Detection Rate of Recurrent Medullary Thyroid Carcinoma Using Fluorine-18 Dihydroxyphenylalanine Positron Emission Tomography

Rationale and Objectives

The aim of this study was to perform a meta-analysis of published data about the diagnostic performance of 18 F-dihydroxyphenylalanine (DOPA) positron emission tomography (PET) or PET/computed tomography (CT) in detecting recurrent medullary thyroid carcinoma (MTC).

Materials and Methods

A comprehensive literature search of studies indexed in the PubMed/MEDLINE, Scopus, and Embase databases through January 2012 and regarding 18 F-DOPA PET or PET/CT in patients with suspected recurrent MTC was carried out. Pooled detection rates (DR) in per patient and per lesion analyses were calculated. A subanalysis considering serum levels of calcitonin and carcinoembryonic antigen, device used, and carbidopa pretreatment was also performed.

Results

Eight studies including 146 patients with suspected recurrent MTC were included. The DRs of 18 F-DOPA PET and PET/CT in per patient and per lesion analyses were 66% and 71%, respectively. DRs significantly increased in patients with serum calcitonin ≥1000 ng/L (86%) and calcitonin doubling times <24 months (86%).

Conclusions

Fluorine-18-DOPA PET and PET/CT may be useful functional imaging methods in detecting recurrent MTC. The DR of recurrent MTC using these imaging methods increases in patients with higher calcitonin levels and lower calcitonin doubling times.

Medullary thyroid carcinoma (MTC) is an uncommon neuroendocrine tumor that originates from parafollicular C cells and accounts for approximately 5% of thyroid tumors, occurring in either sporadic (75% of cases) or familial (25% of cases) forms. This tumor is frequently aggressive; the most frequent sites of metastatic disease are the cervical and thoracic lymph nodes, lungs, liver, and bone. The mainstay of treatment for MTC is surgical resection .

Serum calcitonin represents the most sensitive and accurate tumor marker in the postoperative management and surveillance of MTC. In about one third of patients with MTC lesions, carcinoembryonic antigen (CEA) levels may also be increased, and this finding has prognostic significance, because increased CEA levels are characteristic of advanced forms when the tumor tends toward dedifferentiation. Serum calcitonin and CEA doubling times are efficient tools for assessing tumor progression and are useful prognostic factors in patients with MTC . In the presence of a significant increase of serum calcitonin or CEA levels after surgery, the search for recurrent or metastatic disease by imaging is indicated . These imaging modalities include neck ultrasound, computed tomography (CT), magnetic resonance imaging, positron emission tomography (PET) with different radiopharmaceuticals, and bone scintigraphy .

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Materials and methods

Search Strategy

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Study Selection

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Data Abstraction

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Quality Assessment

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Table 1

Questions Used to Assess the Risk for Bias and Concerns Regarding Applicability for Studies Included in This Meta-analysis

Domain 1 (patient selection)

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Domain 2 (index test)

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Domain 3 (reference standard)

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Domain 4 (flow and timing)

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Statistical Analyses

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Results

Literature Search

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Table 2

Basic Study and Patient Characteristics

Authors Journal Year Country Patients with MTC Undergoing 18 F-DOPA PET or PET/CT Mean Age (y) Men Treglia et al Eur J Nucl Med Mol Imaging 2012 Italy 18 53 33% Kauhanen et al J Nucl Med 2011 Finland 19 52 53% Luster et al Thyroid 2010 Germany 26 (28 scans) 48 46% Marzola et al Eur J Surg Oncol 2010 Italy 18 51 44% Beheshti et al Eur Radiol 2009 Austria 19 ∗ 59 38% Koopmans et al J Nucl Med 2008 Netherlands 21 56 48% Beuthien-Baumann et al Eur J Nucl Med Mol Imaging 2007 Germany 15 56 53% Hoegerle et al Eur J Nucl Med 2001 Austria 10 ∗ 57 55%

CT, computed tomography; DOPA, dihydroxyphenylalanine; MTC, medullary thyroid carcinoma; PET, positron emission tomography.

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Table 3

Technical Aspects of the Studies Using 18 F-DOPA PET and PET/CT for Detecting Recurrent or Residual Medullary Thyroid Carcinoma

