Research ArticleClinical Investigations

Combined 18F-Fluoride and 18F-FDG PET/CT Scanning for Evaluation of Malignancy: Results of an International Multicenter Trial

Andrei Iagaru, Erik Mittra, Camila Mosci, David W. Dick, Mike Sathekge, Vineet Prakash, Victor Iyer, Paula Lapa, Jorge Isidoro, Joao M. de Lima and Sanjiv Sam Gambhir
Journal of Nuclear Medicine February 2013, 54 (2) 176-183; DOI: https://doi.org/10.2967/jnumed.112.108803

Abstract

18F-FDG PET/CT is used in a variety of cancers, but because of variable rates of glucose metabolism, not all cancers are reliably identified. 18F− PET/CT allows for the acquisition of highly sensitive and specific images of the skeleton. We prospectively evaluated combined 18F−/18F-FDG as a single PET/CT examination for evaluation of cancer patients and compared it with separate 18F− PET/CT and 18F-FDG PET/CT scans. Methods: One hundred fifteen participants with cancer were prospectively enrolled in an international multicenter trial evaluating 18F− PET/CT, 18F-FDG PET/CT, and combined 18F−/18F-FDG PET/CT. The 3 PET/CT scans were performed sequentially within 4 wk of one another for each patient. Results: 18F−/18F-FDG PET/CT allowed for accurate interpretation of radiotracer uptake outside the skeleton, with findings similar to those of 18F-FDG PET/CT. In 19 participants, skeletal disease was more extensive on 18F− PET/CT and 18F−/18F-FDG PET/CT than on 18F-FDG PET/CT. In another 29 participants, 18F− PET/CT and 18F−/18F-FDG PET/CT showed osseous metastases where 18F-FDG PET/CT was negative. The extent of skeletal lesions was similar in 18 participants on all 3 scans. Conclusion: This trial demonstrated that combined 18F−/18F-FDG PET/CT shows promising results when compared with separate 18F− PET/CT and 18F-FDG PET/CT for evaluation of cancer patients. This result opens the possibility for improved patient care and reduction in health-care costs, as will be further evaluated in future trials.

PET and PET/CT performed with 18F-FDG is used in a variety of cancers, for which it has changed the practice of oncology (1). However, because of variable rates of glucose metabolism, not all malignant lesions are reliably identified, contributing to the overall limitations of this method (2). The initial staging of patients diagnosed with certain cancers includes imaging with 18F-FDG PET/CT and 99mTc-methylenediphosphonate (99mTc-MDP) bone scintigraphy as separate studies (3,4). 99mTc-MDP bone scintigraphy is the method of choice for evaluation of osseous metastases, since it allows a whole-body survey at a relatively low cost. Before the introduction of 99mTc-based agents, bone scintigraphy with sodium fluoride-18 (18F−) was performed using γ-cameras, despite the fact that 511-keV photons are suboptimal for conventional nuclear medicine scanners (5). 18F− is a positron emitter; therefore, imaging the skeleton with 18F-NaF PET/CT allows for the acquisition of highly sensitive and specific images (6). High-quality images of the skeleton can be obtained starting less than 1 h after the intravenous administration of 18F−(7). The Society of Nuclear Medicine and Molecular Imaging published practice guidelines for 18F− PET/CT (8), and the Centers for Medicare and Medicaid Services approved reimbursement of 18F− PET/CT when performed through the National Oncologic PET Registry.

After completing a pilot study on 14 participants (9), we reported the feasibility of combining 18F− and 18F-FDG in a single PET/CT scan for cancer detection. We now present the results of a prospective international multicenter study that further investigated combined 18F−/18F-FDG PET/CT for evaluation of the extent of malignancy.

