Benefit of contrast-enhanced PET/CT versus non-contrast-enhanced PET/CT relative to lesion detection, lesion characterization, and diagnostic accuracy in patients with cancer CURRENT STATUS: REVIEW

To investigate the benefit of contrast-enhanced PET/CT (PET/CECT) versus non-contrast-enhanced PET/CT (PET/NCCT) relative to lesion detection, characterization, and diagnostic accuracy in cancer patients. This prospective study included patients aged >18 years with histopathologically proven cancer who underwent F-18FDG PET/CT at during the December 2014 to November 2017 study period. PET/NCCT was performed followed by PET/CECT scan in all patients. The results of PET/NCCT, PET/CECT, and pre/post-contrast enhanced PET/CT (PET/NCCT-CECT) for each patient were interpreted by 1 nuclear medicine physician and 1 radiologist. The sensitivity, specificity, accuracy, positive predictive value (PPV), and negative predictive value (NPV) were calculated from ROC curve analysis.


Conclusions
F-18FDG PET/CT demonstrated no significant advantage over PET/NCCT for lesion detection, lesion characterization, or diagnostic accuracy in patients with cancer. The use of intravenous contrast material should be limited to select cases in order to reduce the risk of renal toxicity and/or anaphylactic reaction, and to minimize unnecessary costs.

Background
Integrated positron emission tomography and computed tomography or PET/CT scan using [F-18] fluorodeoxyglucose ([F-18]FDG) is a well-accepted imaging technique that is used for diagnosis, staging, response assessment, recurrence detection, and follow-up among patients with suspected or definitively diagnosed cancer. PET/CT was shown to have greater diagnostic accuracy than PET or CT alone relative to primary tumor detection, lymph node metastasis, and distant metastasis. (1) In order to obtain a diagnostically efficacious CT scan when combined with PET, the administration of intravenous contrast material may be required. The use of intravenous contrast material facilitates precise identification and differentiation of vascular and parenchymatous organ tissue from surrounding tissues. Moreover, the evaluation of lesion enhancement improves lesion detection and lesion characterization. Additionally, assessment of a lesion's relationship with adjacent vascular structures is important for surgical planning. (2,3) Some previous studies suggested that contrast-enhanced PET/CT improves the detection and characterization of liver lesions in patients with colorectal cancer (2) , recurrent rectal cancer (4) , ovarian cancer (5) , and lung cancer. (6) In contrast, other studies found no significant difference between non-contrast-enhanced CT and contrast-enhanced CT integrated with PET in patients with malignant lymphoma (7) , and in patients with head and neck cancer. (8,9) Importantly, intravenous contrast material should be used only when the potential benefits outweigh the potential risks since contrast material can cause renal toxicity and/or anaphylactic reaction in some patients. Some authors recommend against routine intravenous contrast administration for PET/CT, but they agree that it may be selectively used in patients with early-stage head and neck cancer that requires meticulous anatomic and topographic data to plan the operation, and in patients with advanced-stage cancer for assessing vascular invasion. (9) No consensus has yet been reached regarding if, how, and when intravenous contrast material should be used in PET/CT study.
Accordingly, the aim of this study was to investigate the benefit of contrast-enhanced PET/CT versus non-contrast-enhanced PET/CT relative to lesion detection, characterization, and diagnostic accuracy in patients with cancer.

Methods
A flow diagram describing patient enrollment and the study protocol is shown in Figure 1. All PET/CT studies were performed at least 4 weeks after biopsy or surgery, 6 weeks after chemotherapy, 12 weeks after radiotherapy, and 2 weeks after granulocyte-colony stimulating factor (GCSF) treatment to prevent false-positive results due to inflammatory changes. Clinical, histopathological, radiological follow-up, and other correlative investigation were used as reference standards to evaluate the diagnostic accuracy of PET/CT.

PET/CT protocol
All data were acquired using an integrated PET/CT system (Discovery ® ; GE Healthcare, Milwaukee, WI, USA) that integrates a 16-detector row CT scanner with a lutetium oxyorthosilicate (LSO)-based PET scanner. Patients fasted at least 6 hours prior to [F-18]FDG administration, and blood glucose level was checked using a glucose meter (Stat Strip ® ; Nova Biomedical, Waltham, MA, USA) just before [F-18]FDG administration.
Tracer injection was performed only in patients whose blood glucose level was less than 150 mg/dL. Whole-body emission images were obtained 60 minutes after intravenous administration of [F-18]FDG (0.14-0. In all patients, 2 ml/kg of non-ionic contrast material using either Iopamidol (Iopamiro ® ; Bracco Imaging, Milano, Italy) or Iohexol (Omnipaque ® ; GE Healthcare, Milwaukee, WI, USA) or Ioversol (Optiray ® ; Guerbet, Cedex, France) or Iodixanol (Visipaque ® , GE Healthcare, Milwaukee, WI, USA) was intravenously injected. Whole body CT (30-300 mAs using Automatic Exposure Control (AEC) and smart mA, 14.0 noise index, 120 kVp, and helical thickness of 2.5 mm collimation) was performed immediately before and after contrast injection. Contrast-enhanced CT scan was performed after contrast injection using the appropriate delay time (40 seconds for lesion at head/neck/chest, and 70 seconds for lesion at abdomen). PET data was acquired in 3-D mode, 3 minutes per bed position, and reconstruction was performed using an ordered subset expectation maximization algorithm (3D Iterative [VUE Point]).

