help button home button Endocrine Society JCEM
HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS
Journal of Clinical Endocrinology & Metabolism , doi:10.1210/jc.2007-0938
This Article
Right arrow Abstract Freely available
Right arrow Full Text (PDF)
Right arrow Submit a related Letter to the Editor
Right arrow Alert me when this article is cited
Right arrow Alert me when eLetters are posted
Right arrow Alert me if a correction is posted
Right arrow Citation Map
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrow Request Copyright Permission
Citing Articles
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Oudoux, A.
Right arrow Articles by Kraeber-Bodéré, F.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Oudoux, A.
Right arrow Articles by Kraeber-Bodéré, F.
Right arrowPubmed/NCBI databases
*Compound via MeSH
*Substance via MeSH
Medline Plus Health Information
*Thyroid Cancer
Related Collections
Right arrow Thyroid
Right arrow Endocrine Oncology
The Journal of Clinical Endocrinology & Metabolism Vol. 92, No. 12 4590-4597
Copyright © 2007 by The Endocrine Society

Sensitivity and Prognostic Value of Positron Emission Tomography with F-18-Fluorodeoxyglucose and Sensitivity of Immunoscintigraphy in Patients with Medullary Thyroid Carcinoma Treated with Anticarcinoembryonic Antigen-Targeted Radioimmunotherapy

Aurore Oudoux, Pierre-Yves Salaun, Claire Bournaud, Loïc Campion, Catherine Ansquer, Caroline Rousseau, Stéphane Bardet, Françoise Borson-Chazot, Jean-Philippe Vuillez, Arnaud Murat, Eric Mirallié, Jacques Barbet, David M. Goldenberg, Jean-François Chatal and Françoise Kraeber-Bodéré

Nuclear Medicine (A.O., C.A., F.K.-B.), Endocrinology (A.M.), and Endocrine Surgery (E.M.) Departments, University Hospital, 44093 Nantes, France; Nuclear Medicine (P.-Y.S., C.R., F.K.-B.) and Statistic (L.C.) Departments, René Gauducheau Cancer Center, 44805 Nantes, France; Nuclear Medicine Department (C.B., F.B.-C.), University Hospital, 69495 Lyon, France; Nuclear Medicine Department (S.B.), François Baclesse Cancer Center, 14076 Caen, France; Nuclear Medicine Department (J.-P.V.), University Hospital, 38043 Grenoble, France; Oncology Research Department (J.B., J.-F.C., F.K.-B.), Institut National de la Santé et de la Recherche Médicale Unité Mixte de Recherche 601, 44093 Nantes, France; and Garden State Cancer Center (D.M.G.), Center for Molecular Medicine and Immunology, Belleville, New Jersey 07109-0023

Address all correspondence and requests for reprints to: Françoise Kraeber-Bodéré, Oncology Research Department, Institut National de la Santé et de la Recherche Médicale U601, Institut de Biologie, 9 quai Moncousu, 44093 Nantes Cedex 1, France. E-mail: francoise.bodere{at}chu-nantes.fr.


   Abstract
Top
 Abstract
Introduction
 Patients and Methods
 Results
 Discussion
 References
 
Context: Patients with progressive medullary thyroid carcinoma (MTC) undergo multiple imaging procedures for diagnosis of relapse and staging.

Objective: Our objective was to assess the sensitivity and prognostic value of 18F-2-fluoro-2-deoxy-D-glucose (FDG) positron emission tomography (PET)/computed tomography (CT), and the imaging sensitivity of pretargeted iodine-131-radioimmunotherapy (RIT) in patients with progressive MTC.

Design/Setting/Patients: We performed a prospective multicenter study in high-risk patients with rapidly progressing MTC enrolled in a phase-II pretargeted RIT study, as documented by short serum calcitonin (Ct) or carcinoembryonic antigen (CEA) doubling time (DT).

Interventions/Main Outcome Measures: Patients underwent neck-thoracic-abdominal CT, spine and pelvic magnetic resonance imaging, whole-body post-RIT immunoscintigraphy (IS) with iodine-131, and whole-body 18F-FDG-PET/CT imaging. Imaging sensitivity and the correlation between FDG uptake and biomarkers DT were evaluated.

Results: A total of 33 patients with mean CEA and Ct DTs of 1.90 yr (range 0.21–8.50) and 1.52 yr (range 0.09–6.01), respectively, were evaluated. Sensitivity of FDG-PET/CT was 83% for neck, 85% for mediastinal, 75% for lung, 60% for liver, and 67% for bone metastases; overall sensitivity was 76%. Median standardized uptake value (SUVmax) was 5.23 (2.06–13.90). SUVmax correlated significantly with Ct DT (P = 0.011) and minimal DT (minimal value between CEA DT and Ct DT) (P = 0.027). Overall sensitivity of post-RIT IS, CT, and bone magnetic resonance imaging were 94, 74, and 85%, respectively.

Conclusions: These results demonstrate the value of FDG-PET/CT for staging of patients with progressive MTC, especially in the neck and mediastinum, with possible prognostication by SUV quantification. Post-RIT IS was the most sensitive of the imaging modalities studied prospectively.