MATERIALS AND METHODS

The Institutional Review Boards of the 4 participating institutions (Aalborg University [Denmark], Coimbra University [Portugal], Pretoria University [South Africa], and Stanford University [United States]) approved this study. One hundred fifteen consecutive participants (including 14 from the pilot study) were recruited prospectively from November 2007 to July 2012. All participants (63 men and 52 women; age range, 19–84 y; average age ± SD, 58.5 ± 14.3 y) gave written informed consent before enrollment in the trial. All cancer types were included in the study in order to simulate actual clinical experience. Seventeen percent of the participants were referred to determine the initial treatment strategy (formerly diagnosis and initial staging), whereas 83% of the patients were referred for determining a subsequent treatment strategy (including treatment monitoring, restaging, and detection of suspected recurrence). This classification is based on the National Coverage Determination for 18F-FDG PET for Oncologic Conditions from the Centers for Medicare and Medicaid Services (10). The diagnoses included prostate cancer (41 participants), breast cancer (39 participants), sarcoma (22 participants), and other cancers (13 participants). The participants’ clinical data are summarized in Tables 1 and 2. All participants underwent 18F− PET/CT, 18F-FDG PET/CT, and combined 18F−/18F-FDG PET/CT. The interval between the first and third scans ranged from 3 to 28 d (average, 6.7 ± 4.9 d).

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TABLE 1

Clinical Data of Patient Population Included in This Study

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TABLE 2

Clinical Data of Participants for Whom 18F− PET/CT and Combined 18F−/18F-FDG PET/CT Resulted in More Lesions Detected Than Did 18F-FDG PET/CT

PET/CT Protocols and Image Reconstruction

Whole-body images were obtained using the following PET/CT scanners: Discovery LS 600 and 690 (GE Healthcare; Stanford), Discovery VCT (GE Healthcare; Aalborg), Discovery ST (GE Healthcare; Coimbra), and Biograph 40 (Siemens; Pretoria). The patients fasted at least 6 h before the 18F-FDG scans (separate or combined), and blood glucose levels were less than 150 mg/dL at the time of the 18F-FDG injection. Approximately 60 min after intravenous administration of the radiopharmaceutical, a multislice helical noncontrast CT scan was obtained from the skull vertex to the toes. This scan was used for attenuation correction and anatomic localization of the administered radiopharmaceuticals. Immediately after the CT scan, an emission PET scan was acquired over the same anatomic regions. The PET images were corrected using segmented attenuation data from the CT scan. PET images were reconstructed with a standard iterative algorithm; reformatted into axial, coronal, and sagittal views; and reviewed centrally (Stanford). The prescribed doses were 370–555 MBq (10–15 mCi) for 18F-FDG, 185–370 MBq (5–10 mCi) for 18F−, and 555 MBq (15 mCi) of 18F-FDG + 185 MBq (5 mCi) of 18F− for the combined scan. For the 18F−/18F-FDG scans, the 2 radiotracers were delivered from the local cyclotron facilities in separate syringes and administered sequentially, with less than a minute delay. The order of administration was not controlled.

Image Analysis

The 18F− PET/CT, 18F-FDG PET/CT, and 18F−/18F-FDG PET/CT images were interpreted in randomized order by 2 board-certified nuclear medicine physicians unaware of the diagnosis and the results of other imaging studies, using the software provided by the manufacturer (Xeleris; GE Healthcare). The readers were masked to the 2 other scans when reading 1 scan in a given patient in order to avoid recall bias. Discrepancies were resolved by a consensus reading. A direct comparison for each detected lesion was performed among the 3 scans. For image interpretation, visual analysis was used instead of quantitative analysis. For 18F− PET/CT, areas of focally increased 18F− skeletal uptake were read as malignant unless a benign etiology for this uptake was identified at the same location on the corresponding CT images. For 18F-FDG PET/CT, focal 18F-FDG uptake less than that of the mediastinal blood pool was considered benign, uptake equal to that of the mediastinal blood pool was considered uncertain, and uptake greater than that of the mediastinal blood pool was considered malignant. Prior work has shown the validity of qualitative assessment of 18F-FDG uptake in various malignancies (11–15). For the 18F−/18F-FDG PET/CT scans, the above-mentioned criteria were combined to define focal uptake as benign, uncertain, or malignant.

