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Oncology Research Department (E.M., A.F.-C., J.B., J.F.C., F.K.-B.), Inserm U601, 44093 Nantes, France; Nuclear Medicine Department (J.P.V.), University Hospital, 38043 Grenoble, France; Nuclear Medicine Department (S.B.), François Baclesse Cancer Center, 14021 Caen, France; Radiology (E.F., B.D.) and Endocrinology (B.C., A.M.) Departments, University Hospital, 44093 Nantes, France; Nuclear Medicine Department (L.F.), René Gauducheau Cancer Center, 44805 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, Inserm U601, Institut de Biologie, 9 quai Moncousu, 44093 Nantes Cedex 1, France. E-mail: francoise.bodere{at}chu-nantes.fr.
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Abstract |
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 Top Abstract IntroductionPatients and MethodsResultsDiscussionReferences |
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Introduction |
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TopAbstractIntroductionPatients and MethodsResultsDiscussionReferences |
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MTC cells also express a high density of carcinoembryonic antigen (CEA), and several clinical studies have evaluated radioimmunotherapy (RIT) with radiolabeled anti-CEA monoclonal antibodies in MTC patients (11, 12, 13). The pretargeting technique using anti-CEA x anti-diethylenetriamine pentaacetic acid (anti-DTPA) bispecific antibody (BsMAb) F6 x 734 and bivalent hapten, where the first step involves targeting with the BsMAb followed by giving the radiolabeled peptide to the arm that the BsMAb binds, showed an 80% sensitivity and 100% specificity in MTC patients with confirmed tumors (14). In a phase I/II trial assessing F6 x 734 BsMAb and [131I]di-DTPA bivalent hapten for the therapy of patients with advanced MTC, pain relief was observed in four and responses in nine of the 19 assessable patients. These responses corresponded to tumor stabilization in four patients and a reduction in tumor biomarkers and/or in the sum of the products of the longest perpendicular diameters of all measured lesions of at least 25% in five patients. Five patients had a morphological tumor response. The duration of response ranged from 3 to more than 18 months. Surprisingly, however, the hematological toxicity was higher and the maximal tolerated dose lower than in patients with other CEA-expressing tumors [e.g. colorectal carcinomas (CRC)], despite more frequent previous chemotherapy and external radiotherapy being administered to the non-MTC patients (15). In a dose-optimization study evaluating the toxicity of chimeric hMN-14 x m734 BsMAb and [131I]di-DTPA in patients with CEA-positive tumors, grade III/IV leukopenia and/or thrombocytopenia was observed in six of nine MTC patients injected with 2.4–3.1 GBq of 131I, but only in two of 12 non-MTC patients injected with 2.2–5.5 GBq (15). Bone involvement (BI) is known to increase the hematological toxicity of internal radiotherapy (16) and could thus explain the toxicity observed with moderate radiation doses administered by RIT. Previous reports showed that MRI is useful in the detection of BI in solid tumors, with a sensitivity of 80–90% and a specificity of 90–100% (17, 18). MRI can identify bone metastases at an earlier stage of growth, before reactivity of the osteoclasts occurs, because this high-resolution technique allows visualization of the bone marrow directly, which represents the initial site of neoplastic infiltration (19, 20, 21).
The purpose of this study was to evaluate, retrospectively, the prevalence of BI using MRI and post-RIT immunoscintigraphy (IS) in 35 MTC patients enrolled in two phase-I/II clinical pretargeted RIT trials using anti-CEA x anti-DTPA BsMAbs and [131I]di-DTPA bivalent hapten. Post-RIT IS conducted in the MTC patients was compared with IS performed in 12 CRC patients, as a control group, because of the low frequency of bone metastases in patients with this cancer type (22).
