Ina Binse

68Ga-DOTATOC Versus 68Ga-DOTATATE PET/CT in Functional Imaging of Neuroendocrine Tumors

Radiolabeled somatostatin analogs represent valuable tools for both in vivo diagnosis and therapy of neuroendocrine tumors (NETs) because of the frequent tumoral overexpression of somatostatin receptors (sst). The 2 compounds most often used in functional imaging with PET are 68Ga-DOTATATE and 68Ga-DOTATOC. Both ligands share a quite similar sst binding profile. However, the in vitro affinity of 68Ga-DOTATATE in binding the sst subtype 2 (sst2) is approximately 10-fold higher than that of 68Ga-DOTATOC. This difference may affect their efficiency in the detection of NET lesions because it is the sst2 that is predominantly overexpressed in NET. We thus compared the diagnostic value of PET/CT with both radiolabeled somatostatin analogs (68Ga-DOTATATE and 68Ga-DOTATOC) in the same NET patients. Methods: Forty patients with metastatic NETs underwent 68Ga-DOTATOC and 68Ga-DOTATATE PET/CT as part of the work-up before prospective peptide receptor radionuclide therapy. The performance of both imaging methods was analyzed and compared for the detection of individual lesions per patient and for 8 defined body regions. A region was regarded positive if at least 1 lesion was detected in that region. In addition, radiopeptide uptake in terms of the maximal standardized uptake value (SUVmax) was compared for concordant lesions and renal parenchyma. Results: Seventy-eight regions were found positive with 68Ga-DOTATATE versus 79 regions with 68Ga-DOTATOC (not significant). Overall, however, significantly fewer lesions were detected with 68Ga-DOTATATE than with 68Ga-DOTATOC (254 vs. 262, P < 0.05). Mean 68Ga-DOTATATE SUVmax across all lesions was significantly lower than 68Ga-DOTATOC (16.0 ± 10.8 vs. 20.4 ± 14.7, P < 0.01). Mean SUVmax for renal parenchyma was not significantly different between 68Ga-DOTATATE and 68Ga-DOTATOC (12.7 ± 3.0 vs. 13.2 ± 3.3). Conclusion: 68Ga-DOTATOC and 68Ga-DOTATATE possess a comparable diagnostic accuracy for the detection of NET lesions, with 68Ga-DOTATOC having a potential advantage. The approximately 10-fold higher affinity for the sst2 of 68Ga-DOTATATE does not prove to be clinically relevant. Quite unexpectedly, SUVmax of 68Ga-DOTATOC scans tended to be higher than their 68Ga-DOTATATE counterparts.

Differential uptake of (68)Ga-DOTATOC and (68)Ga-DOTATATE in PET/CT of gastroenteropancreatic neuroendocrine tumors.

PURPOSE Abundant expression of somatostatin receptors (sst) is a characteristic of neuroendocrine tumors (NET). Thus, radiolabeled somatostatin analogs have emerged as important tools for both in vivo diagnosis and therapy of NET. The two compounds most often used in functional imaging with positron emission tomography (PET) are (68)Ga-DOTATATE and (68)Ga-DOTATOC. Both analogs share a quite similar sst binding profile. However, the in vitro affinity of (68)Ga-DOTATATE in binding the sst subtype 2 (sst2) is approximately tenfold higher than that of (68)Ga-DOTATOC. This difference may affect their efficiency in detection of NET lesions, as sst2 is the predominant receptor subtype on gastroenteropancreatic NET. We thus compared the diagnostic value of PET/CT with both radiolabeled somatostatin analogs ((68)Ga-DOTATATE and (68)Ga-DOTATOC) in the same patients with gastroenteropancreatic NET. PATIENTS AND METHODS Twenty-seven patients with metastatic gastroenteropancreatic NET underwent (68)Ga-DOTATOC and (68)Ga-DOTATATE PET/CT as part of the workup before prospective peptide receptor radionuclide therapy (PRRT). The performance of both imaging methods was analyzed and compared for detection of individual lesions per patient and for eight defined body regions. A region was regarded as positive if at least one lesion was detected in that region. In addition, radiopeptide uptake in terms of the maximal standardized uptake value (SUV(max)) was compared for concordant lesions and renal parenchyma. RESULTS Fifty-one regions were found positive with both (68)Ga-DOTATATE and (68)Ga-DOTATOC. Overall, however, significantly fewer lesions were detected with (68)Ga-DOTATATE in comparison with (68)Ga-DOTATOC (174 versus 179, p < 0.05). Mean (68)Ga-DOTATATE SUV(max) across all lesions was significantly lower compared with (68)Ga-DOTATOC (16.9 ± 6.8 versus 22.1 ± 12.0, p < 0.01). Mean SUV(max) for renal parenchyma was not significantly different between (68)Ga-DOTATATE and (68)Ga-DOTATOC (12.6 ± 2.6 versus 12.6 ± 2.7). CONCLUSIONS (68)Ga-DOTATOC and (68)Ga-DOTATATE possess similar diagnostic accuracy for detection of gastroenteropancreatic NET lesions (with a potential advantage of (68)Ga-DOTATOC) despite their evident difference in affinity for sst2. Quite unexpectedly, maximal uptake of (68)Ga-DOTATOC tended to be higher than its (68)Ga-DOTATATE counterpart. However, tumor uptake shows high inter- and intraindividual variance with unpredictable preference of one radiopeptide. Thus, our data encourage the application of different sst ligands to enable personalized imaging and therapy of gastroenteropancreatic NET with optimal targeting of tumor receptors.