In the subgroup of participants with more skeletal lesions detected on 18F− PET/CT and combined 18F−/18F-FDG PET/CT than on 18F-FDG PET/CT, CT images of the bones were also evaluated independently by 2 board-certified radiologists masked to the diagnosis and the results of the PET scanning. Discrepancies were resolved by a consensus reading.

Each patient had all 3 scans acquired on the same scanner to avoid variability. Phantom studies were not conducted to calibrate the scanners used at the 4 participating institutions. However, because no quantitative or semiquantitative analyses were used, lack of calibration did not interfere with the results of the study.

RESULTS

The injected doses of 18F-FDG ranged from 358.9 to 684.5 (9.7–18.5 mCi) (average, 503.2 ± 92.5 MBq [13.6 ± 2.5 mCi]) for the separate scans and from 162.8 to 662.3 MBq (4.4–17.9 mCi) (average, 444 ± 88.8 MBq [12.0 ± 2.4 mCi]) for the combined scans (P = 0.0007). The injected doses of 18F− ranged from 144.3 to 503.2 MBq (3.9–13.6 mCi) (average, 251.6 ± 96.2 MBq [6.8 ± 2.6 mCi]) for the separate scans and from 136.9 to 518 MBq (3.7–14 mCi) (average, 196.1 ± 51.8 MBq [5.3 ± 1.4 mCi]) for the combined scans (P = 0.0001). The time from intravenous administration of the radiopharmaceuticals to imaging ranged from 43 to 157 min (average, 81.1 ± 20.2) for the separate 18F-FDG scans, from 39 to 154 min (average, 84.5 ± 23.7) for the separate 18F− scans, and from 52 to 213 min (average, 86.0 ± 26.5) for the combined scans. These time differences were not statistically significant. The variations in doses and times from injection to imaging are part of routine clinical practice even at major academic centers (16).

For the 96 patients referred for imaging as part of the subsequent treatment strategy, the time from the most recent treatment to the first scan done as part of the research protocol ranged from 1.5 to 204 mo (average, 44.4 mo).

Combining the findings of the separate 18F− PET/CT and 18F-FDG PET/CT scans resulted in identification of malignant lesions in 82 of the 115 participants. One patient diagnosed with prostate cancer had a pelvic osseous bone metastasis seen on 18F-FDG PET/CT but not on 18F− PET/CT. 18F− PET/CT identified bone metastases in 67 of the 115 participants, whereas 18F-FDG PET/CT detected bone metastases in 38 of the 115 participants. A typical example in Figure 1, of a 74-y-old man with recently diagnosed prostate cancer, shows extensive pelvic osseous metastases seen on the 18F− and combined PET scans but not on 18F-FDG PET. However, 18F-FDG PET/CT detected extraosseous malignant lesions in 48 of the 115 participants. Figure 2 illustrates extensive extraosseous metastases seen on the 18F-FDG and combined scans in a 45-y-old woman with breast cancer. The most common extraskeletal sites of metastases were lymph nodes (28/115 participants), lungs (14/115 participants), and liver (8/115 participants). 18F−/18F-FDG PET/CT missed three 18F-FDG–avid lung nodules in 2 participants and two 18F−-avid skull lesions in another 2 participants. These 4 participants had other sites of disease that were clearly identified on both the individual tracer scans and the combined scans; thus, the missed lesions would not have affected the overall staging.

FIGURE 1.
FIGURE 1.

A 74-y-old man with metastatic prostate cancer. (A–C) Extensive pelvic osseous metastases (arrows) are not identified on 18F-FDG PET scan (A) but are clearly seen on 18F− (B) and combined PET (C) scans. (D) CT demonstrates sclerotic changes.

FIGURE 2.
FIGURE 2.

A 45-y-old woman with metastatic breast cancer. Extensive soft-tissue metastases (arrowheads) are seen on 18F-FDG (A) and combined PET (C) scans. A single bone metastasis (arrow) is visualized on all 3 scans.

