18F-fluorodihydroxyphenylalanine vs other radiopharmaceuticals for imaging neuroendocrine tumours according to their type

Abstract

6-Fluoro-((18)F)-L-3,4-dihydroxyphenylalanine (FDOPA) is an amino acid analogue for positron emission tomography (PET) imaging which has been registered since 2006 in several European Union (EU) countries and by several pharmaceutical firms. Neuroendocrine tumour (NET) imaging is part of its registered indications. NET functional imaging is a very competitive niche, competitors of FDOPA being two well-established radiopharmaceuticals for scintigraphy, (123)I-metaiodobenzylguanidine (MIBG) and (111)In-pentetreotide, and even more radiopharmaceuticals for PET, including fluorodeoxyglucose (FDG) and somatostatin analogues. Nevertheless, there is no universal single photon emission computed tomography (SPECT) or PET tracer for NET imaging, at least for the moment. FDOPA, as the other PET tracers, is superior in diagnostic performance in a limited number of precise NET types which are currently medullary thyroid cancer, catecholamine-producing tumours with a low aggressiveness and well-differentiated carcinoid tumours of the midgut, and in cases of congenital hyperinsulinism. This article reports on diagnostic performance and impact on management of FDOPA according to the NET type, emphasising the results of comparative studies with other radiopharmaceuticals. By pooling the results of the published studies with a defined standard of truth, patient-based sensitivity to detect recurrent medullary thyroid cancer was 70 % [95 % confidence interval (CI) 62.1-77.6] for FDOPA vs 44 % (95 % CI 35-53.4) for FDG; patient-based sensitivity to detect phaeochromocytoma/paraganglioma was 94 % (95 % CI 91.4-97.1) for FDOPA vs 69 % (95 % CI 60.2-77.1) for (123)I-MIBG; and patient-based sensitivity to detect midgut NET was 89 % (95 % CI 80.3-95.3) for FDOPA vs 80 % (95 % CI 69.2-88.4) for somatostatin receptor scintigraphy with a larger gap in lesion-based sensitivity (97 vs 49 %). Previously unpublished FDOPA results from our team are reported in some rare NET, such as small cell prostate cancer, or in emerging indications, such as metastatic NET of unknown primary (CUP-NET) or adrenocorticotropic hormone (ACTH) ectopic production. An evidence-based strategy in NET functional imaging is as yet affected by a low number of comparative studies. Then the suggested diagnostic trees, being a consequence of the analysis of present data, could be modified, for some indications, by a wider experience mainly involving face-to-face studies comparing FDOPA and (68)Ga-labelled peptides.

Fig. 1

MTC treated by total thyroidectomy and lymph node dissection. a–b The patient presented with an occult biochemical recurrence 1.5 years later [serum calcitonin (CTN)=1,130 ng/l, carcinoembryonic antigen (CEA) =46 μg/l] and was referred to FDOPA PET/CT. On the early images after injection (a), a clear focus was visible, corresponding on CT to a left lymph node in the left upper mediastinum, with smaller and less intense contralateral foci. But the foci were no longer visible 1 h later on the whole-body acquisition (b) and the examination was considered as doubtful. c–e Another 1.5 years later, the markers were still rising (CTN=2,400 ng/ml, CEA =59 μg/l) and the patient was referred for FDG and FDOPA PET/CT prior to surgical exploration. On FDG PET/CT, 1 h after injection, a faint uptake (SUV_max =1.8) was visible by the left mediastinal lymph node (the most intense FDOPA uptake 1.5 years before) (c) but no other lesion (d). On FDOPA PET/CT (e), the left mediastinal focus took up FDOPA (SUV_max =2.9) together with several other foci: one left supraclavicular focus and one upper thoracic focus on the left side and two foci in the right upper mediastinum. Their intensity decreased after 1 h. The dissection and histological examination of the left supraclavicular region found two metastatic lymph nodes, 8 and 5 mm in size. CTN levels dropped to 1,600 ng/l. f Nineteen months later, another FDOPA PET was performed for restaging prior to surgery. With the exception of the left supraclavicular focus which had been resected, all other foci were viable, and their uptake at 1 h was now as intense as on the early images. This observation illustrates the importance of early image acquisition after FDOPA injection for early detection of metastatic MTC and the better performance of FDOPA as compared to FDG in a slow-growing form of MTC

Fig. 2

Right block of images FDOPA PET/CT: anterior and left lateral maximum intensity projection, transverse slice. Left block corresponding FDG PET/CT images. FDOPA PET/CT was performed for characterising a left adrenal tumour (dashed arrow) discovered incidentally on FDG PET/CT performed for staging a squamous cell carcinoma of the anal canal (full arrow) in an asymptomatic patient. As the adrenal tumour took up both FDOPA and FDG, it was interpreted as an aggressive phaeochromocytoma. This was confirmed on histological examination. This observation illustrates the increase in specificity brought by FDOPA for characterising NET

Fig. 3

a–b In a haemodialysed patient candidate for renal grafting, systematic CT discovered a tumour of the terminal ileum evocative of a carcinoid origin with mesenteric locoregional adenopathies, the largest being 35 mm in size. Biopsy of a right iliac adenopathy confirmed a metastatic well-differentiated NET (Ki-67<1 %). FDOPA PET/CT performed for staging showed the primary carcinoid tumour in the terminal ileum (a dotted arrow) and large lymphadenopathy with two satellite lymph nodes (a black arrows), but also a focus in the upper left abdomen, SUV_max =4.7 (a, b green arrow) corresponding on CT to a dense content in a renal cyst. c FDG PET/CT was performed to better characterise the renal anomaly that took up FDG (c green arrow on the transverse slice) with a somewhat lower intensity than FDOPA (SUV_max = 3.9). As expected, the metastatic carcinoid tumour in the right abdomen did not take up FDG (c). Thus the renal cystic lesion was probably not of a carcinoid origin. A CT-guided biopsy of the renal lesion was performed and histology revealed a renal carcinoma. This observation illustrates the ability of FDOPA to detect carcinoid tumours with low aggressiveness, but also renal carcinomas, and the synergy between FDOPA and FDG PET/CT

Fig. 4

FDOPA PET/CT: maximum intensity projection, transverse slice and coronal slice. Search for focal hyperplasia of pancreatic beta cells in an infant with hyperinsulinism. FDOPA PET/CT localised a focus in the tail of the pancreas which was resected. Histological examination confirmed clustered beta-cell hyperplasia and the infant became euglycaemic