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¹ Department of Nuclear Medicine, Hôpital Saint-Louis, Assistance Publique-Hôpitaux de Paris, Avenue Claude Vellefaux, 75475 Paris Cedex 10, France
² Imagerie Moléculaire Diagnostique et Ciblage Thé rapeutique, B2T, IUH, Université Paris 7, Hôpital Saint-Louis, 75475 Paris Cedex 10, France
³ DSV/I²BM/SHFJ/LIME, Commissariat à l’Energie Atomique, 91000 Orsay, France
⁴ Departments of Nuclear Medicine and
⁵ Endocrinology, Hôpital Saint-Antoine, Assistance Publique-Hôpitaux de Paris, 75012 Paris, France
⁶ Department of Endocrine Surgery, Hôpital Saint-Louis, Assistance Publique-Hôpitaux de Paris, 75475 Paris Cedex 10, France

(Correspondence should be addressed to E Hindié; Email: elif.hindie{at}sls.aphp.fr)

	Abstract

Top Abstract Introduction Patients and methods Results Discussion References

 
Bone is the second most frequent target of distant metastases in patients with differentiated thyroid cancer, and such forms carry a very poor prognosis. The impact of ¹³¹I therapy in this setting is controversial. We describe the diagnostic circumstances and outcome of patients with bone metastases recently managed in two institutions. Among 921 consecutive thyroid cancer patients who had total thyroidectomy and ¹³¹I ablation between January 2000 and December 2004 and who were subsequently monitored, bone metastases had been diagnosed in 16 patients. In three cases, the bone metastases were non-functioning (negative ¹³¹I uptake) . These patients were treated with surgery and radiotherapy but progressed rapidly. The other 13 patients had functioning (positive ¹³¹I uptake) bone metastases. In five of them, thyroid cancer was revealed by signs of distant involvement (bone pain, n = 4; dyspnea, n = 1). The bone metastases progressed in these five patients, despite local therapy and multiple courses of ¹³¹I. The bone metastases in the remaining eight patients were discovered on the post-surgery ¹³¹I therapy scan. Complementary radiological studies were negative except in one patient in whom one of the metastases (a 5 mm lesion of the right humerus) was visible on magnetic resonance imaging (MRI). Six of these patients showed a good response to ¹³¹I therapy, with ¹³¹I uptake and Tg levels becoming undetectable or showing a sharp fall. One patient refused ¹³¹I therapy; bone metastases became visible on MRI within 1 year and the Tg level rose tenfold. The disease progressed in one patient despite ¹³¹I therapy. Post-surgical ¹³¹I ablation can contribute to early detection of bone metastases at a time when the Tg level may be only moderately elevated, when other radiological studies are negative, and when the disease is potentially curable by ¹³¹I therapy.

	Introduction

Top Abstract Introduction Patients and methods Results Discussion References

 
About 3 to 5% of patients with differentiated thyroid cancer develop bone metastases (Bernier et al. 2001, Haq & Harmer 2005, Durante et al. 2006). Bone metastases are less frequent than pulmonary metastases but carry a far worse prognosis (Haq & Harmer 2005, Durante et al. 2006).

Iodine 131 (¹³¹I) has been used since 1946 to treat patients with functioning metastases (Seidlin et al. 1946). ¹³¹I uptake is found in more than two-thirds of patients with distant metastases and in roughly equal proportions of patients with lung or bone involvement (Durante et al. 2006). However, the impact of ¹³¹I therapy on bone metastases is controversial (Proye et al. 1992).

In a historical report by Brown, only 1 (5%) out of 21 patients with bone metastases treated with ¹³¹I survived 5 years (Brown et al. 1984), but efficacy seems to have improved in recent years (Bernier et al. 2001, Petrich et al. 2001, Haq & Harmer 2005, Durante et al. 2006). Bernier et al.(2001) obtained a 15% survival rate at 10 years in patients with bone metastases. By comparison, more than 60% of patients with metastases confined to the lungs survive for 10 years (Casara et al. 1993, Hindie et al. 2003, Durante et al. 2006).

Bone metastases are rarely detected at an early stage. Here, we analyzed the diagnostic circumstances and outcome of patients with bone metastases in a series of patients with differentiated thyroid cancer recently managed in two institutions.