   Introduction
Top
 Abstract
 Introduction
Patients and Methods
 Results
 Discussion
 References
 
MEDULLARY thyroid carcinoma (MTC) is characterized by relatively slow tumor growth yet early lymphatic metastatic spread (1). Metastases are already present in 35% of patients at initial diagnosis (2). The prognosis of MTC varies from long-term survival to a much shorter duration in patients with poor prognostic factors, including age, tumor-node-metastasis (TNM) stage, European Organization for the Research and Treatment of Cancer score, preoperative and postoperative serum concentrations of calcitonin (Ct) and carcinoembryonic antigen (CEA), and Ct and CEA doubling time (DT) (3, 4, 5). Our group showed previously that TNM stage, European Organization for the Research and Treatment of Cancer score, and Ct DT are significant predictors of survival by univariate analysis, but only Ct DT remained an independent predictor of survival by multivariate analysis (5). Thus, Ct DT was a better predictor than CEA DT.

Surgery can cure patients with localized tumor. However, MTC is often diagnosed at an advanced stage, resulting in a low cure rate. Indeed, 48–80% of patients are resected with stage-III or -IV TNM, i.e. with lymph node involvement or extrathyroidal invasion (6, 7, 8, 9). In patients with abnormal residual Ct levels after initial complete surgery, Ct and CEA serum DT measurements help establish the prognosis, ultrasound (US) and computed tomography (CT) can assess neck involvement, CT is useful in the chest, abdomen and pelvis, and magnetic resonance imaging (MRI) reveals liver and bone/bone marrow spread (10, 11, 12, 13, 14, 15).

2-Fluoro-2-deoxy-D-glucose (FDG) positron emission tomography (PET) is widely used for staging, prognostication, restaging, and assessment of therapeutic response in many cancers (16). However, the benefits of FDG-PET in endocrine tumors are not clear because FDG fails to visualize well-differentiated cancers. FDG uptake has been reported only in endocrine tumors with a high proliferative index of activity, indicating a possible prognostic value (17, 18, 19). In MTC, several reports have indicated a benefit of FDG-PET, especially for cervical and mediastinal lymph node evaluation (20, 21, 22, 23, 24).

The aim of this prospective study was to evaluate the sensitivity and prognostic value of FDG-PET, performed using an integrated PET/CT system, in progressive MTC patients included in an ongoing phase-II pretargeted radioimmunotherapy (RIT) trial, also in relationship to Ct and CEA DTs. Another objective was to assess the imaging sensitivity of pretargeted iodine-131 (131I) as part of the RIT regimen.


   Patients and Methods
Top
 Abstract
 Introduction
 Patients and Methods
Results
 Discussion
 References
 
Patient population

High-risk, histologically proven, MTC patients older than 18 yr of age, with progressive MTC, as documented by serum Ct or CEA DT (<5 yr), were studied. The minimal Ct serum value was 100 pg/ml, but there was no minimal CEA serum value. Patients were not screened with anti-CEA diagnostic scintigraphy before enrollment. All of these patients were included in an ongoing pretargeted RIT phase-II clinical trial. All subjects had a Karnofsky performance status of 70% or more and a minimum life expectancy of more than 8 wk. The patients were at least 4 wk beyond any major surgery, external radiotherapy, or chemotherapy, and at least 3 months after internal radiotherapy. They had normal hepatic (bilirubin ≥ 2 mg/dl), renal (creatinine ≥ 135 µmol/liter), and hematological (leukocytes ≥ 4,000/mm3; platelets ≥ 100,000/mm3) functions. The baseline levels for blood human antimouse antibody and human antihumanized antibody were normal. The phase II clinical trial was approved by the local ethics committees, and all patients gave their signed informed consent.

Conventional examinations

Conventional staging of MTC patients included clinical examination, Ct and CEA serum level monitoring for DT determinations, and random, not directed, bone marrow biopsies. Biomarker DT was determined as previously described by Barbet et al. (5). Morphological imaging studies included US of the neck, CT of the neck, chest, abdomen, and pelvis, and MRI of the spine and pelvis. CT was performed with spiral CT after iv injection of iodinated contrast material, with slice thickness ranging from 5–10 mm. Bone MRI was performed as described previously (15).

Post-RIT immunoscintigraphy (IS)

Anti-CEA x anti-diethylenetriamine pentaacetic acid (DTPA) bispecific monoclonal antibody (BsMAb), hMN-14 x m734, and di-DTPA bivalent hapten were provided by IBC Pharmaceuticals, Inc. (Morris Plains, NJ). Radiolabeling of the hapten with 131I was performed using the iodogen method, as described previously (25). The specific activity was 38–62 MBq/nmol. The radiochemical purity was greater than 95%, and the immunoreactivity of the preparations was above 90%. The patients were infused with 40 mg/m2 of BsMAb and 1.8 GBq/m2 of 131I-di-DTPA 4–6 d later. Whole-body scintigraphy was performed in all patients 5–10 d after infusion of the radiolabeled hapten. Anterior and posterior views were taken with a dual-headed camera equipped with a high-energy collimator. Single-photon emission CT also was performed in some patients to provide higher contrast and better identification of the tumor site(s).

FDG-PET

Scans were performed with a Discovery LS PET/CT scanner (General Electric Medical Systems, Milwaukee, WI). Patients fasted 4 h before PET acquisitions, and blood glucose had to be less than 7 mmol/liter before injection of 310–450 MBq (5–7 MBq/kg) of 18F-FDG. Intravenous injection was followed by a period of approximately 60 min when the patients remained in a quiet room. No muscle relaxants were administered. The patients were allowed to breathe normally during PET and CT acquisitions. PET data were acquired in the two-dimensional mode and were reconstructed using CT data, for attenuation correction, using the ordered-subsets expectation maximization algorithm and without CT-based attenuation correction.

