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Figure 27.6 A 99mTc(V)-DMSA whole-body scan following surgery for medullary thyroid cancer demonstrating residual tumor in lower left neck. B 111I indium octreotide scan in same patient showing lower uptake in remnant tumor.

The role of 99mTc-MIBI has been investigated as an imaging agent in patients with recurrent MTC. Learoyd et al. [59] compared the uptake of 99mTc-MIBI with CT in patients with recurrent

MTC and demonstrated that 99mTc-MIBI is more sensitive than CT for detecting recurrence in the head, neck, and chest, but CT was more sensitive for detecting disease in the liver. The 99mTc bone scan was more sensitive for detecting bone metastases than 99mTc-MIBI. Ugur et al. [60] compared the sensitivities of 99mTc-MIBI, 201Tl, and 99mTc(V)-DMSA and showed them to be 47%, 19%, and 95%, respectively. These data confirm that at present 99mTc(V)-DMSA is the most sensitive radionuclide imaging agent available. Juweid et al. have used 99mTc-MIBI to explore the multidrug resistance of MTC [61].

Following successful imaging of the adrenal medulla by Wieland et al. [14] in 1980, the role of 123/131I-MIBG in MTC has been investigated in MTC. Nakajo et al. [62] in 1983 studied a number of patients with neuroectodermal tumors, including one patient with MTC. They reported no uptake in MTC. The first positive case of 131I-MIBG uptake in a patient with MEN2A was reported by Endo et al. [63] in 1984. Uptake in both the primary MTC and the coexistent pheochromocytoma was observed. In the same year Connell et al. [64] also described 131I-MIBG uptake in a primary tumor of a patient with familial MTC. The first report of uptake in metastatic MTC was made by Sone et al. [65] in 1985, who studied a nonfamilial case of MTC with bone and liver metastases. Uptake was seen in all sites of known disease.

Following the publication of these case reports a number of series of cases have been reported. Poston et al. [66] in 1985 studied six patients, three with sporadic MTC, two with MEN2A, and one with MEN2B. Although all patients studied were postoperative with calci-tonin evidence of recurrence, only one patient had a positive study. The results of many series of MTC patients studied with MIBG have been published [5,67-71]. The later series have been performed with 123I-MIBG that has increased resolution, but none of the studies have utilized SPECT. In most studies a sensitivity of 30% is reported, and this is confirmed when the cumulative experience is reviewed.

Several studies have been undertaken to compare the sensitivities of different radiophar-maceuticals in MTC. Clarke et al. [72] in 1988 compared the uptake of 99mTc(V)-DMSA, 131I-MIBG, and 99mTc-MDP in patients with MTC and showed that 99mTc(V)-DMSA was the most sen sitive agent for detecting sites of MTC. Verga et al. [5] in 1989 compared 99mTc(V)-DMSA and 123I- or 131I-MIBG and again confirmed that 99mTc(V)-DMSA was the more sensitive agent.

The technical aspects of 123I- or 131I-MIBG imaging in MTC need to be considered. In patients with primary disease or suspected neck recurrence who have not undergone total thyroidectomy, it is essential to block the thyroid prior to administration of MIBG. Unless adequate blockade with potassium iodate is achieved, interpretation of uptake in the neck will be extremely difficult. Whole-body images at 4 and 24 hours should be acquired, and SPECT imaging of the neck and liver at 24 hours will increase lesion detection in patients imaged with 123I-MIBG. The role for 131I-MIBG in diagnostic imaging is debated. The slow tumor accumulation of MIBG may indicate that the later imaging possible with 131I-MIBG compared with 123I-MIBG may increase the sensitivity of lesion detection.

Although 131I- and 123I-MIBG have been shown to have an unacceptably low sensitivity for diagnostic imaging, the therapeutic potential of 131I-MIBG in those patients in whom good uptake is demonstrated should be recognized.

A number of patients with MTC have now been treated with 131I-MIBG and a palliative response has been achieved in about 50% of patients so treated [73]. Partial response has been observed in a further 25% of patients, with response times lasting up to 18 months [74,75] (Figure 27.7).

111In octreotide is also used to detect recurrence in patients with rising calcitonin levels indicating recurrent MTC. SPECT imaging will enhance lesion detection in the neck and liver. Sensitivities of 65% have been reported in detecting MTC lesions, although the sensitivity is lower in the liver as a result of nonspecific uptake (Figure 27.6B) [76].