Evaluation of 18F−/18F-FDG PET/CT Versus 18F− PET/CT

Two skull lesions seen on 18F− scans were missed on the corresponding 18F−/18F-FDG combined scans. These missed lesions did not change the participants’ management, because other skeletal lesions were identified and altered the staging accordingly. The 2 missed skull lesions are presented in Figure 3.

FIGURE 3.
FIGURE 3.

Skull lesions (arrows) are identified in 2 participants on CT (A) and 18F− PET (B) scans but not on combined 18F− scans (C).

Evaluation of 18F−/18F-FDG PET/CT Versus 18F-FDG PET/CT

Visual analysis showed that 18F−/18F-FDG PET images allow for accurate interpretation of uptake in the soft tissues. However, small pulmonary nodules were missed in 2 participants. These nodules, less visible on the combined scan than on the 18F-FDG scan, are shown in Figure 4.

FIGURE 4.
FIGURE 4.

A 53-y-old woman with soft-tissue sarcoma. Lung nodule (arrowheads) is seen on CT (A) and 18F-FDG PET (B) scans but is not easily identifiable on combined 18F−/18F-FDG scans (C).

Evaluation of 18F− PET/CT Versus 18F-FDG PET/CT

In 19 participants, skeletal metastases were more extensive on 18F− PET/CT and combined 18F−/18F-FDG PET/CT than on 18F-FDG PET/CT. When CT data were analyzed alone, bone metastases were identified in 17 patients, fewer lesions than on the PET data were seen in 1 patient, and findings were negative despite lesions seen on PET in 1 patient. In 29 participants, 18F− PET/CT showed osseous metastases not present on 18F-FDG PET/CT. In this subgroup, CT alone identified bone metastases in 15 patients, whereas fewer lesions than on the PET data were seen in 8 patients and CT was negative despite lesions seen on PET in 6 patients. The extent of osseous metastases was similar in another 18 patients on all 3 scans. In 1 participant, 18F-FDG PET/CT showed focal radiopharmaceutical uptake in a lytic skeletal metastasis not identified prospectively on 18F− PET/CT. In retrospect, a rim of increased 18F− uptake was noted around this lesion. The remaining 47 (of 115 total) patients had no osseous metastases identified on any of the 3 scans.

DISCUSSION

Published data support the use of bone imaging (99mTc-MDP or 18F−) and 18F-FDG PET/CT for detection of skeletal metastases in selected cancer patients, as both lytic and sclerotic lesions may coexist and have different mechanisms of radiotracer uptake. The spatial resolution of 99mTc-MDP planar scintigraphy and SPECT affects their sensitivity for detection of osseous metastases. Thus, the transition to the better resolution of PET/CT for detection of osseous metastases appears appealing, with 18F− as the radiotracer of choice. 18F− PET/CT is superior to 99mTc-MDP planar scintigraphy and SPECT for bone lesion detection (17–20). Semiquantitative analysis based on 18F− PET/CT is also more accurate than 99mTc-MDP SPECT for assessing the response to treatment of bone metastases (21).

18F-FDG PET/CT provides unique information on the glucose metabolism of certain skeletal lesions (22). The location of a metastasis in the skeleton and the aggressiveness of the tumor itself are important with regard to the extent of the metabolic response induced and therefore the amount of 18F-FDG uptake (23). Published data suggest that 18F-FDG PET is less sensitive than bone scintigraphy for prostate cancer in the detection of osseous metastatic lesions but may be useful in the detection of metastatic nodal and soft-tissue disease (24,25). Other investigators have shown that the level of 18F-FDG uptake in prostate cancer lesions is an independent prognostic factor and provides complementary prognostic information to 99mTc-MDP bone scans (26).