A region of interest of 5–10 mm was placed manually over the area of maximal activity on slices with the clearest definition of the disease locations and in the adjacent slices. The standardized uptake value (SUV) was calculated based on the measured activity, decay-corrected injected dose, and patient body weight.

Qualitative imaging analysis

Qualitative image evaluation was performed in individual patients. CT and MRI were analyzed by consensus of two radiologists, and PET and post-RIT IS evaluated separately by two nuclear medicine physicians. There was a central reading of the imaging results in two investigational centers experienced in oncology: University Hospitals of Nantes and Lyon, France. For both ethical and practical reasons, every suspected involved lesion was not evaluated by histology. Therefore, the gold standard was determined on the basis of histology and follow-up according to Response Evaluation Criteria in Solid Tumors (RECIST) criteria (significant tumor progression). When confirmation of involvement was not possible by histology or follow-up, a lesion detected only by one imaging modality was considered uncertain and not evaluable, as was also for a stable lesion. True-positive (TP) results corresponded to an abnormal image by an imaging method confirmed by histopathology or by follow-up according to RECIST criteria. A negative finding on an imaging method was considered to be false negative (FN) if positive by one other imaging method plus histopathology, or by one other imaging method plus follow-up according to RECIST criteria. Sensitivity per lesion was calculated for each imaging modality for soft tissue evaluation and sensitivity per patient for bone/bone marrow evaluation. Sensitivity was (TP/TP + FN) x 100 on an anatomical-site basis.

Statistical analysis

Correlations between CT DT, CEA DT, minimal DT (minimal value between CT DT and CEA DT) and SUVmax were determined by the nonparametric Spearman’s test. Comparisons of SUVmax median values according to CT DT and minimal DT (<9 months vs. ≥9 months) used the nonparametric Mann-Whitney U test.


   Results
Top
 Abstract
 Introduction
 Patients and Methods
 Results
Discussion
 References
 
Patient characteristics

Table 1Go shows the patients’ demographic data. A total of 33 patients (21 males and 12 females; mean age 53 yr, range 23–80) was evaluated in this study. All patients were treated initially by total thyroidectomy, 29 patients (93%) underwent central and cervical lymph node dissection, 19 (61%) mediastinal lymph node dissection, and seven patients (22%) had been treated by external radiation. One patient was treated previously by systemic chemotherapy, one by meta-iodobenzylguanidine therapy, and one by RIT. Biological and imaging examinations were performed in the month preceding RIT. Serum Ct levels ranged from 193–87,047 pg/ml (normal < 10 pg/ml) and CEA levels from 2.25–3,814 ng/ml (normal < 5 ng/ml). Mean CEA and Ct DT were 1.90 (0.21–8.50) and 1.52 yr (0.09–6.01), respectively. Eight patients showed an intermediate Ct and CEA DT between 2 and 5 yr, and 25 patients showed a short Ct or CEA DT less than 2 yr.


View this table:
[in this window]
[in a new window]

  		TABLE 1. Demographics

 
All patients had evidence of metastatic disease on imaging: 30 of 33 patients showed detectable disease by RECIST criteria, and three of 33 had normal CT and MRI studies but abnormal foci on FDG-PET. Metastases were located in the neck of 23 patients (70%), mediastinum of 20 (63%), lungs of 10 (31%), liver of 18 (56%), bone/bone marrow of 22 (69%), and in other sites (brain, heart, axillary, and celiac lymph nodes) of six patients (19%). In soft tissues, 123 metastatic sites were confirmed by histology or follow-up: 35 in the neck, 26 in the mediastinum, 12 in the lungs, 25 in the liver, and six in other sites. Diffuse or focal bone involvement was confirmed in 22 patients by histology or follow-up. Around 10% of metastatic sites (15 biopsied patients) were confirmed by histology and the others by follow-up.

Conventional imaging results

CT was performed in all patients for the thorax, abdomen, and pelvis, but the neck was not explored in one patient (Table 2Go). There were 21 of 35 neck lesions, 18 of 26 mediastinal lymph nodes, 10 of 12 lung metastases, 25 of 25 liver lesions, and two of five in other tumor sites (brain was not explored by CT) detected by CT. Thus, the sensitivity of CT was 60% for neck, 69% for mediastinal, 83% for lung, and 100% for liver metastases, and the overall sensitivity was 74%.


View this table:
[in this window]
[in a new window]

  		TABLE 2. Sensitivity of imaging modalities

 
MRI was performed in all patients. Two patients had confirmed bone involvement out of the field of view of spine and pelvic MRI (localized on cranium, rib, and arm). So, only 20 patients with confirmed bone involvement were evaluable on MRI. Spine and pelvic MRI was positive in 17 of 20 patients with bone involvement, corresponding to a sensitivity of 85%. MRI was FN in three patients: two disclosed by bone biopsy, and one detected by IS and confirmed by follow-up.

