was obtained from all individual participants included in the study.