Authors Study Design Tracers Used Device Mean 18 F-DOPA Injected Activity Time between Injection and Image Acquisition (min) Acquisition Protocol for PET Image Analysis Reference Standard Treglia et al Retrospective multicenter 18 F-DOPA, 18 F-FDG, 68 Ga-SMS PET/CT 4 MBq/kg 60 Static acquisition (3 min per bed position), no carbidopa premedication Qualitative Histology and/or clinical/imaging follow-up Kauhanen et al Prospective multicenter 18 F-DOPA, 18 F-FDG PET/CT 243 MBq 60 Static acquisition (3 min per bed position) carbidopa premedication Qualitative and semiquantitative Histology and/or clinical/imaging follow-up Luster et al Retrospective single center 18 F-DOPA PET/CT 298 MBq 60 Static acquisition (4 min per bed position), carbidopa premedication Qualitative and semiquantitative Histology and/or clinical/imaging follow-up Marzola et al Multicenter 18 F-DOPA, 18 F-FDG PET/CT 2.2 MBq/kg 60 Static acquisition (3 min per bed position), no carbidopa premedication Qualitative and semiquantitative Histology Beheshti et al Prospective single center 18 F-DOPA, 18 F-FDG PET/CT 4 MBq/Kg 30 Static acquisition (4 min per bed position), no carbidopa premedication Qualitative and semiquantitative Histology and/or clinical/imaging follow-up Koopmans et al Prospective single center 18 F-DOPA, 18 F-FDG PET 180 MBq 60 Static acquisition (5 min per bed position), carbidopa premedication Qualitative Histology and/or clinical/imaging follow-up Beuthien-Baumann et al Retrospective single center 18 F-DOPA, 18 F-FDG, 18 F-OMFD PET 4.8 MBq/Kg 45 Static acquisition, carbidopa premedication Qualitative Histology and/or clinical/imaging follow-up Hoegerle et al Prospective single center 18 F-DOPA, 18 F-FDG PET 220 MBq 90 Static acquisition, no carbidopa premedication Qualitative Histology and/or clinical/imaging follow-up

CT, computed tomography; DOPA, dihydroxyphenylalanine; FDG, fluorodeoxyglucose; OMFD, methylfluorodihydroxyphenylalanine; PET, positron emission tomography; SMS, somatostatin analogue.

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Quality Assessment

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Table 4

Results of the Quality Assessment According to the QUADAS-2 Tool: Evaluation of the Risk for Bias and Applicability Concerns

Study Risk for Bias Applicability Concerns Patient Selection Index Test Reference Standard Flow and Timing Patient Selection Index Test Reference Standard Treglia et al Low Low Unclear High Low Low Low Kauhanen et al Low Low Unclear High Low Low Low Luster et al Low Low High High Low Low Low Marzola et al Low Low Low Low Low Low Low Beheshti et al Low Low Unclear High Low Low Low Koopmans et al Low Low Unclear High Low Low Low Beuthien-Baumann et al High Unclear High High Low Low High Hoegerle et al Unclear Low Low High Low Low Low

QUADAS-2, Revised Quality Assessment of Diagnostic Accuracy Studies.

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Diagnostic Performance

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Table 5

Detection Rates of 18 F-DOPA PET and PET/CT in the Included Studies

Study Detection Rate Patient-based Analysis ( n = 139) Lesion-based Analysis ( n = 124) Calcitonin ≥ 1000 ng/L † ( n = 45) Calcitonin < 150 ng/L † ( n = 28) Calcitonin ≥ 150 ng/L † ( n = 93) CEA ≤ 5 ng/mL † ( n = 29) CEA > 5 ng/mL † ( n = 69) Treglia et al 13/18 72% 61/72 85% 5/7 100% 2/2 100% 11/16 69% 3/4 75% 10/14 71% Kauhanen et al 11/19 58% 61/118 52% 5/6 83% 0/5 0% 11/14 79% 3/8 37% 8/11 73% Luster et al 14/19 ‡ 74% 35/51 68% 8/8 100% 3/8 37% 11/11 100% - - - - Marzola et al 15/18 83% 84/111 76% - - - - - - - - - - Beheshti et al 14/19 74% 50/53 ∗ 94% ∗ 5/6 83% 1/2 50% 13/17 76% 4/6 67% 10/13 77% Koopmans et al 13/21 62% 95/134 71% 11/12 92% 1/5 20% 12/16 75% 2/7 29% 11/14 79% Beuthien-Baumann et al 7/15 47% NC 0/1 0 2/6 33% 5/9 56% 2/4 50% 3/7 43% Hoegerle et al 5/10 50% 17/27 63% 4/5 80% 0/0 NC 5/10 50% 0/0 NC 5/10 50% Pooled results 66% 71% 86% 39% 73% 48% 64% 95% confidence interval 58%–74% 67%–75% 73%–95% 20%–61% 63%–82% 29%–67% 52%–74% Heterogeneity (I 2 test) 15% 87% 0% 16% 46% 0% 51%

CEA, carcinoembryonic antigen; CT, computed tomography; DOPA, dihydroxyphenylalanine; NC, not calculable; PET, positron emission tomography.

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Table 6

Detection Rates of 18 F-DOPA PET and PET/CT in the Included Studies

Study Detection Rate CTDT > 24 Months ∗ ( n = 42) CTDT < 24 Months ∗ ( n = 35) CTDT > 12 Months ∗ ( n = 50) CTDT < 12 Months ∗ ( n = 27) Only PET/CT ∗ ( n = 93) Carbidopa Premedication ∗ ( n = 74) No Carbidopa Premedication ∗ ( n = 65) Treglia et al 4/9 44% 9/9 100% 6/11 55% 7/7 100% 13/18 72% - - 13/18 72% Kauhanen et al 6/11 55% 5/8 62% 9/14 64% 2/5 40% 11/19 58% 11/19 58% - - Luster et al - - - - - - - - 14/19 † 74% 14/19 † 74% - - Marzola et al - - - - - - - - 15/18 83s% - - 15/18 83% Beheshti et al 2/6 33% 12/13 92% 3/7 43% 11/12 92% 14/19 74% - - 14/19 74% Koopmans et al 9/16 56% 4/5 80% 10/18 56% 3/3 100% - - 13/21 62% - - Beuthien-Baumann et al - - - - - - - - - - 7/15 47% - - Hoegerle et al - - - - - - - - - - - - 5/10 50% Pooled results 50% 86% 56% 85% 72% 61% 72% 95% confidence interval 34%–66% 70%–95% 41%–70% 66%–96% 62%–81% 49%–72% 60%–83% Heterogeneity (I 2 test) 0% 50% 0% 67% 0% 0% 13%