IS

Post-RIT IS was performed in 30 of 33 patients (114 assessable lesions). There were 31 of 32 neck lesions, 22 of 22 mediastinal lymph nodes, 12 of 12 lung metastases, 18 of 22 liver tumors, and six of six other sites detected by IS. Bone involvement was found in 18 of 20 patients. The sensitivity of IS was 97% for neck, 100% for mediastinal and lung, 82% for liver, and 90% for bone lesions; the overall sensitivity was 94%.

FDG-PET/CT

Whole-body FDG-PET/CT was performed in all patients. FDG-PET/CT detected abnormal hot spots in 29 of 35 lesions in the neck, 22 of 26 in the mediastinum, nine of 12 in the lungs, 15 of 25 in the liver, and four of five in other sites (the brain was not explored by FDG-PET/CT). FDG-PET/CT detected bone/bone marrow involvement in 14 of 21 evaluable patients; one of the 22 patients with confirmed bone involvement had bone metastasis on the cranium, out of the field of view of FDG-PET. The sensitivity of FDG-PET/CT was 83% for neck, 85% for mediastinal, 75% for lung, 60% for liver, and 67% for bone lesions. The overall sensitivity of FDG-PET/CT was 76%.

Combined CT and FDG-PET/CT analysis for soft tissues allowed detection of 33 of 35 (94%) neck, 25 of 26 (96%) mediastinal, and 12 of 12 (100%) lung metastases. The combined MRI, bone marrow biopsy, and FDG-PET/CT analysis for bone/bone evaluation detected metastases in 20 of 22 (91%) patients. A total of 112 confirmed lesions was assessable using IS and FDG-PET/CT. For these lesions, IS and FDG-PET/CT results were concordant for 85 lesions (76%): 80 TPs and five FNs (four in liver detected by CT and confirmed by follow-up, and one in bone marrow confirmed by biopsy). IS and FDG-PET/CT results were discordant for 27 of 112 lesions (24%): 24 were detected by IS and three by FDG-PET/CT (one in bone confirmed by MRI and follow-up, one in neck, and one in liver confirmed by CT and follow-up). Figure 1Go shows FDG-PET/CT images revealing neck and mediastinal metastases, and Fig. 2Go depicts FDG PET/CT and post-RIT IS images performed in another MTC patient with lung metastases. Figure 3Go presents images made in yet another MTC patient, showing FDG-PET/CT and MRI detection of bone involvement.


Figure 1
View larger version (29K):
[in this window]
[in a new window]

  		FIG. 1. FDG-PET/CT images performed in a MTC patient showing neck and mediastinal metastases (arrows). Left, Coronal FDG-PET image; middle, transversal CT and fusion images; and right, transversal FDG-PET images.

 

Figure 2
View larger version (20K):
[in this window]
[in a new window]

  		FIG. 2. FDG-PET/CT fusion images (A), FDG-PET images (B), and post-RIT IS (C) performed in a MTC patient showing lung metastases (arrows).

 

Figure 3
View larger version (29K):
[in this window]
[in a new window]

  		FIG. 3. MRI (A) and FDG-PET/CT images (B) performed in a MTC patient showing spine and pelvic involvement(arrows).

 
SUV and biomarkers DT analysis

SUVmax was determined in 21 patients, with a median SUVmax of 5.23, ranging from 2.06–13.90. Statistical analysis confirmed a significant correlation between Ct and CEA DT (Spearman’s rho = 0.76; P = 0.0004) (Fig. 4Go). SUVmax correlated significantly with Ct DT (Spearman’s rho = – 0.56; P = 0.011) and minimal DT value (minimal value between CEA DT and Ct DT) (Spearman’s rho = –0.48; P = 0.027), as shown in Figs. 5Go and 6Go. SUVmax did not correlate with CEA DT (Spearman’s rho = –0.33; P = 0.20). Regarding the minimal DT value (minimal value between CEA DT and Ct DT), the SUVmax of patients with DT less than 9 months (median 7.40, range 4.75–13.90) was significantly higher than the SUVmax of patients with DT more than 9 months (median 4.51, range 2.06–9.72) (P = 0.029). In terms of the Ct DT, the SUVmax of patients with DT less than 9 months (median 7.39, range 4.75–13.90) was significantly higher than the SUVmax of patients with DT more than 9 months (median 4.47, range 2.06–9.72) (P = 0.025).


Figure 4
View larger version (5K):
[in this window]
[in a new window]

  		FIG. 4. Correlation between Ct and CEA DTs.

 

Figure 5
View larger version (5K):
[in this window]
[in a new window]

  		FIG. 5. Correlation between SUVmax and Ct DTs.

 

Figure 6
View larger version (5K):
[in this window]
[in a new window]

  		FIG. 6. Correlation between SUVmax and minimal DT values (minimal value between CEA DT and Ct DT).

 

   Discussion
Top
 Abstract
 Introduction
 Patients and Methods
 Results
 Discussion
References
 
Treatment of metastatic MTC remains a challenge. Some groups have recommended repeated lymph node dissection in the neck and mediastinum (26, 27). The rate of postoperative normalization of serum Ct is low (27, 28). A review of several studies indicates that chemotherapy is associated with a partial response rate lower than 30%, and with severe morbidity (29, 30). Thus, new therapeutic strategies are needed. Our group demonstrated the efficacy of anti-CEA pretargeted RIT (31, 32). Overall survival (OS) of 29 patients with advanced progressive MTC treated with anti-CEA/anti-DTPA BsMAb and 131I-di-DTPA was compared with 39 contemporaneous untreated MTC patients with comparable prognostic indicators (32). In the entire population, the OS was not significantly different between treated and untreated patients (P = 0.059). OS was significantly longer in high-risk patients (Ct DT < 2 yr) treated than in high-risk untreated patients (P < 0.030). Of patients defined as biological responders by a more than 100% increase in Ct DT, 47% experienced significantly longer survival than nonresponders (P < 0.035) and untreated patients (P < 0.010). There were no reported objective responses after RIT according to RECIST criteria. In MTC patients with metastatic disease, comprehensive imaging is needed to obtain better staging, to assess tumor progression, possibly to determine prognostic factors, and to assess therapeutic response.