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Patients and Methods |
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TopAbstractIntroductionPatients and MethodsResultsDiscussionReferences |
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Patients more than 18 yr of age, with histologically proven MTC (group I) or CRC (group II) recurrences documented by a rise in serum Ct or CEA concentration and by conventional imaging or IS, were evaluated. All subjects had a Karnofsky performance status of at least 70% and a minimum life expectancy of more than 9 wk. The patients were at least 4 wk beyond any major surgery, external radiotherapy, or chemotherapy and at least 3 months after internal radiotherapy with [131I]metaiodobenzyl guanidine for the MTC group. They had normal hepatic (bilirubin 
2 mg/dl), renal (creatinine 135 µmol/liter), and hematological (leukocytes 4000/mm3; platelets 100,000/mm3) functions. The baseline level for blood human antimouse antibody was less than or equal to 2 µg/ml, as reported previously (13, 15). The protocols were approved by the local ethics committees, and all patients gave their signed informed consent.
Conventional staging
Conventional staging of MTC patients included clinical examination, CT of neck, chest, abdomen, and pelvis, and ultrasound of neck and liver. A bone scintigraphy was recorded 2–4 h after iv injection of 500–700 MBq of 99mTc-diphosphonate, using a large field-of-view 
-camera together with a low-energy, high-resolution, collimator (DHD Sophy Camera, Sopha Medical, Buc, France). Random, undirected bone marrow biopsies were performed in three MTC patients and bone surgery in two patients. Conventional staging of CRC patients included clinical examination, bone scintigraphy, and CT scans of neck, chest, abdomen, and pelvis.
Bone MRI
MRI was performed using a 1.5-T system (Magnetom Vision, Siemens, Erlangen, Germany). The patients were supine, and images of the spine were acquired with a body coil for sagittal T1-weighted spin-echo sequence (TR/TE, 600/12 ms; flip angle, 130°; matrix, 356 x 512 pixels; field of view, 500 x 500; four acquisitions; slice thickness, 5 mm) to study the sternum as well as a spine coil for Flash Gradient Echo T2-weighted sequence (TR/TE, 273/18 ms; flip angle, 30°; matrix, 192 x 256; field of view, 500; two acquisitions; slice thickness, 6 mm), sagittal T1-weighted spin-echo, and gadolinium contrast enhanced with fat saturation (TR/TE, 615/12 ms; flip angle, 150°; matrix, 356 x 512; field of view, 500; four acquisitions; slice thickness, 6 mm). The pelvic girdle was investigated with axial and coronal Flash-Gradient echo T2-weighted images (TR/TE, 250/18 ms; flip angle, 30°; matrix, 192 x 256; field of view, 500; two acquisitions; slice thickness, 6 mm).
Antibody and hapten preparation, testing, and radiolabeling
Anti-CEA x anti-DTPA BsMAbs, mF6 x m734, and hMN-14 x m734 were provided by Immunotech (Marseille, France) and IBC Pharmaceuticals, Inc. (Morris Plains, NJ), respectively. These BsMAbs were made by coupling an equimolar amount of the Fab' fragment of anti-CEA monoclonal antibody (murine F6 or humanized hMN-14) to the Fab' fragment of the murine anti-DTPA-indium monoclonal antibody (m734) activated by o-phenylene-bismaleimide. The bivalent hapten used was N-
-(diethylenetriamine-N,N,N',N''-tetraacetic acid-N''-acetyl)-tyrosyl-N-
-(diethylenetriamine-N,N,N',N''-tetraacetic acid-N''-acetyl) lysine (di-DTPA-TL) obtained by reaction of the dianhydride of DTPA with tyrosyl-lysine diacetate. Radiolabeling of the hapten with 131I was performed under contract with CIS Bio International (Schering AG, Saclay, France), using the iodogen method. The specific activity was 38–62 MBq/nmol. The radiochemical purity was greater than 95%, and the immunoreactivity of the preparations was above 90%.
IS
The patients were infused with 12–75 mg/m2 of BsMAb mF6 x m734 or hMN-14 x m734 and then 0.87–3.3 GBq/m2 of [131I]di-DTPA was injected. BsMAb and radiolabeled hapten were administered by a slow infusion (30–60 min) at a 4- to 5-d interval. A shielded PerfuCis pump (CIS Bio International) was used for infusion of the radiolabeled hapten. Vital signs were monitored before and for 2 h after infusion. Patients were kept in lead-shielded rooms for 5–10 d.