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Discussion

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Conclusions

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References

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6. Whiting P.F., Rutjes A.W., Westwood M.E., et. al.: QUADAS-2: a revised tool for the quality assessment of diagnostic accuracy studies. Ann Intern Med 2011; 155: pp. 529-536.
7. Zamora J., Abraira V., Muriel A., et. al.: Meta-DiSc: a software for meta-analysis of test accuracy data. BMC Med Res Methodol 2006; 6: pp. 31.
8. Kauhanen S., Seppänen M., Ovaska J., et. al.: The clinical value of [18F]fluoro-dihydroxyphenylalanine positron emission tomography in primary diagnosis, staging, and restaging of neuroendocrine tumors. Endocr Relat Cancer 2009; 16: pp. 255-265.
9. Treglia G., Castaldi P., Villani M.F., et. al.: Comparison of (18)F-DOPA, (18)F-FDG and (68)Ga-somatostatin analogue PET/CT in patients with recurrent medullary thyroid carcinoma. Eur J Nucl Med Mol Imaging 2012; 39: pp. 569-580.
10. Kauhanen S., Schalin-Jäntti C., Seppänen M., et. al.: Complementary roles of 18F-DOPA PET/CT and 18F-FDG PET/CT in medullary thyroid cancer. J Nucl Med 2011; 52: pp. 1855-1863.
11. Luster M., Karges W., Zeich K., et. al.: Clinical value of 18-fluorine-fluorodihydroxyphenylalanine positron emission tomography/computed tomography in the follow-up of medullary thyroid carcinoma. Thyroid 2010; 20: pp. 527-533.
12. Marzola M.C., Pelizzo M.R., Ferdeghini M., et. al.: Dual PET/CT with (18)F-DOPA and (18)F-FDG in metastatic medullary thyroid carcinoma and rapidly increasing calcitonin levels: comparison with conventional imaging. Eur J Surg Oncol 2010; 36: pp. 414-421.
13. Beheshti M., Pöcher S., Vali R., et. al.: The value of 18F-DOPA PET-CT in patients with medullary thyroid carcinoma: comparison with 18F-FDG PET-CT. Eur Radiol 2009; 19: pp. 1425-1434.
14. Koopmans K.P., de Groot J.W., Plukker J.T., et. al.: 18F-dihydroxyphenylalanine PET in patients with biochemical evidence of medullary thyroid cancer: relation to tumor differentiation. J Nucl Med 2008; 49: pp. 524-531.
15. Beuthien-Baumann B., Strumpf A., Zessin J., et. al.: Diagnostic impact of PET with 18F-FDG, 18F-DOPA and 3-O-methyl-6-[18F]fluoro-DOPA in recurrent or metastatic medullary thyroid carcinoma. Eur J Nucl Med Mol Imaging 2007; 34: pp. 1604-1609.
16. Hoegerle S., Altehoefer C., Ghanem N., et. al.: 18F-DOPA positron emission tomography for tumour detection in patients with medullary thyroid carcinoma and elevated calcitonin levels. Eur J Nucl Med 2001; 28: pp. 64-71.
17. Treglia G., Castaldi P., Rindi G., et. al.: Diagnostic performance of gallium-68 somatostatin receptor PET and PET/CT in patients with thoracic and gastroenteropancreatic neuroendocrine tumours: a meta-analysis. Endocrine 2012; Feb 20, Epub ahead of print
18. Conry B.G., Papathanasiou N.D., Prakash V., et. al.: Comparison of (68)Ga-DOTATATE and (18)F-fluorodeoxyglucose PET/CT in the detection of recurrent medullary thyroid carcinoma. Eur J Nucl Med Mol Imaging 2010; 37: pp. 49-57.
19. Pałyga I., Kowalska A., Gąsior-Perczak D., et. al.: The role of PET-CT scan with somatostatin analogue labelled with gallium-68 (68Ga-DOTA-TATE PET-CT) in diagnosing patients with disseminated medullary thyroid carcinoma (MTC). Endokrynol Pol 2010; 61: pp. 507-511.
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Detection Rate of Recurrent Medullary Thyroid Carcinoma Using Fluorine-18 Dihydroxyphenylalanine Positron Emission Tomography

Rationale and Objectives

Materials and Methods

Results

Conclusions

Materials and methods

Search Strategy

Study Selection

Data Abstraction

Quality Assessment

Statistical Analyses

Results

Literature Search

Quality Assessment

Diagnostic Performance

Discussion

Conclusions

References

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