In this prospective study, we showed the benefit of 18F-FDG-PET/CT in progressive MTC patients, especially for the evaluation of neck, mediastinal, and lung sites. FDG-PET/CT showed a better sensitivity than CT for neck and mediastinal, and was equivalent for lung metastases. CT appeared to be better for liver assessment, and MRI for evaluation of bone/bone marrow spread, probably because of the small size of liver and bone marrow metastases and the physiological uptake of FDG in these tissues. We did not compare FDG-PET with US for neck exploration, however, US probably has a higher sensitivity but a lower specificity. Indeed, Simeone et al. (33) reported a 96% sensitivity and 83% specificity. Moreover, because our gold standard included imaging follow-up, sensitivity of CT for liver exploration should be probably lower if patients had undergone hepatic arteriography, MRI, or laparoscopic liver biopsy, which showed higher sensitivity than CT in previous studies (14, 34).

In our group of progressive MTC patients, the SUVmax correlated with Ct DT and minimal DT values (minimal values between CEA DT and Ct DT), suggesting a prognostic value of 18F-FDG uptake. However, SUVmax did not correlate with CEA DT, but the number of CEA DT values was lower, and we demonstrated previously that Ct DT was a better prognostic predictor than CEA DT (proportion of variance explained 63.3 and 47.0%, respectively) (5). Recently, Ong et al. (35) reported only a 62% overall sensitivity of FDG-PET in a series of 28 MTC patients, but this was a retrospective study including probably progressive and nonprogressive patients. They found no correlation between Ct DT and SUV, but the DT was determined using only two Ct values and not the method we used, which had more sampling points (5). Indeed, we found that accuracy is increased by using a systematic blood sampling protocol including at least four data points to calculate the DT reliably. Our results suggest that 18F-FDG-PET/CT should be performed in patients with progressive MTC to improve disease staging, better identify a prognostic risk group, and select the most appropriate treatment. However, 18F-FDG-PET/CT should not replace the role of the validated Ct DT for prognostication.

In the present study, post-RIT IS showed the best sensitivity. IS sensitivity was equivalent to MRI for bone involvement, and better than CT and FDG-PET/CT for disclosing neck, mediastinal, and lung lesions. IS had a lower sensitivity than CT only for liver tumors (82 vs. 100%), probably explained by the high physiological liver uptake that induced a low lesion-to-background ratio, especially for small lesions. We reported comparable results previously in another series of 35 MTC patients with metastases in the neck in 81% of the cases, mediastinum in 54%, lungs in 34%, liver in 43%, and bone/bone marrow in 74% (15). In that study the patients did not undergo FDG-PET, but we demonstrated a benefit of MRI for bone/bone marrow assessment, and a high sensitivity of post-RIT IS for soft tissue and bone/bone marrow lesions. Other studies have reported a lower sensitivity of about 60% for indium-111 or technetium-99m-labeled anti-CEA antibodies, but the two-step pretargeting technique used here improved the contrast and imaging sensitivity (36, 37, 38). Moreover, the use of therapeutic doses of 131I also improved sensitivity, similar to the detection of metastases from differentiated thyroid carcinoma, in which the sensitivity of 131I-scintigraphy is significantly higher with therapeutic activities (3.7 GBq) than diagnostic doses (370 MBq) (39). Moreover, IS provided whole-body imaging and allowed assessment of the brain (in contrast to FDG-PET). Indeed, RIT doses of 131I given by pretargeting permitted IS to reveal an unknown brain metastasis in our series. Thus, these results suggest the use of the two-step pretargeting method with positron-emitting radionuclides, such as iodine-124 or Ga-68 (immunoPET) for improving the imaging of such tumors as MTC, characterized by a high antigen expression of the targeted antigen, CEA. ImmunoPET should provide the same sensitivity as post-RIT IS, but with lower injected activities. Indeed, Freudenberg et al. (40) reported the advantage of 124I-PET/CT in the staging of patients with differentiated thyroid cancer. Lesion-based evaluation showed a lesion detectability of 56, 87, and 100% for CT, 124I-PET, and combined 124I-PET/CT imaging, respectively, whereas lesion detection of 131I-whole-body scintigraphy was 83%.

The sensitivity of anti-CEA immunoPET in MTC should be independent of disease progression, in contrast to FDG-PET. Indeed, we showed good tumor targeting with anti-CEA IS in progressive and nonprogressive MTC patients (31, 32). Moreover, 124I-immunoPET could provide a better selection of patients for RIT and adjusting the injected activity by a pre-RIT PET dosimetry study. Recently, using a similar pretargeting system as undertaken here, McBride et al. (41) demonstrated, in mice xenografted with a CEA-expressing colon carcinoma, the feasibility of immunoPET using BsMAb and 124I-peptide, particularly for improving targeting specificity compared with 18F-FDG.