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 (DHD Sophy Camera, Sopha Medica) equipped with a high-energy collimator. Planar images of the thorax, abdomen, or pelvis were obtained for a few patients using the DST camera equipped with a high-energy collimator. Single-photon emission computed tomography of the thorax or abdomen also was performed in some patients to provide higher contrast and better identification of the tumor site(s).
Qualitative bone imaging analysis
Qualitative image evaluation was performed in individual patients. MRI was analyzed by consensus of two radiologists, and bone scintigraphy and post-RIT IS separately by two nuclear medicine physicians. With MRI, a positive metastatic bone lesion was defined as a focal hypointense bone marrow signal relative to adjacent normal bone marrow on T1-weighted spin-echo images, with an increase of signal intensity on the contrast-enhanced T1-weighted spin-echo sequences. With bone scintigraphy, a metastatic bone lesion was defined visually as an area of focally increased uptake of radioactivity relative to adjacent or the contralateral bone region, and with IS, a positive image was an area of focally increased uptake of radioactivity relative to the adjacent or contralateral region or a diffusely increased accretion in the spine and pelvis. BI was considered as positive when at least two different imaging methods or at least one imaging method and histopathology were positive. Thus, true-positive (TP) results corresponded to an abnormal bone image on the imaging method of interest, confirmed by histopathology or by another imaging technique (CT, bone scintigraphy, MRI, or IS) performed 30 d before or after the imaging study. True-negative (TN) results constituted a normal bone image confirmed by histopathology and/or another imaging technique. False-negative (FN) was considered a negative finding on the considered imaging method and a positive finding on one imaging method plus histopathology or by two imaging methods. A false-positive (FP) image was a positive finding on the imaging method of concern and negative findings on the other imaging methods and histopathology. For each imaging modality, sensitivity per patient, specificity, accuracy, positive predictive value (PPV) , and negative predictive value (NPV) were calculated, respectively, by the following formulas: sensitivity (%) = (TP/TP + FN) x 100; specificity (%) = (TN/TN + FP) x 100; accuracy = (TP + TN/TP + FN + FP + TN) x 100; PPV (%) = (TP/TP + FP) x 100; and NPV (%) = (TN/TN + FN) x 100.
Quantitative IS analysis
For each patient, two rectangular regions of interest (ROI) were drawn on the posterior view. The first ROI was drawn around the lumbar spine, and the second, same-sized ROI was defined on a background region. For each patient’s imaging session, a quantitative index was determined and calculated as the ratio between the detected counts found in the first ROI to that in the second ROI.
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Results |
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TopAbstractIntroductionPatients and MethodsResultsDiscussionReferences |
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Thirty-five patients (21 men and 14 women), 30–71 yr old, with documented recurrences of MTC (group I) were evaluated (Table 1
). All MTC patients were treated initially by total thyroidectomy and central and laterocervical lymph node dissection. Thirty-two patients had sporadic and three had familial disease (multiple endocrine neoplasia 2a and familial MTC). Serum Ct levels ranged from 173–100,000 pg/ml (normal, <10) and CEA titers from 4–548 ng/ml (normal, <6) at the time of RIT. Twenty-six MTC patients (74.3%) were considered positive for BI by undirected, random bone marrow biopsy, by bone surgery, or by two or three positive imaging methods.
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). Their serum CEA titers ranged from 8–460 ng/ml (normal, <6). BI was found in only 2 of the CRC patients (16.7%).