The Impact of Somatostatin Receptor–Directed PET/CT on the Management of Patients with Neuroendocrine Tumor: A Systematic Review and Meta-Analysis

Somatostatin receptor (SSTR) imaging is widely used for guiding the management of neuroendocrine tumor (NET) patients. 68Ga-DOTATATE approval by the U.S. Food and Drug Administration has triggered widespread clinical interest in SSTR PET/CT throughout the United States. Here, we performed a systematic review and meta-analysis to evaluate the impact of SSTR PET/CT on the management of patients with NETs. Methods: A comprehensive literature search was performed using The National Center for Biotechnology Information PubMed online database, applying the following key words: “management” AND “PET” AND “neuroendocrine”. Fourteen of 190 studies were deemed suitable based on the following inclusion criteria: original research, cohort study, number of patients 10 or more, and reported change in management after SSTR PET/CT. Change in management across studies was determined by a random-effects model. Results: A total of 1,561 patients were included. Overall, change in management occurred in 44% (range, 16%–71%) of NET patients after SSTR PET/CT. In 4 of 14 studies, SSTR PET/CT was performed after an 111In-Octreotide scan. In this subgroup, additional information by SSTR PET/CT led to a change in management in 39% (range, 16%–71%) of patients. Seven of 14 studies differentiated between inter- and intramodality changes, with most changes being intermodality (77%; intramodality, 23%). Conclusion: The management was changed in more than one third of patients undergoing SSTR PET/CT even when performed after an 111In-Octreotide scan. Intermodality changes were 3 times more likely than intramodality changes, underlining the clinical impact of SSTR PET/CT.

High Level of Agreement Between Pretherapeutic 124I PET and Intratherapeutic 131I Imaging in Detecting Iodine-Positive Thyroid Cancer Metastases

The aim of this retrospective study was to assess the level of agreement between PET and scintigraphy using diagnostic amounts of 124I and therapeutic amounts of 131I, respectively, in detecting iodine-positive metastases in patients with differentiated thyroid carcinoma. Methods: The study included patients who underwent PET/CT 24 and 120 h after administration of approximately 25 MBq of 124I and subsequently underwent imaging 5–10 d after administration of 1–10 GBq of 131I. For each patient, the intratherapeutic 131I imaging comprised a whole-body scintigraphy scan and a SPECT/CT scan of the neck to distinguish between metastatic and thyroid remnant tissues. Iodine uptake was rated as a metastatic focus if located outside the thyroid bed. Lesion- and patient-based analyses were performed. Results: The study included 137 patients with 227 metastases iodine-positive on both functional imaging modalities. In the lesion-based analysis, 124I PET and 131I imaging detected 98% (223/227) and 99% (225/227) of the iodine-positive metastases, respectively; the level of agreement between 124I PET and 131I imaging was 97% (221/227). Four metastases (3 lymph node and 1 bone) in 4 patients were 124I-negative but 131I-positive, and 2 lymph node metastases in 2 patients were 131I-negative but 124I-positive. In the patient-based analysis, 61 of the 137 patients presented with iodine-positive metastases. 124I PET and 131I imaging detected at least one iodine-positive metastasis in 97% (59/61) and 98% (60/61) of the patients, respectively. The level of agreement was 95% (58/61). Both imaging modalities concordantly identified 76 of 137 patients without pathologic iodine uptake. Conclusion: Because of the high level of agreement, pretherapeutic 124I PET/CT is an adequate methodology in the detection of iodine-positive metastases and can be used as a reliable tool for staging of thyroid cancer patients and individualized treatment planning.