In conclusion, these results showed the benefit of using 18F-FDG-PET in patients with progressive MTC, especially for mediastinal and lung metastases. 18F-FDG uptake correlated with Ct DT, suggesting a prognostic value. Surprisingly, however, IS after therapeutic doses of 131I as part of pretargeted RIT showed the best imaging results compared with CT, MRI, and FDG-PET.


   Acknowledgments
 
We thank Drs. L. Amati, F. Archambaud, J. Bertherat, C. Bremont-Weil, M. Chupin, B. Conte-Devolx, C. Corone, D. Drui, C. Ghiringelli, P. Giraud, C. Houzard, V. Jacquin, E. Lachaume, P. Mahot-Moreau, S. Perdu, B. Perrin, O. Schneegans, and F. Tenenbaum.


   Footnotes
 
This work was supported by Programe Hospitalier de Recherche Clinique 2002.

This study is registered at www.clinicaltrials.gov.

Disclosure Statement: A.O., P.-Y.S., C.B., L.C., C.A., C.R., S.B., F.B.-C., J.-P.V., A.M., E.M., J.B., J.-F.C., and F.K.-B. have nothing to declare. D.M.G. declares a financial interest in IBC Pharmaceuticals, Inc. (shareholder, director, and officer), which owns and supplied the bispecific antibody and hapten used for radioimmunotherapy in this trial.

First Published Online September 18, 2007

Abbreviations: BsMAb, Bispecific monoclonal antibody; CEA, carcinoembryonic antigen; Ct, calcitonin; CT, computed tomography; DT, doubling time; DTPA, diethylenetriamine pentaacetic acid; FDG, 2-fluoro-2-deoxy-D-glucose; FN, false negative; 131I, iodine-131; IS, immunoscintigraphy; MRI, magnetic resonance imaging; MTC, medullary thyroid carcinoma; OS, overall survival; PET, positron emission tomography; RECIST, Response Evaluation Criteria in Solid Tumors; RIT, radioimmunotherapy; SUV, standardized uptake value; TNM, tumor-node-metastasis; TP, true-positive; US, ultrasound.

Received April 30, 2007.

Accepted September 7, 2007.


   References
Top
 Abstract
 Introduction
 Patients and Methods
 Results
 Discussion
 References
 