Image interpretation
The reconstructed, attenuation-corrected images of all PET/CT datasets were reviewed by one board-certified nuclear medicine physician (14-years' experience) and one diagnostic radiologist (11-years' experience), both of whom were blinded to patient clinical information, using an AW Workstation (GE Healthcare, Milwaukee, WI, USA).
Images without attenuation correction were available for evaluation in cases with suspicious artifacts. For non-contrast PET/CT, a lesion was defined as either a focus of increased [F-18]FDG uptake compared with background, or as morphologic change with features that increase suspicion of the presence of a tumor. For contrast-enhanced PET/CT, abnormal enhancement was added to the criteria adopted for non-contrast PET/CT (e.g., enhancement >15 HU in pulmonary nodule sized >8 mm). (10)(11)(12)(13) Lymph node metastasis was considered in lymph nodes with FDG avidity and when their shortest axial diameter was >11 mm in the jugulodigastric region and >10 mm in the cervical/abdominal/pelvic region (>5 mm in rectal cancer), or if irregular border or central necrosis was evident, or if there was a cluster of three or more lymph nodes of borderline size. (14)(15)(16) Distant metastasis was defined as a focally increased [F-18]FDG activity compared with background, with associated soft tissue mass outside of the primary lesion or bony destruction. Equivocal lesion detected by PET or CT that failed to satisfy any of the aforementioned diagnostic criteria was designated as an indeterminate lesion.
Study outcome was assessed by comparing total number, characterization scores (0-7), and diagnostic confidence (determinate vs. indeterminate) for all lesions detected by the three PET/CT techniques. Both patient-based and lesion-based data were collected and analyzed. To compare diagnostic performance, we compared the interpretation obtained from PET/CT studies with the corresponding results from intra-operative findings, pathologic study, or change in imaging findings during a minimum follow-up period of 6 months. Among patients with no intraoperative findings, lesions that decreased in size or that remain unchanged without receiving any further treatment were considered benign, while progressive lesions were considered to be malignant.

Statistical analysis and sample size calculation
All data were analyzed using the statistical software package PASW Statistics for Windows, was performed to assess diagnostic performance relative to the results obtained from intra-operative finding, pathological study, or change in imaging findings from each technique. The sensitivity, specificity, accuracy, likelihood ratio, positive predictive value (PPV), and negative predictive value (NPV) of all techniques were determined. Net reclassification improvement (NRI) of PET/CECT as compared to PET/NCCT was also calculated, with malignancy from final diagnosis being considered an event.
The sample size for this study was calculated using data from a study by Cantwell, et al. (2) Using a detection rate of liver lesion by non-contrast enhanced PET/CT in patients with colorectal cancer of 70%, a significance level of 0.05, and a power of 80%, the calculated sample size was 33. To cover the three most common types of cancer for which PET/CT study is requested and to compensate for a 10% loss of data for any reason, the calculated minimum sample size was 110 patients.

Demographic data
There were 110 cancer patients included. The types of cancer that were presented included lymphoma, lung cancer, gastrointestinal and hepatobiliary tract cancer, genitourinary cancer, and other cancers (5 breast cancer, 3 sarcoma, 2 melanoma, 2 metastatic cancer of unknown primary, and 1 thyroid cancer). The mean age of patients was 52.45±17.14 years, and 52.7% were female. Approximately one-third of patients were indicated for PET/CT to monitor response during treatment -with or without baseline study. Detailed demographic and clinical data of the study population are shown in Table   1.

Lesion detection and characterization
No significant difference was observed between the PET/CT technique used and the total/individual lesion score at the primary tumor site, lymph node, or distant organ. The details of lesions detected by each PET/CT technique are summarized in Table 2.
We also evaluated correlation between potential factors and the possibility of indeterminate lesions detected by each PET/CT technique, as shown in Table 4 From 371 total detectable lesions, the most common location was thoracic lymph node (n=76), followed by lung (n=59), bone (n=47), liver (n=44), and abdominal lymph node (n=31). The average size of all 291 measurable lesions was 1.73±1.68 cm. From ROC curve analysis, the best cut-off for detectable lesion size was 1.25 cm, with a sensitivity and specificity of 71.1% and 71.2%, respectively. Interestingly, there were significant differences in lesion size between definite and indeterminate lesions in some techniques, but in the opposite ways. Specifically, inderminate lesions tended to be found more often in larger lesions at the primary site, but in smaller lesions at distant metastatic sites.