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In the MTC group (I), bone scintigraphy was performed in 30 patients and revealed BI in 17 (56.6% of patients) (Fig. 1). Results of bone scintigraphy are summarized in Tables 1
and 3. Bone scintigraphy was interpreted as positive in 16 patients with BI and in one patient with unconfirmed BI. Conventional bone imaging sensitivity was 72.7%, specificity 87.5%, and accuracy 76.7%. Moreover, CT allowed detection of neck lymph nodes in 23 patients (65.7%), mediastinal lymph nodes in 13 (37.1%), lung metastases in 11 (31.4%), liver metastases in 13 (37.1%), and an adrenal mass in two patients (5.7%).
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). Bone MRI
The results of bone MRI are summarized in Tables 1 and 3. Spine and pelvic MRI was performed in 29 MTC patients and disclosed BI in 22 (75.8% of patients). Bone MRI was interpreted as positive in 21 patients with BI and in one patient with unconfirmed BI. The sensitivity was 100%, specificity 87.5%, and accuracy 96.6%. Figure 1 shows images performed in an MTC patient, for whom bone scintigraphy and MRI showed BI, and Fig. 2 depicts images performed in another MTC patient, for whom bone scintigraphy was doubtful, showing spine heterogeneity; the bone lesions were confirmed by MRI. Figure 3 has images made in yet another MTC patient, showing MRI detection of BI that was missed by bone scintigraphy.
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In group I, IS images showed BI in 31 of 35 MTC patients (88.6%) (Table 1). IS was considered to be positive in the 26 patients with BI and in five patients with unconfirmed BI. The sensitivity of post-RIT IS was 100%, specificity 44.4%, and accuracy 85.7% (Table 3). Combined bone scintigraphy, MRI, and IS revealed BI (with at least one of the three imaging methods being positive) in 33 patients (94.2%). In patients with both positive MRI and IS, the sites of positivity for tumor were the same.
Figures 1–3 provide scans performed in MTC patients, for whom post-RIT IS confirmed BI. Moreover, IS revealed neck foci in 25 patients (71.4%), mediastinal disease in 17 (48.5%), lung involvement in six (17.1%), and liver disease in seven patients (25.7%). Combined conventional imaging and IS detected neck metastases in 26 patients (81.2%), mediastinal metastases in 19 (54.2%), lung metastases in 12 (34.3%), and liver metastases in 15 patients (42.8%).
In the CRC patients (group II), IS visualized mediastinal and/or lung foci in six patients (50.0%), liver foci in two (16.7%), abdominal lesions in three (25.0%), pelvic disease in six (50.0%), and BI in four patients (33.3%) (Table 2). Two of these four patients had known bone metastases by conventional staging. Figure 4 shows the IS recorded in a CRC patient with no BI disclosed by conventional imaging and no increased focal or diffuse uptake of radioactivity in the skeleton by IS. Figure 5 is an IS of a CRC patient confirming the BI seen by bone scintigraphy.
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Quantitative scintigraphy analysis was performed in three MTC and in three CRC patients, and the results are summarized in Fig. 6. Quantitative analysis confirmed visual IS analysis, showing higher lumbar-to-background ratios in MTC than in CRC patients at 3–10 d after injection of the radiolabeled hapten. For group I MTC patients, the spine-to-background ratios ranged from 1.93–2.02 on d 3, 1.82–2.24 on d 6, 1.97–2.41 on d 8, and 1.79–1.83 on d 10. For group II CRC patients, the ratios were lower, ranging from 1.36–1.48 on d 3, 1.25–1.53 on d 6, 1.07–1.52 on d 8, and 1.07–1.50 on d 10.
