David W. Dick

Novel Strategy for a Cocktail 18F-Fluoride and 18F-FDG PET/CT Scan for Evaluation of Malignancy: Results of the Pilot-Phase Study

18F-FDG PET/CT is used for detecting cancer and monitoring cancer response to therapy. However, because of the variable rates of glucose metabolism, not all cancers are identified reliably. Sodium 18F was previously used for bone imaging and can be used as a PET/CT skeletal tracer. The combined administration of 18F and 18F-FDG in a single PET/CT study for cancer detection has not been reported to date. Methods: This is a prospective pilot study (November 2007–November 2008) of 14 patients with proven malignancy (6 sarcoma, 3 prostate cancer, 2 breast cancer, 1 colon cancer, 1 lung cancer, and 1 malignant paraganglioma) who underwent separate 18F PET/CT and 18F-FDG PET/CT and combined 18F/18F-FDG PET/CT scans for the evaluation of malignancy (a total of 3 scans each). There were 11 men and 3 women (age range, 19–75 y; average, 50.4 y). Results: Interpretation of the combined 18F/18F-FDG PET/CT scans compared favorably with that of the 18F-FDG PET/CT (no lesions missed) and the 18F PET/CT scans (only 1 skull lesion seen on an 18F PET/CT scan was missed on the corresponding combined scan). Through image processing, the combined 18F/18F-FDG scan yielded results for bone radiotracer uptake comparable to those of the 18F PET/CT scan performed separately. Conclusion: Our pilot-phase prospective trial demonstrates that the combined 18F/18F-FDG administration followed by a single PET/CT scan is feasible for cancer detection. This combined method opens the possibility for improved patient care and reduction in health care costs.

Prospective comparison of combined 18F-FDG and 18F-NaF PET/CT vs. 18F-FDG PET/CT imaging for detection of malignancy

PurposeTypically, 18F-FDG PET/CT and 18F-NaF PET/CT scans are done as two separate studies on different days to allow sufficient time for the radiopharmaceutical from the first study to decay. This is inconvenient for the patients and exposes them to two doses of radiation from the CT component of the examinations. In the current study, we compared the clinical usefulness of a combined 18F-FDG/18F-NaF PET/CT scan with that of a separate 18F-FDG-only PET/CT scan.MethodsThere were 62 patients enrolled in this prospective trial. All had both an 18F-FDG-alone PET/CT scan and a combined 18F-FDG/18F-NaF PET/CT scan. Of the 62 patients, 53 (85%) received simultaneous tracer injections, while 9 (15%) received 18F-NaF subsequent to the initial 18F-FDG dose (average delay 2.2 h). Images were independently reviewed for PET findings by two Board-Certified nuclear medicine physicians, with discrepancies resolved by a third reader. Interpreters were instructed to only report findings that were concerning for malignancy. Reading the 18F-FDG-only scan first for half of the patients controlled for order bias.ResultsIn 15 of the 62 patients (24%) neither the 18F-FDG-only PET/CT scan nor the combined 18F-FDG/18F-NaF PET/CT scan identified malignancy. In the remaining 47 patients who had PET findings of malignancy, a greater number of lesions were detected in 16 of 47 patients (34%) using the combined 18F-FDG/18F-NaF PET/CT scan compared to the 18F-FDG-only PET/CT scan. In 2 of these 47 patients (4%), the 18F-FDG-only scan demonstrated soft tissue lesions that were not prospectively identified on the combined study. In 29 of these 47 patients (62%), the combined scan detected an equal number of lesions compared to the 18F-FDG-only scan. Overall, 60 of all the 62 patients (97%) showed an equal or greater number of lesions on the combined scan than on the 18F-FDG-only scan.ConclusionThe current study demonstrated that 18F-FDG and 18F-NaF can be combined in a single PET/CT scan by administering the two radiopharmaceuticals simultaneously or in sequence on the same day. In addition to patient convenience and reduced radiation exposure from the CT component, the combined 18F-FDG/18F-NaF PET/CT scan appeared to increase the sensitivity for detection of osseous lesions compared to the 18F-FDG-only PET/CT scan in the studied population.