The use of both 18F− PET/CT and 18F-FDG PET/CT may be needed in patients with selected cancers. In this study we combined 2 separate scans into a single imaging procedure, providing evidence of the superiority of this approach, which may be cost-effective and convenient for selected cancer patients. Before the advent of combined PET/CT technology, Hoegerle et al. reported the use of combined 18F−/18F-FDG administration for PET (27). Indeed, the authors attempted to use skeletal 18F− uptake as a surrogate for anatomic localization of abnormal 18F-FDG in the absence of fused PET and CT. In their study, the images obtained after combined administration were not compared with separate 18F− and 18F-FDG scans in every participant. With the availability of PET/CT, an entirely new combined radiotracer approach allows for a strategy for patient management not previously possible.

Skull lesions seen on 18F− PET and subcentimeter-sized lung nodules seen on 18F-FDG PET were missed on the combined scan in 4 participants. One missed skull lesion was from a combined scan acquired at 213 min after injection of 170.2 MBq (4.6 mCi) of 18F− and 488.4 MBq (13.2 mCi) of 18F-FDG. Therefore it is conceivable that the delayed time to imaging may have contributed to the nonvisualization. The proximity to the rib cage of the lung nodules less visible on the combined scan than on the separate 18F-FDG scan and the 18F− uptake in the osseous structures may have contributed to this lack of clear identification. However, none of these missed lesions changed the participants’ management, because other lesions were identified. We anticipate that future research optimizing the ratio of 18F− to 18F-FDG dosages in the combined scan may solve the infrequent issue of less well visualized lesions on the combined scan than on the separate scans. In fact, recent data suggest that a ratio of 1:5 may be optimal when 18F− and 18F-FDG are administered for the cocktail approach (27). We are also exploring image reconstruction strategies that will minimize the chance of such missed lesions on the combined scan.

We acknowledge that some of the lesions that were identified on the combined scans due to the addition of 18F− may represent treatment-related changes (i.e., bone repair) and not active metastases, as our patient population included patients already treated. However, additional lesions were also found in patients presenting for initial staging. Although this may represent a limitation of the study, our goal was to demonstrate that 18F−/18F-FDG PET/CT shows promising results, not to document the performance of CT or separate 18F-FDG PET or 18F− PET for detection of true-positive malignant lesions. Therefore, we did not assess the identified lesions as true-positive, true-negative, false-positive, or false-negative at the central-site reading. This issue will be further evaluated in future research.

Other limitations of this study included the participants’ heterogeneous cancer types, the selection bias toward patients with known malignancy, and the different disease stages of the participants. To come to statistically sound conclusions regarding the appropriate indications for 18F−/18F-FDG PET/CT, further prospective enrollment of subjects is needed, focusing on particular cancer groups. Furthermore, bone marrow–stimulating therapy induces intense 18F-FDG uptake in the skeleton (29) and may play a confounding role in the evaluation of osseous structures on 18F−/18F-FDG PET. This particular instance of evaluation of response to therapy by 18F−/18F-FDG PET/CT also needs to be separately evaluated in future studies. Another limitation of the study is that semiquantitative analysis of the radiopharmaceutical uptake such as standarized uptake value measurements was not performed. Semiquantitative analysis of 18F− PET/CT scans is still an evolving field that has no standardized procedures and lacks validation (8). Issues such as the effect of 18F− on bone and soft-tissue uptake of 18F-FDG when given simultaneously also have not been explored. An analysis of these issues was beyond the scope of the current study. Although this kind of analysis should certainly be addressed in future evaluations, the conclusions on the feasibility of combined 18F−/18F-FDG scans drawn from this study remain valid. The limitations and issues identified in this trial, as well as potential solutions to investigate them, are listed in Table 3.