Diagnostic performance
There were 17 patients (15.5%, 48 lesions) who did not follow-up at our center, so their Of the other 252 lesions with definite impression by both PET/NCCT and PET/CECT, there was no lesion that was identified as benign in PET/NCCT that was changed to malignant by PET/CECT (or vice versa) regardless of final diagnosis group. Therefore, the calculated NRI e , NRI ne , and sum NRI were all 0 ( Table 6) .

Adverse reaction from contrast material
Two patients developed skin rash within 24 hours after intravenous contrast injection for a prevalence of adverse reaction of 1.8%. Both events were mild in severity, and no active treatment was required. No serious adverse events were observed during this study.

Discussion
In contrast to the added beneficial effect of intravenous contrast material found and reported in some studies (2)(3)(4)(5)(6) , we found no significantly added value from the use of however, they expose the patient to added and unnecessary radiation, even though only minimal exposure from the low-dose CT used in PET/CT is claimed. Similar results were also observed in previous studies in patients with lymphoma (7) , and head and neck cancer. (8)(9) Despite the reported added value of contrast material in PET/CT study that has been reported in cancers of the head and neck, abdominal and pelvic regions, and possibly in tumors with mild or no [F-18]FDG avidity (2,4,5,6,8) , our results failed to show statistically significant added value of contrast-enhanced CT regardless of the region of the detectable lesions. However, there were 16 indeterminate lesions from PET/NCCT that were definitely classified by PET/CECT, and 5 of those were found to be malignant in the final diagnosis.
Most of those lesions were small intra-abdominal lesions with faint FDG activity that were easier to identify and diagnose via the use of contrast enhancement.
There was no significant correlation between incidence of indeterminate lesion at the primary site or lymph node and gender, primary cancer type, or indication for PET/CT. However, significant correlation was found between indeterminate metastatic lesions with respectively. All of these results show no significant incremental advantage of intravenous material in PET/CT study. In addition, the unnecessary use of contrast material should be avoided due to its potentially serious side effects. The incidence rate of side effects in this study was a low 1.8% due to our strict adherence to setting-specific guidelines. Moreover, the cost of contrast material is approximately 100 USD per patient, which makes it a high unnecessary expense in cases that will not benefit from contrast enhancement. Taken together, our data do not support the routine use of contrast material in whole body PET/CT study.
We admit that this study has some limitations. First, this was a single-center study with a relatively small sample size compared to previous publications. [F-18]FDG PET/CT study in Thailand has limited indications for reimbursement (currently only in colorectal cancer and non-small cell lung cancer), so this technique is still underutilized. This explains why the sample size is so small and why the study period is so long. Second, most of the enrolled PET/CT studies were performed post-treatment, which may affect the detection rate of malignant diseases. The prevalence of malignancy was only 35% among all detectable lesions. Third, only a small number of case (n=14, 12.7%) had pathologically proven lesions detected by PET/CT, particularly among lesions identified as benign or indeterminate. However, with the mean follow-up of approximately 2 years, lesions that decreased in size or that remain unchanged without receiving any further treatment were considered benign, while progressive lesions were considered to be malignant. Fourth and last, contrast-enhanced PET/CT in this study was performed in single-phase manner, so our results may not be generalizable to multi-phase contrast-enhanced PET/CT, which was previously suggested by some authors. (17) In contrast to other reports that studied in specific types of cancer, the strengths of this study are its prospective design and the fact that we studied different types of cancer, which increases the generalizability of our findings. However, further investigation in those cancers with a small number of cases, as well as in other indications, is needed to confirm the results of this study.

Conclusions
The results of this prospective study revealed no significant advantage of [F-18]FDG PET/CT over PET/NCCT for lesion detection, lesion characterization, or diagnostic accuracy in patients with cancer. Although the rate of adverse events was extremely low, the use of intravenous contrast material should be limited to select cases in order to reduce the risk of renal toxicity and/or anaphylactic reaction, and to minimize unnecessary costs.  PET, positron emission tomography; NCCT, non-contrast computed tomography; CECT, contrast-enhanced CT; score 0= no abnormality detected; 1= focal FDG uptake without CT abnormality; 2 = focal FDG uptake with CT abnormality, favored benign; 3 = focal FDG uptake with CT abnormality, favored malignant; 4 = CT abnormality without FDG avidity, favored benign; 5 = CT abnormality without FDG avidity, favored malignant; 6 = focal FDG uptake with CT abnormality, indeterminate and 7 = CT abnormality without FDG avidity, indeterminate P value of **PET/NCCT vs PET/CECT, ***PET/CECT vs PET/NCCT-CECT, ****PET/NCCT vs PET/NCCT-CECT