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

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.

Pilot prospective evaluation of 99mTc-MDP scintigraphy, 18F NaF PET/CT, 18F FDG PET/CT and whole-body MRI for detection of skeletal metastases.

Objective The aim of this study was to compare 99mTc-MDP bone scanning, 18F NaF PET/CT, 18F FDG PET/CT, and whole-body MRI (WBMRI) for detection of known osseous metastases. Patients and Methods This prospective pilot trial (September 2007-April 2009) enrolled 10 participants (5 men, 5 women, 47–81 years old) diagnosed with cancer and known osseous metastases. 18F NaF PET/CT, 18F FDG PET/CT, and WBMRI were performed within 1 month for each participant. Results The image quality and evaluation of extent of disease were superior by 18F NaF PET/CT compared to 99mTc-MDP scintigraphy in all patients with skeletal lesions and compared to 18F FDG PET/CT in 3 of the patients with skeletal metastases. 18F NaF PET/CT showed osseous metastases where 18F FDG PET/CT was negative in another 3 participants. Extraskeletal metastases were identified by 18F FDG PET/CT in 6 participants. WBMRI with the combination of iterative decomposition of water and fat with echo asymmetry and least-squares estimation, short tau inversion recovery, and diffusion-weighted imaging pulse sequences showed fewer lesions than 18F NaF PET/CT in 5 patients, same number of lesions in 2 patients, and more lesions in 1 patient. WBMRI showed fewer lesions than 18F FDG in 3 patients and same lesions in 6 patients. Conclusions Our pilot phase prospective trial demonstrated superior image quality and evaluation of skeletal disease extent with 18F NaF PET/CT compared to 99mTc-MDP scintigraphy and 18F FDG PET/CT, as well as the feasibility of multisequence WBMRI. In addition, 18F FDG PET/CT provided valuable soft-tissue information that can change disease management. Further evaluation of these findings using the recently introduced PET/MRI scanners is warranted.

Regulatory Requirements for PET Drug Production

The Food and Drug Administration (FDA) issued the final rule for title 21 of Code of Federal Regulations part 212 regarding the regulations on current good manufacturing practice for PET drugs. The regulations are intended to ensure that PET drugs meet the safety and quality assurance requirements of the Federal Food, Drug, and Cosmetic Act. The new regulation became effective December 12, 2011, but the FDA used regulatory discretion to allow new drug applications and abbreviated new drug applications to be filed until June 12, 2012, without interruption of the existing PET drug production for human use. The production of PET drugs for both clinical use and clinical research use are outlined in this continuing education module, including an overview of specific requirements for compliance. Additionally, FDA preapproval inspections and postapproval reporting requirements are reviewed.

Diversification of 99Mo/99mTc Supply

The article by Bénard et al. in this month’s issue of The Journal of Nuclear Medicine (1) is an important work, showing the feasibility of producing large quantities of 99mTc on a biomedical cyclotron and extraction of the 99mTc from the target material, converting it to a chemical form suitable for conventional compounding of nuclear medicine drugs. The authors state “with some modifications of existing cyclotron infrastructure, this approach can be used to implement a decentralized medical isotope production model. This method eliminates the need for enriched uranium and the radioactive waste associated with the processing of uranium targets.” The recent planned and unplanned shutdowns of nuclear reactors producing 99Mo highlight the need for alternative production methods, necessitating a review of the current state of

Combined 18F-fluoride and 18F-FDG PET/CT: a response based on actual data from prospective studies.