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Discussion |
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TopAbstractIntroductionPatients and MethodsResultsDiscussionReferences |
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- and Auger-emitters, may be more favorable choices for patients with cancer dissemination to their bone marrow. To confirm the suspicion of BI, bone marrow biopsy is the gold standard, but it is invasive and therefore not readily accepted by patients. Moreover, a limited sample, obtained with an undirected or random biopsy, can be falsely negative. For example, metastatic BI is found in approximately 50% of small-cell lung cancer patients and in up to 85% of breast carcinoma patients at autopsy, but staging procedures detected malignant bone marrow lesions in only 2–30% of patients with these tumors (23). BI was documented histologically in three cases in the present study. To confirm the BI suggested by post-RIT IS, a spine and pelvic MRI was added to the workup before enrollment of the patients. Previous reports suggested that low-intensity lesions on T1-weighted images and high-intensity or iso-intensity lesions on T2-weighted images in the bone marrow indicate infiltration with cancer and showed that MRI is suitable to detect BI of solid tumors, particularly small-cell lung cancer and breast carcinoma, with a sensitivity between 80 and 90% (17, 18, 19, 20, 21, 23, 24, 25, 26). In one study comparing bone marrow MRI and (undirected) bone marrow biopsy, the detection rate of bone marrow disease was 46% with MRI and 14% with biopsy (23). In the 36 patients in whom MRI was positive, biopsy was negative in 25 cases (23).
In the present investigation, BI was suspected by bone scintigraphy, MRI, or IS in 94.2% of MTC patients and confirmed in 74.3%. In the literature, the rate of BI in advanced MTC has been reported to be 30.3% (98 of 324) in a meta-analysis of 324 cases in 14 clinical studies (3, 12, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38). This detection rate is markedly lower than that found in our study, but imaging techniques in the preious studies included only bone scintigraphy and CT. In this report, as is known for other neuroendocrine tumors (39, 40), MRI appeared to be a sensitive imaging technique for detecting the spread of MTC. It had a higher sensitivity for BI than bone scintigraphy, which detects BI at a relatively advanced stage of tumor infiltration, when an osteoblastic reaction has occurred. These results suggested that MRI should be performed routinely in MTC patients with elevated serum CT level even when bone scintigraphy is normal and even in patients with relatively low CT levels. The advantage of bone scintigraphy is the evaluation of the whole skeleton, and in this study, bone scintigraphy detected bone metastases in 57% of MTC patients. The specificity and accuracy of bone scintigraphy appeared to be relatively good (87.5 and 76.7%, respectively), which is likely because of the evaluated population having a high prevalence of bone metastases and minimal bone infection or rheumatoid arthritis, which could also result in positive bone scans. Previous studies have shown that bone marrow scintigraphy using radiolabeled colloids or radiolabeled antigranulocyte antibodies had a high sensitivity for the detection of BI (41, 42). [18F]Fluorodeoxyglucose positron emission tomography (PET), in which sensitivity depends on the histological type and metabolism of the tumor, also appears of interest for the detection of BI and provides, like IS, an evaluation of disease throughout the body (18). [18F]Dihydroxyphenylalanine PET is another functional imaging procedure that seems to provide encouraging results in neuroendocrine tumors (43). Indeed, neuroendocrine tumors are capable of taking up amino acids, converting them by means of decarboxylation to biogenic amines, and then storing them in vesicles.
In the current investigation, the sensitivity of IS for BI in MTC patients was high. The two-step pretargeting technique improved the tumor-to-nontumor contrast compared with the conventional one-step (directly labeled antibody) method (14, 44). In the detection of metastases from differentiated thyroid carcinoma, the sensitivity of 131I scintigraphy was significantly higher with therapeutic activities (3.7 GBq) than with diagnostic doses (370 MBq) (45). Similarly, the high therapeutic doses of radioactivity used in our study could explain the high incidence of BI suspected on post-RIT IS.
The relatively low specificity of IS deserves further consideration. It is related to five patients who had a diffuse bone marrow uptake with consequent hematological toxicity after RIT. All of these patients had no bone biopsy and showed negative bone scintigraphy and MRI, warranting FP findings for IS. However, it cannot be excluded that such positive IS results could be related to a diffuse BI not confirmed by other imaging methods. This situation can be compared with that of differentiated thyroid carcinoma, where lung micrometastases are detected only after 131I therapy and not on low-dose diagnostic scans (45). However, the high bone marrow uptake in MTC patients could have been nonspecific, related to the method and not the tumor type.