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TABLE 3

Limitations and Issues Identified in this Trial, as Well as Potential Solutions to Investigate Them

With regard to radiation exposure, 99mTc-MDP bone scintigraphy results in approximately 4.2 mSv (420 mrem) and 18F-FDG PET/CT in approximately 26.5 mSv (2,650 mrem) (1.1 mSv/MBq [110 mrem/mCi] from 18F-FDG and 10 mSv [1,000 mrem] from low-dose CT), or a total of 30.7 mSv (3,070 mrem). Combining 18F− PET/CT and 18F-FDG PET/CT in a single examination will result in a total of 31.5 mSv (3,150 mrem) (1.1 mSv/MBq [110 mrem/mCi] from 18F-FDG, 1.0 mSv/MBq [100 mrem/mCi] from 18F−, and 10.0 mSv [1,000 mrem] from low-dose CT). Using these estimates and the range and average of injected doses, the participants in the study received 10.67–20.35 mSv (1,067–2,035 mrem) (average, 15.18–2.75 mSv [1,518 ± 275 mrem]) from the separate 18F-FDG scans, 3.90–13.60 mSv (390–1,360 mrem) (average, 6.90–2.60 mSv [690 ± 260 mrem]) from the separate 18F− scans, and 4.84–19.69 mSv (484–1,969 mrem) (average, 13.31 ± 2.64 mSv [1,331 ± 264 mrem]) from 18F-FDG and 3.70–14.00 mSv (370–1,400 mrem) (average, 15.18 ± 2.75 mSv [1,518 ± 275 mrem]) from 18F− in the combined scans. The newest PET/CT scanners have increased sensitivity, and the doses of 18F-FDG and 18F− can be reduced further (30), resulting in less radiation exposure from 18F−/18F-FDG PET/CT. Thus, instead of patients having to get a separate 99mTc-MDP bone scan or 18F-FDG PET/CT study, usually on different days, our strategy allows for a single combined PET/CT scan with potentially more utility, lower radiation dose, and greater patient convenience. The recent introduction of hybrid PET/MR technology in clinical practice (31–33) may lead to the use of the combined approach with PET/MR scanners in specific indications, resulting in even less radiation exposure.

Using the current reimbursement rate from the Centers for Medicare and Medicaid Services, we estimate that approximately $273 in reimbursement may be saved per patient by performing 18F−/18F-FDG PET/CT instead of separate 18F-FDG PET/CT and 99mTc-MDP bone scintigraphy. Not everyone referred for these imaging procedures will be a candidate for the combined scan. However, considering that approximately 2 million 99mTc-MDP bone scans are performed annually to evaluate malignancy in the United States, and assuming that approximately 500,000 18F-FDG PET/CT scans are performed in the same population, the combined scan can potentially amount to a total of approximately $136.5 million saved annually in reimbursement (Table 4). Therefore, this strategy may allow for potentially significant cost savings for the health-care system. Although these estimates may be representative of the health-care costs in the United States, the actual savings in the health-care systems of the other participating centers is unknown.

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TABLE 4

Cost Estimates for Separate 99mTc-MDP Bone Scan and 18F-FDG PET/CT vs. Combined 18F−/18F-FDG PET/CT Scan

CONCLUSION

This prospective multicenter trial indicated promising results for 18F−/18F-FDG PET/CT when compared with separate 18F− PET/CT and 18F-FDG PET/CT in the evaluation of cancer patients. This finding opens the possibility for improved patient care and reduction of health-care costs. Further evaluation of this proposed imaging modality is warranted to identify the most suitable scenarios for routine clinical use.

DISCLOSURE

The costs of publication of this article were defrayed in part by the payment of page charges. Therefore, and solely to indicate this fact, this article is hereby marked “advertisement” in accordance with 18 USC section 1734. This research was supported in part by NCI ICMIC CA114747, and the clinical studies were supported in part by the Doris Duke Foundation and NECSA/NTP. No other potential conflict of interest relevant to this article was reported.

Acknowledgments

We thank Drs. Srihari Sampath and Srinath Sampath for assistance with the interpretation of CT images of the bones, all the technologists at the participating sites, our research fellow Khun Visith Keu, our clinical research coordinators Lindee Burton and Euodia Jonathan, and Dr. Frederick Chin in the Cyclotron Facility, as well as all the participants and their families. The ClinicalTrials.gov identifier for this study is NCT00725387.

Footnotes

  • Published online Dec. 14, 2012

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  • Received for publication May 21, 2012.
  • Accepted for publication August 30, 2012.
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