Dear Sir, We read with interest the Editorial titled “Critical considerations on the combined use of F-FDG and F-fluoride for PET assessment of metastatic bone disease” by Cheng et al., published in the European Journal of Nuclear Medicine and Molecular Imaging on 22 May 2013 [1]. It is our intention to provide a rebuttal to the Editorial’s viewpoints. In the first paragraph, the authors suggest that combined F-fluoride and F-FDG PET/CT has been proposed as a method to improve cancer diagnosis, staging, and therapy monitoring. In our published work, we acknowledged that this approachmight not work for all patients and we suggested that further evaluation of this proposed imaging modality is warranted to identify the most suitable scenarios for routine clinical use [2]. The authors present incorrectly the chronological timeline of our work. Their reference 4 is indeed our pilot study [3]; however, reference 5 is not a pilot study, but a large prospective international study that enrolled 115 participants diagnosed with cancer at four institutions in Denmark, Portugal, South Africa and the US. In addition, another collaboration with an institution in India resulted in another publication reporting the results of combined F-fluoride and F-FDG PET/CT in another 62 cancer patients [4]. Cheng et al. mention the letters to the Editor published in the Journal of Nuclear Medicine in response to the publication of our pilot study [5, 6], yet they omit our response to these letters [7]. It is first argued that F-FDG PET/CT is superior to bone scintigraphy and therefore there is no advantage to adding F-fluoride PET/CT to F-FDG PET/CT. We find it surprising that the authors used citations of work that compared PET/ CTwith planar scintigraphy to support their perspective. Even a comparison of PET/CT and SPECT/CT may not be fair. F-fluoride PET/CT is superior for bone lesion detection when compared to Tc-MDP planar scintigraphy and SPECT [8–10]. Again, our own data are misrepresented as a pilot study, when in reality we reported the results from 52 patients with cancer who were prospectively enrolled [11]. In our published work we quoted publications that indicate that F-FDG PET/ CT provides unique information regarding the glucose metabolism of certain skeletal lesions [12]. However, other published data suggest that F-FDG PET is less sensitive than bone scintigraphy in the detection of osseous metastatic lesions in prostate cancer, but may be useful in the detection of metastatic nodal and soft tissue disease [13–15]. F-fluoride PET/CTalso correlates with PSA levels that are important for monitoring disease progression [15]. We do acknowledge that F-FDG PET/CToutperforms F-fluoride PET/CT in certain malignancies such as lung cancer [16, 17], but only three of the 115 participants in our study were diagnosed with lung cancer. Cheng et al. mention that although the sensitivity of F-fluoride PET is high for osteoblastic lesions, its low specificity is an important concern. As an example, they mention that degenerative change is the most common finding on F-fluoride imaging with intense uptake, but often has only mild to A. Iagaru (*) Division of Nuclear Medicine and Molecular Imaging, Stanford University Medical Center, 300 Pasteur Dr, Stanford, CA 94305, USA e-mail: aiagaru@stanford.edu

PET/MRI: Safety Considerations

Safety is an important consideration in PET/MRI and is complicated by the coexistence of the safety concerns of MRI and PET. These issues have significant impact on both patient workflow and the design of the PET/MRI facility. When considering patient workflow, one must consider where patients will be injected with the radiotracer and when screening for MRI safety occurs. Additionally, PET/MRI facilities should be designed with both MRI and radiation safeties in mind. Below we discuss the specific safety concerns associated with PET and MRI separately.

Localization of Unknown Primary Site with 68Ga-DOTATOC PET/CT in Patients with Metastatic Neuroendocrine Tumor

Localization of the site of the unknown primary tumor is critical for surgical treatment of patients presenting with neuroendocrine tumor (NET) with metastases. Methods: Forty patients with metastatic NET and unknown primary site underwent 68Ga-DOTATOC PET/CT in a single-site prospective study. The 68Ga-DOTATOC PET/CT was considered true-positive if the positive primary site was confirmed by histology or follow-up imaging. The scan was considered false-positive if no primary lesion was found corresponding to the 68Ga-DOTATOC–positive site. All negative scans for primary tumor were considered false-negative. A scan was classified unconfirmed if 68Ga-DOTATOC PET/CT suggested a primary, however, no histology was obtained and imaging follow-up was not confirmatory. Results: The true-positive, false-positive, false-negative, and unconfirmed rates for unknown primary tumor were 38%, 7%, 50%, and 5%, respectively. Conclusion: 68Ga-DOTATOC PET/CT is an effective modality in the localization of unknown primary in patients with metastatic NET.