Since some therapeutic responses in MTC have been reported using a somatostatin analogue [77], the ability to demonstrate which MTC patients may respond to this agent should prove of great benefit given the high cost of treatment. Therapy has been undertaken with high doses of mIn octreotide utilizing the radiation effect of Auger electrons [78]. Various 90Y-labeled compounds have been evaluated although some studies have reported renal tox-icity as a dose limiting factor [79].

The importance of detecting recurrent disease to facilitate surgery and prolong symptomfree survival has been emphasized earlier. Numerous studies have been undertaken with 18FDG in patients with calcitonin elevations indicating the site of recurrent MTC (Figure 27.8). A multicenter study by Diehl et al. [80] concluded that 18FDG is sensitive in detecting recurrent disease and compares favorably with other radionuclide and non-radionuclide imaging techniques. Other studies have suggested that 18FDG-PET imaging is more sensitive in patients with rapidly progressive disease than in patients with slowly rising calcitonin levels [81].

Results from imaging with monoclonal antibodies have been varied, ranging from 0% with anticalcitonin antibody to 78% with 131I-anti-CEA antibody. The results of imaging with monoclonal antibodies in patients with MTC have been compared with imaging with other radiopharmaceuticals by a number of groups. Cabezas et al. [16] compared imaging with 131I-anti-CEA antibody and 131I-MIBG and showed

Figure 27.7 131I-MIBG posttherapy scan in a patient with metastatic medullary thyroid cancer. Good uptake of therapy dose at metastatic sites is identified.

Figure 27.7 131I-MIBG posttherapy scan in a patient with metastatic medullary thyroid cancer. Good uptake of therapy dose at metastatic sites is identified.

ANTERIOR

CORONAL

SAGITTAL

TRANSAXIAL

Figure 27.8 18FDG-PET scan in patient with history of medullary thyroid cancer and a rising calcitonin. Other imaging investigations failed to identify the location of recurrence but the 18FDG-PET scan demonstrated uptake in bihilar nodes. As recurrence was inoperable, patient was referred for chemotherapy.

significantly higher lesion detection with the antibody. They also compared the relative sensitivity of CT imaging with the two radionuclide techniques and showed that CT imaging was also inferior to 131I-anti-CEA imaging. Sandrock et al. [71] compared the results of imaging with 131I-MIBG, 201Tl, and 111In-anti-CEA antibody and also concluded that imaging with the antibody yielded the best results. Troncone et al. [70] evaluated 99mTc(V)-DMSA, 131I-MIBG, and 131I-anti-CEA antibody and showed that the sensitivity of imaging with 99mTc(V)-DMSA and 131I-anti-CEA antibody was far superior to imaging with MIBG. As the target to background ratio of anti-CEA antibody is low, the Marseille group have developed a two-step targeting technique of a bispecific antibody. The first arm (Fab fragment) recognizes the CEA tumor expression and the second arm (Fab fragment) is specific for the bivalent di-DTPA-indium hapten. In the first step of the process the non-labeled antibody is injected and binds to the tumor cells expressing CEA, Four to 5 days later, the bivalent hapten which is radiolabeled is injected and binds to the anti-hapten arm of the antibody. In the interval before injection of the radiolabeled compound bispecific antibody is gradually degraded by normal tissues [82]. Preliminary studies have been encouraging in a French multicenter study in patients with MTC and preliminary results of a phase I/II clinical trial been published [83].

Juweid et al. [84] explored high dose 131I-MN-14F(ab)(2) anti-CEA antibody and autologous hemopoietic stem cell rescue in patients with rapidly progressive disease, with all patients achieving disease stabilization and some showing tumor regression. The same group has also undertaken animal studies using combinations of 90Y-labeled CEA antibody with doxoru-bicin and Taxol. The efficacy of the combined treatments was greater than either treatment given alone [85].

Imaging studies in patients with MTC using 111In diethylenetriamine pentaacetic acid-Dglu(1)-minigastrin have demonstrated a 91% sensitivity for detecting tumor, even in patients with occult disease. Dose escalation studies are now being undertaken to assess the efficacy and toxicity of 90Y-minigastrin in patients with advanced metastatic disease. Initial results are reported as promising although nephrotoxicity is a major concern [22]. A summary of the advantages and disadvantages of the various radiopharmaceuticals used to image patients with MTC is given in Table 27.1.

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