124I PET Assessment of Response of Bone Metastases to Initial Radioiodine Treatment of Differentiated Thyroid Cancer

Iodine-positive bone metastases (BMs) are often resistant after initial radioiodine therapy applying the standard-activity approach. A comprehensive lesion-based response study for BMs has not, to our knowledge, yet been performed. In this study, pretherapy and follow-up 124I PET/CT data on BMs from differentiated thyroid cancer patients were retrospectively analyzed to assess the relationship between absorbed dose (AD) of radiation and response after initial radioiodine treatment. Methods: Before and after initial radioiodine therapy, patients underwent serial PET/CT scanning after administration of 20–40 MBq of 124I. The pretherapy PET data were used to segment BM volumes and to predict the average ADs after administration of dosimetry-guided 131I activity. The lower volume limit of determinability of the applied segmentation method was a sphere volume of 0.16 mL. This volume limit classified the BMs into known-volume and fixed-volume groups with their respective average and minimum ADs. Follow-up 124I and 18F-FDG PET/CT data after treatment were analyzed to assess lesion-based therapy response. Response rates at different AD thresholds were calculated and were expressed as the percentage of completely responding BMs above the respective AD threshold. BMs with a maximum extent greater than twice the PET spatial resolution were visually scored for nonuniformity. Results: In total, 61 BMs in 10 patients were included, of which 46 and 15 comprised the known-volume group and the fixed-volume group, respectively. The median follow-up time was 5.6 mo (range, 3.7–23.2 mo). The median average and median minimum ADs in therapy were 183 Gy (range, 39–3,600 Gy) and 270 Gy (range, 63–1,300 Gy), respectively. A range of response rate of 70%–80% was achieved at an AD threshold range of 350–650 Gy. There were 26 BMs that were amenable to visual assessment of nonuniformity, of which two thirds (17/26) were scored as clearly nonuniform, and the majority (11/17) of these nonuniform BMs responded incompletely. Conclusion: Both the high AD threshold associated with high response rates and the low median AD per unit of 131I activity elucidate the difficulty in achieving therapeutic efficacy for BMs when a single standard activity is administered. The relatively high AD threshold range is possibly a result of distinct levels of spatial nonuniformity in ADs.

68Ga-DOTATOC-PET/CT in patients with iodine- and 18F-FDG-negative differentiated thyroid carcinoma and elevated serum thyroglobulin

This study evaluated the impact of 68Ga-DOTATOC PET/CT in detecting recurrence or metastases in differentiated thyroid carcinoma (DTC) patients with elevated serum thyroglobulin and both negative radioiodine imaging and negative 18F-FDG PET/CT. Methods: 68Ga-DOTATOC PET/CT (CT without contrast, low-dose) was performed on average 6 wk after negative 18F-FDG PET/CT (CT contrast-enhanced, full-dose) in 15 consecutive radioiodine-negative DTC patients with elevated and rising thyroglobulin. Visual assessment of 68Ga-DOTATOC PET/CT images used a 4-point scale for classification of lesions (0, no pathologic findings; 1, benign; 2, equivocal; 3, malignant). PET findings were correlated with the histologic subtype of tumor, levels of serum thyroglobulin, and morphologic findings on full-dose CT and neck ultrasound. Histology or clinical and imaging follow-up served as a reference standard. Analysis was performed on a patient and lesion basis. Results: 68Ga-DOTATOC PET/CT was true-positive in 5 patients (10 tumor lesions) and was false-positive in 1 patient. The rate of positive 68Ga-DOTATOC PET/CT was significantly higher in poorly differentiated/oxyphilic carcinomas (4/4 patients) than in papillary (1/5) or follicular (0/6) tumors. Thyroglobulin levels tended to be higher in patients with tumor localization on 68Ga-DOTATOC PET/CT, but differences were not significant. In 2 of 5 patients with true-positive findings on 68Ga-DOTATOC PET/CT, CT alone but not ultrasound identified 2 of 10 tumor lesions, but in both patients 68Ga-DOTATOC-PET/CT revealed further tumor lesions not detected on CT alone. Conclusion: 68Ga-DOTATOC PET/CT should be considered in the case of negative 18F-FDG PET/CT in radioiodine-negative DTC patients with elevated and rising thyroglobulin. Imaging with 68Ga-DOTATOC appears promising especially in poorly differentiated and oxyphilic subtypes of DTC.