  1. Marsh DJ, Learoyd DL, Robinson BG 1995 Medullary thyroid carcinoma: recent advances and management update. Thyroid 5:407–424[Medline]
  2. Lairmore TC, Wells Jr SA 1991 Medullary carcinoma of the thyroid: current diagnosis and management. Semin Surg Oncol 7:92–99[CrossRef][Medline]
  3. van Heerden JA, Grant CS, Gharib H, Hay ID, Ilstrup DM 1990 Long term course of patients with persistent hypercalcitoninemia after apparent curative primary surgery for medullary thyroid carcinoma. Ann Surg 212:395–400[Medline]
  4. Saad MF, Fritsche HA, Samaan NA 1984 Diagnostic and prognostic values of carcinoembryonic antigen in medullary carcinoma of the thyroid. J Clin Endocrinol Metab 58:889–894[Abstract/Free Full Text]
  5. Barbet J, Campion L, Kraeber-Bodere F, Chatal JF, GTE Study Group 2005 Prognostic impact of serum calcitonin and carcinoembryonic antigen doubling-times in patients with medullary thyroid carcinoma. J Clin Endocrinol Metab 90:6077–6084[Abstract/Free Full Text]
  6. Machens A, Gimm O, Ukkat J, Hinze R, Schneyer U, Dralle H 2000 Improved prediction of calcitonin normalization in medullary thyroid carcinoma patients by quantitative lymph node analysis. Cancer 88:1909–1915[CrossRef][Medline]
  7. Fleming J, Lee J, Bouvet M, Schultz P, Sherman S, Sellin R, Friend K, Burgess A, Cote G, Gagel R, Evans D 1999 Surgical strategy for the treatment of medullary thyroid carcinoma. Ann Surg 230:697–707[CrossRef][Medline]
  8. Raffaitin P, Hamy A, Mirallie E, Meurette G, Duplessis R, Lemeunier P, Murat A, Le Bodic M, Le Neel JC, Paineau J, Visset J 1999 Facteurs pronostiques de survie sans récidive clinique dans les cancers médullaires du corps thyroïde: à propos de 52 cas opérés. Ann Endocrinol (Paris) 60:435–442[Medline]
  9. Weber T, Schilling T, Franck-Raue K, Colombo-Benkmann M, Hinz U, Ziegler R, Klar E 2001 Impact of modified radical neck dissection on biochemical cure in medullary thyroid carcinomas. Surgery 30:1044–1049
  10. Schwerk WB, Grun R, Wahl R 1985 Ultrasound diagnosis of C-cell carcinoma of the thyroid. Cancer 55:624–630[CrossRef][Medline]
  11. Crow JP, Azar-Kia B, Prinz RA 1989 Recurrent occult thyroid carcinoma detected by MR imaging. AJR Am J Roentgenol 152:1255–1256[Free Full Text]
  12. Frank-Raue K, Raue F, Buhr HJ, Baldauf G, Lorenz D, Ziegler R 1992 Localization of occult persisting medullary thyroid carcinoma before microsurgical reoperation: high sensitivity of selective venous catheterization. Thyroid 2:113–117[Medline]
  13. Raue F, Winter J, Frank-Raue K, Lorenz D, Herfarth C, Ziegler R 1989 Diagnostic procedure before reoperation in patients with medullary thyroid carcinoma. Horm Metab Res Suppl 21:31–34[Medline]
  14. Dromain C, de Baere T, Lumbroso J, Caillet H, Laplanche A, Boige V, Ducreux M, Duvillard P, Elias D, Schlumberger M, Sigal R, Baudin E 2005 Detection of liver metastases from endocrine tumors: a prospective comparison of somatostatin receptor scintigraphy, computed tomography, and magnetic resonance imaging. J Clin Oncol 23:70–78[Abstract/Free Full Text]
  15. Mirallie E, Vuillez JP, Bardet S, Frampas E, Dupas B, Ferrer L, Faivre-Chauvet A, Murat A, Charbonnel B, Barbet J, Goldenberg DM, Chatal JF, Kraeber-Bodere F 2005 High frequency of bone/bone marrow involvement in advanced medullary thyroid cancer. J Clin Endocrinol Metab 90:779–788[Abstract/Free Full Text]
  16. Juweid ME, Cheson BD 2006 Positron-emission tomography and assessment of cancer therapy. N Engl J Med 354:496–507[Free Full Text]
  17. Bombardieri E, Seregni E, Villano C, Chiti A, Bajetta E 2004 Position of nuclear medicine techniques in the diagnostic work-up of neuroendocrine tumors. Q J Nucl Med Mol Imaging 48:150–163[Medline]
  18. Adams S, Baum R, Rink T, Schumm-Drager PM, Usadel KH, Hor G 1998 Limited value of flurine-18 fluorodeoxyglucose PET for the imaging of neuroendocrine tumors. Eur J Nucl Med 25:79–83[CrossRef][Medline]
  19. Eriksson B, Bergstrom M, Orlefors H, Sundin A, Oberg K, Langstrom B 2000 Use of PET in neuroendocrine tumors. In vivo applications and in vitro studies. Q J Nucl Med 44:68–76[Medline]
  20. Khan N, Oriuchi N, Higuchi T, Endo K 2005 Review of fluorine-18–2-fluoro-2-deoxy-D-glucose positron emission tomography (FDG-PET) in the follow-up of medullary and anaplastic thyroid carcinomas. Cancer Control 12:254–260[Medline]
  21. Szakall Jr S, Esik O, Bajzik G, Repa I, Dabasi G, Sinkovics I, Agoston P, Tron L 2002 18F-FDG PET detection of lymph node metastases in medullary thyroid carcinoma. J Nucl Med 43:66–71[Abstract/Free Full Text]
  22. Brandt-Mainz K, Muller SP, Gorges R, Saller B, Bockisch A 2000 The value of fluorine-18 fluorodeoxyglucose PET in patients with medullary thyroid cancer. Eur J Nucl Med 27:490–496[CrossRef][Medline]
  23. de Groot JW, Links TP, Jager PL, Kahraman T, Plukker JT 2004 Impact of 18F-fluoro-2-deoxy-D-glucose positron emission tomography (FDG-PET) in patients with biochemical evidence of recurrent or residual medullary thyroid cancer. Ann Surg Oncol 11:786–794[CrossRef][Medline]
  24. Diehl M, Risse JH, Brandt-Mainz K, Dietlein M, Bohuslavizki KH, Matheja P, Lange H, Bredow J, Korber C, Grunwald F 2001 Fluorine-18 fluorodeoxyglucose positron emission tomography in medullary thyroid cancer: results of a multicentre study. Eur J Nucl Med 28:1671–1676[CrossRef][Medline]