To consider this possibility, the study included 12 patients with CRC, which is characterized by a low frequency of bone metastases (8% in patients with isolated liver metastases) (22). In this group, injected with the same amount of bispecific antibody and the same activity of [131I]hapten as in the MTC group, hematological toxicity was observed only with higher injected radioactivity, and quantitative analysis of IS showed a lower bone marrow uptake (15). In another RIT study evaluating high doses of [131I]MN-14 anti-CEA antibody in advanced MTC, the authors reported the detection of 97% of known or suspected disease sites, with excellent targeting of bone and bone marrow, often better than that seen by CT or bone scan, and confirmed by MRI or bone marrow biopsy (12).
Several investigations have evaluated the early dissemination of MTC by RT-PCR (46, 47). Weber et al. (46) evaluated two RT-PCR-based assays for the detection of disseminated tumor cells in blood, bone marrow, and lymph node samples, using frozen tissue and blood samples in 19 patients with MTC. Disseminated tumor cells were detected with cytokeratin-20- and preprogastrin-releasing peptide-PCR in 28% of preoperative blood samples for each. MTC cells were found in three of eight bone marrow samples with cytokeratin-20, and disseminated MTC cells were detected in 26% of histologically tumor-free cervical lymph nodes. These results might therefore explain the low biochemical cure rates reported in the literature and demonstrate an early hematogenous dissemination and bone marrow involvement of MTC, supporting our imaging data.
In this study, the accuracy of imaging methods for revealing spread to soft tissues was not determined in MTC patients, because only CT and IS were performed without confirmation by a third imaging method, like MRI, or by histopathology. However, combined CT and IS seemed to be more revealing than either modality alone, increasing the detection rate of metastases in the neck, mediastinum, lung, and liver. Liver metastases were detected in 42.8% of advanced MTC patients. However, physiological liver uptake of the radiolabeled hapten made visualization of small lesions difficult (14). Moreover, conventional imaging, including CT and ultrasound, is not very sensitive for the detection of liver metastases. Esik et al. (27) reported results of angiography in 36 patients with MTC and a high Ct serum level after total thyroidectomy. Liver metastases were visualized in 89% of patients vs. only 14% with conventional imaging, but the CT technique was not optimal and probably did not use a multiphase protocol. Moreover, these metastases were most often small (2–35 mm) and multiple (5–169 per patient). Furthermore, the rate of cervical lymph node metastases was 81.2% in our study, confirming the 71–80% rates published previously (48). The frequency of this involvement depends upon the type of surgery and the imaging technique (27). For example, [18F]fluorodeoxyglucose PET appears to be more sensitive than conventional imaging modalities for localizing lymph node metastases in MTC (48).
In conclusion, we have demonstrated a much higher rate of BI in MTC than hitherto reported, because of the high sensitivity of MRI and post-RIT IS. Bone MRI is thus recommended in the postsurgical workup of such patients to choose the best therapeutic intervention. Such results suggest the need for systemic therapies, like RIT, to complement surgery in the management of MTC, to control the very frequent bone marrow dissemination of this tumor, mainly in the situation of progressive (clinically and biologically) disease. However, moderate doses of radioactivity may be injected, as in this study, to better treat BI, yet prevent severe hematological toxicity.
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Footnotes |
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Abbreviations: BI, Bone involvement; BsMAb, bispecific antibody; CEA, carcinoembryonic antigen; CRC, colorectal carcinoma; Ct, calcitonin; CT, computed tomography; DTPA, diethylenetriamine pentaacetic acid; FN, false-negative; FP, false-positive; IS, immunoscintigraphy; MRI, magnetic resonance imaging; MTC, medullary thyroid carcinoma; NPV, negative predictive value; PET, positron emission tomography; PPV, positive predictive value; RIT, radioimmunotherapy; ROI, region of interest; TN, true-negative; TP, true-positive.
Received July 29, 2004.
Accepted November 17, 2004.
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TopAbstractIntroductionPatients and MethodsResultsDiscussionReferences |
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-2b and octreotide. Cancer 78:1114–1118[CrossRef][Medline]
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