Radioactive Iodine Therapy for Differentiated Thyroid Cancer: Lessons from Confronting Controversial Literature on Risks for Secondary Malignancy

1Section of Nuclear Medicine, Department of Radiology, Pennsylvania State University, Hershey, Pennsylvania; 2Department of Nuclear Medicine, University Hospital Essen, Essen, Germany; 3Nuclear Medicine Unit, Department of Biomedical and Dental Sciences and Morphofunctional Imaging, University of Messina, Messina, Italy; 4Imaging and Nuclear Medicine Department, Brighton and Sussex University Hospitals, Brighton and Sussex Medical School, Brighton, United Kingdom; 5EOC Thyroid Diagnosis and Therapy Centre, Nuclear Medicine and PET/CT Centre, Oncology Institute of Southern Switzerland, Bellinzona and Lugano, Switzerland; 6Nuclear Medicine Department, Monash Health, Melbourne, Victoria, Australia; 7Docrates Cancer Center, Molecular Radiotherapy and Nuclear Medicine, Helsinki, Finland; and 8Department of Nuclear Medicine, Hanyang University College of Medicine, Seoul, Korea

Simultaneous 11C-Methionine Positron Emission Tomography/Magnetic Resonance Imaging of Suspected Primary Brain Tumors.

Introduction The objective of this study was to assess the diagnostic value of integrated 11C- methionine PET/MRI for suspected primary brain tumors, in comparison to MRI alone. Material and Methods Forty-eight consecutive patients with suspected primary brain tumor were prospectively enrolled for an integrated 11C-methionine PET/MRI. Two neuro-radiologists separately evaluated the MRI alone and the integrated PET/MRI data sets regarding most likely diagnosis and diagnostic confidence on a 5-point scale. Reference standard was histopathology or follow-up imaging. Results Fifty-one suspicious lesions were detected: 16 high-grade glioma and 25 low-grade glioma. Ten non-malignant cerebral lesions were described by the reference standard. MRI alone and integrated PET/MRI each correctly classified 42 of the 51 lesions (82.4%) as neoplastic lesions (WHO grade II, III and IV) or non-malignant lesions (infectious and neoplastic lesions). Diagnostic confidence for all lesions, low-grade astrocytoma and high-grade astrocytoma (3.7 vs. 4.2, 3,1 vs. 3.8, 4.0 vs. 4,7) were significantly (p < 0.05) better with integrated PET/MRI than in MRI alone. Conclusions The present study demonstrates the high potential of integrated 11C-methionine-PET/MRI for the assessment of suspected primary brain tumors. Although integrated methionine PET/MRI does not lead to an improvement of correct diagnoses, diagnostic confidence is significantly improved.

Imaging of differentiated thyroid carcinoma: 124I-PET/MRI may not be superior to 124I-PET/CT

We are grateful to Vrachimis et al. for their careful reading of our article BImaging with 124I in differentiated thyroid carcinoma: is PET/MRI superior to PET/CT?^. They correctly observed that in our study the patients were scanned with arms down on PET/MRI, whereas the PET/CT was performed with arms up. We appreciate that they point out possible issues with regard to the different arm positions. However, we cannot follow their assertion that the higher detection rate of 124I-positive DTC lesions on neck PET/MRI compared to PET/CTwas primarily caused by the arm position and not by the higher sensitivity of the PET component of the PET/MRI system. It is well known that CT artifacts can appear if the arms are positioned at the patient’s side. Used for attenuation correction, impaired image quality of CT can lead to artifacts on PET. Although beam hardening artefacts were minimized by automatic mAs adjustment, we routinely check the CT image quality. Besides, additionally detected lesions on PET/MRI were also found on the non-attenuation-corrected PET/MRI images but not on the non-attenuation-corrected PET/CT images. We cannot rule out that the arm position may have decreased the signal-to-noise ratio on the PET/CT images of the neck. Yet, we question that there is a substantial difference between the arms-up and arms-down positions in the paraclavicular region. Interestingly, we not only found a higher sensitivity of PET/MRI in the cervical but also in the paraclavicular region (Fig. 3). Furthermore, although not systematically analyzed, we also found additional PET-positive lesions on PET/MRI of the thorax with arms in the field of view that were not visible on PET/CT with arms kept out of the field of view. We therefore surmise that beyond the arm position, other factors must have contributed to the lower sensitivity found for PET of PET/MRI in the [18 F]FDG PET studies cited by Vrachimis et al. Studies using different tracers should be compared with caution. Beyond differences in tumor-to-background ratio, the lower PET/MRI sensitivity found for [18 F]FDG might be due to lower specificity of this tracer compared to 124I. Thus, Vrachimis et al. interpreted low focal [18 F]FDG uptake compared to the background tissue as benign, as shown in Figure 1 of their article. In contrast to [18 F]FDG, low but focal 124I uptake in a location incompatible with normal radioiodine uptake is highly specific for metastases in DTC patients. The administered activity of 124I was low compared with [18 F]FDG, which might have contributed to a higher rate of lesions with low tracer uptake on 124I-PET imaging. Besides, Wiesmuller et al. not only used a different tracer but also reported about other tumor entities. In contrast to [18 F]FDG, the interval between the PET/CT and the PET/MRI scans was negligible in our study, because the tracer 124I has the advantage of a comparatively long halflife of about 4 days and differences in biodistribution can be disregarded 24 h after tracer administration. A direct comparison with the study of Vrachimis et al. is difficult since the classification of findings as benign or malign was based on a combined reading of morphological and functional images. In contrast to our study, a separate comparison of the PET component of both modalities was not performed. For example, we wonder if the higher detection rate of benign findings on PET/CTcompared to PET/MRI might be at least in part based on the CT component. This reply refers to the letter to the editor at http://dx.doi.org/10.1007/ s00259-016-3318-4.