  25. Kraeber-Bodere F, Bardet S, Hoefnagel CA, Vieira MR, Vuillez JP, Murat A, Ferreira TC, Bardies M, Ferrer L, Resche I, Gautherot E, Rouvier E, Barbet J, Chatal JF 1999 Radioimmunotherapy in medullary thyroid cancer using bispecific antibody and iodine 131-labeled bivalent hapten: preliminary results of a phase I/II clinical trial. Clin Cancer Res 5:3190–3198
  26. Machens A, Gimm O, Ukkat J, Dralle H 1999 Repeat mediastinal lymph node dissection for palliation in advanced medullary thyroid carcinoma. Langenbecks Arch Surg 384:271–276[CrossRef][Medline]
  27. Vitale G, Caraglia M, Ciccarelli A, Lupoli G, Abbruzzese A, Tagliaferri P, Lupoli G 2001 Current approaches and perspectives in the therapy of medullary thyroid carcinoma. Cancer 91:1798–1808
  28. Moley JF, Dilley W, DeBenedetti M 1997 Improved results of cervical re-operation for medullary thyroid carcinoma. Ann Surg 225:734–743[CrossRef][Medline]
  29. Schlumberger M, Abdelmouene N, Delisle MJ, Couette JE 1995 Treatment of advanced medullary thyroid cancer with an alternating combination of 5 FU-streptozocin and 5 FU-dacarbazine. The Groupe d’Etude des Tumeurs à Calcitonine (GETC). Br J Cancer 71:363–365[Medline]
  30. Wu LT, Averbuch SD, Ball DW, De Bustros A, Baylin SB, Mc Guire WP 1994 Treatment of advanced medullary thyroid carcinoma with a combination of cyclophosphamide, vincristine, and dacarbazine. Cancer 73:432–436[CrossRef][Medline]
  31. Kraeber-Bodere F, Rousseau C, Bodet-Milin C, Ferrer L, Faivre-Chauvet A, Campion L, Vuillez JP, Devillers A, Chang CH, Goldenberg DM, Chatal JF, Barbet J 2006 Targeting, toxicity and efficacy of 2-step, pretargeted radioimmunotherapy using a chimeric bispecific antibody and 131-I-labeled bivalent hapten in a phase I optimization clinical trial. J Nucl Med 47:247–255[Abstract/Free Full Text]
  32. Chatal JF, Campion L, Kraeber-Bodere F, Bardet S, Vuillez JP, Charbonnel B, Rohmer V, Chang CH, Sharkey RM, Goldenberg DM, Barbet J, French Endocrine Tumor Group 2006 Survival improvement in medullary thyroid carcinoma patients given pretargeted CEA radioimmunotherapy. J Clin Oncol 24:1705–1711[Abstract/Free Full Text]
  33. Simeone JF, Daniels GH, Hall DA, McCarthy K, Kopans DB, Butch RJ, Mueller PR, Stark DD, Ferrucci Jr JT, Wang CA 1987 Sonography in the follow-up of 100 patients with thyroid carcinoma. AJR Am J Roentgenol 148:45–49[Abstract/Free Full Text]
  34. Esik O, Szavcsur P, Szakall Jr S, Bajzik G, Repa I, Dabasi G, Fuzy M, Szentirmay Z, Perner F, Kasler M, Lengyel Z, Tron L 2001 Angiography effectively supports diagnosis of hepatic metastases in medullary thyroid carcinoma. Cancer 91:2084–2095[CrossRef][Medline]
  35. Ong SC, Schöder H, Patel SG, Tabangay-Lim IM, Doddamane I, Gônen M, Shaha AR, Tuttle RM, Shah JP, Larson SM 2007 Diagnostic accuracy of 18F-FDG PET in restaging patients with medullary thyroid carcinoma and elevated calcitonin levels. J Nucl Med 48:501–507[Abstract/Free Full Text]
  36. Juweid M, Sharkey RM, Behr T, Swayne LC, Rubin AD, Herskovic T, Hanley D, Markowitz A, Dunn R, Siegel J, Kamal T, Goldenberg DM 1996 Improved detection of medullary thyroid cancer with radiolabeled antibodies to carcinoembryonic antigen. J Clin Oncol 14:1209–1217[Abstract/Free Full Text]
  37. Juweid M, Sharkey RM, Behr T, Swayne LC, Herskovic T, Pereira M, Rubin AD, Hanley D, Dunn R, Siegel J, Goldenberg DM 1996 Radioimmunotherapy of medullary thyroid cancer with iodine-131-labeled anti-CEA antibodies. J Nucl Med 37:905–911[Abstract/Free Full Text]
  38. Barbet J, Peltier P, Bardet S, Vuillez JP, Bachelot I, Denet S, Olivier P, Leccia F, Corcuff B, Huglo D, Proye C, Rouvier E, Meyer P, Chatal JF 1998 Radioimmunodetection of medullary thyroid carcinoma using indium-111 bivalent hapten and anti-CEA x anti-DTPA-indium bispecific antibody. J Nucl Med 39:1172–1178[Abstract/Free Full Text]
  39. Schlumberger M, Arcangioli O, Piekarski JD, Tubiana M, Parmentier C 1988 Detection and treatment of lung metastases of differentiated thyroid carcinoma in patients with normal chest X-rays. J Nucl Med 29:1790–1794[Abstract/Free Full Text]
  40. Freudenberg LS, Antoch G, Jentzen W, Pink R, Knust J, Gorges R, Muller SP, Bockisch A, Debatin JF, Brandau W 2004 Value of (124)I-PET/CT in staging of patients with differentiated thyroid cancer. Eur Radiol 14:2092–2098[CrossRef][Medline]
  41. McBride WJ, Zanzonico P, Sharkey RM, Noren C, Karacay H, Rossi EA, Losman MJ, Brard PY, Chang CH, Larson SM, Goldenberg DM 2006 Bispecific antibody pretargeting PET (immunoPET) with an 124I-labeled hapten-peptide. J Nucl Med 47:1678–1688[Abstract/Free Full Text]




This Article
Right arrow Abstract Freely available
Right arrow Full Text (PDF)
Right arrow Submit a related Letter to the Editor
Right arrow Alert me when this article is cited
Right arrow Alert me when eLetters are posted
Right arrow Alert me if a correction is posted
Right arrow Citation Map
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrow Request Copyright Permission
Citing Articles
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Oudoux, A.
Right arrow Articles by Kraeber-Bodéré, F.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Oudoux, A.
Right arrow Articles by Kraeber-Bodéré, F.
Right arrowPubmed/NCBI databases
*Compound via MeSH
*Substance via MeSH
Medline Plus Health Information
*Thyroid Cancer
Related Collections
Right arrow Thyroid
Right arrow Endocrine Oncology

HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS
Endocrinology Endocrine Reviews J. Clin. End. & Metab.
Molecular Endocrinology Recent Prog. Horm. Res. All Endocrine Journals