Fixed 3.7-GBq 131 I Activity for Metastatic Thyroid Cancer Therapy Ignores Science and History

TO THE EDITOR: Deandreis et al. (1) compared the overall survival (OS) of 2 patient groups with metastatic differentiated thyroid cancer (mDTC). One group of patients underwent multiple 131I treatments using a standard administered activity (AA) of 3.7 GBq (100 mCi) at Gustave Roussy (GR), whereas the other group received individualized maximal tolerated activity (MTA) therapy at the Memorial Sloan Kettering Cancer Center (MSKCC). Finding no differences in OS between the approaches of GR and MSKCC, the authors generalized their findings to conclude that therapy using MTAs is no better than multiple standard AAs. We concur with previously expressed concerns regarding the study design (2,3) and would like to offer additional comments. The MTA formalism at MSKCC is not adequately described in the provided references. The individual calculated MTAs at MSKCC were not reported (1), but the AAs were lower than in our experience (4). This raises concern that AAs differ from calculated MTAs. The authors should report MTAs along with AAs, explaining any differences between the two. In the 1950s, Benua and Leeper (5) observed that “metastases treated with either small repeated doses of 131I or with external irradiation seemed to lose the ability to function [that is, accumulate iodine] but continued to grow.” That was their reason for developing the MTA-based approach at MSKCC that permitted administration of much higher AAs. They also observed that thyroid hormone withdrawal was the most effective stimulation for iodine uptake in mDTC, which their successors substituted by recombinant human thyroid-stimulating hormone (rhTSH) without proof of equivalence, as conceded by the authors (“the effect of rhTSH versus THW preparation on 131I efficacy still remains unknown”) (1). Importantly, rhTSH as the preferred stimulation for dosimetry and therapy is highly unusual in global practice. Hence, any conclusion from this study would apply only to MSKCC practice of MTA-guided therapy, and maybe to a few other centers. We are particularly perplexed by the assumption at GR in support of standard activity, which is that “any increase in lesional radiation dose achieved with larger administered activities is unlikely to confer therapeutic benefit.” We administer up to 5 times the GR standard activity under MTA guidance; radiobiologically this is expected to significantly increase the probability of tumor control. What is the radiobiologic basis for the GR assumption? We know that mDTC consists of clonogens with interpatient and intrapatient heterogeneity in radiosensitivity and iodine avidity (6). Standard activity may kill radiosensitive and iodine-avid clones, leaving non–iodine-avid and more radio-resistant ones viable in some patients, who later may develop recurrence. Indeed, in the study designed in part by the senior GR investigator, patients with progressive mDTC were recruited into a novel chemotherapy trial (7). Most of those patients had 2 or more standard 131I therapies, which is expectedly similar to Benua’s observation in the 1950s. Clinically, patients with mDTC have excellent OS, which makes this metric not ideal. Optimizing quality of life and minimizing the side effects are no less important, but not addressed in this work; therefore, applied AAs should be reasonable. In addition, dosimetry does not always result in only increased AA but also quite frequently in a change in therapeutic concept.