	Patients and methods

Top Abstract Introduction Patients and methods Results Discussion References

 
From January 2000 to December 2004, a total of 921 patients with newly diagnosed differentiated thyroid cancer received total thyroidectomy and ablation therapy with 100 mCi (3.7 GBq) ¹³¹I, either at the Nuclear Medicine Department of Saint-Antoine Hospital or at Saint-Louis Hospital (Paris, France), and were subsequently monitored. The first follow-up examination, 6–12 months after ablation therapy, included Tg assay under thyroid-stimulating hormone stimulation.

This analysis focuses on 16 patients (11 females and 5 males) in whom bone metastases were discovered either during the initial work-up or during follow-up. Their mean age was 57.2 years (16–77 years). No other case of bone metastases occurred during the follow-up period of this study (average 45 months).

Non-functioning metastases

Three patients had bone metastases that were nonfunctioning, i.e., did not take up ¹³¹I. These three patients were treated with surgery and/or external beam radiotherapy (Table 1).

In the other 13 patients, all the bone metastases were functioning (¹³¹I-avid). Four of these patients also had functioning lung metastases (Table 2). When bone metastases were suspected on the basis of ¹³¹I whole-body scan, and in order to precisely locate ¹³¹I foci, ¹³¹I scanning was repeated and combined with ^99mTc-HMDP (^99mTc-hydroxy-methylene-diphosphonate) bone scanning, using simultaneous dual-tracer planar imaging, and SPECT (single photon emission computerized tomography) imaging if necessary. In both the institutions, scanning was done with a double-head gamma camera (DST-XL, GEMS). Radiological studies were also performed in every case.

Before any ¹³¹I therapy, patients were instructed to avoid food and medication with high iodine content (a specific list is given). Moreover, urinary iodine was measured in all patients. All patients were thoroughly informed of ¹³¹I therapy and imaging studies.

This retrospective study was done in compliance with the ethical requirements at our Institution.

	Results

Top Abstract Introduction Patients and methods Results Discussion References

 
Discovery of non-functioning metastases

In two patients (patients B and C), bone pain was the first symptom of thyroid cancer. In the third (patient A), nonfunctioning metastases of the cervical spine were discovered, together with neck soft tissue recurrence, 12 months after initial management, and were documented by FDG PET-CT (fluorine-18-deoxyglugose positron emission tomography/computerised tomography) and MRI (Table 1).

Outcome of patients with non-functioning metastases

The three patients concerned had a rapidly progressive disease, despite various treatments (Table 1), and survived for 5 to 34 months (mean 19.3 months; Table 1).

Discovery of functioning metastases

Thyroid cancer was revealed by signs linked to distant metastases in five cases. Back pain was the first symptom of thyroid cancer in four patients (nos 2, 6, 8, 11) and was associated with spinal cord compression in three cases. Dyspnea was the revealing symptom in one patient (no. 13); computerised tomography (CT) showed the presence of multiple lung and bone metastases and an enlarged thyroid. The distribution of bone metastases at initial ¹³¹I therapy in these five patients is shown in Table 2. Off-T4 Tg levels ranged between 31 and 86 960 ng/ml (Table 2).

In the other eight patients, bone metastases were revealed by ¹³¹I scanning during ¹³¹I remnant ablation in seven cases (nos 1, 3, 4, 5, 7, 9, 12), and, in the last case (patient no. 10), during a second course of ¹³¹I given because of a high initial Tg level (147 ng/ml) and because of the large size of the initial thyroid tumor (7 cm). The distribution of bone metastases at initial ¹³¹I therapy in these eight patients is shown in Table 2. The off-T4 Tg level at diagnosis of bone metastases ranged between 7.4 and 9020 ng/ml. In four cases, the stimulated Tg level was lower than 40 ng/ml (nos 3, 4, 5, 7). Complementary radiological studies were negative in seven patients. In the remaining one patient (no. 1), MRI showed a single metastasis (a 5 mm lesion of the right humerus).

Outcome of patients with functioning metastases

The five patients in whom thyroid cancer was revealed by distant metastases (patient nos 2, 6, 8, 11, 13) had a mean follow-up of 49 months. Two of them (nos 6, 8) died. Patient no. 6 received treatment with an anti-angiogenic drug (Nexavar Sorafenib, Bayer), during the last 3 months, which gave a temporary improvement of dyspnea, together with a transient reduction of the size of pulmonary nodules and Tg levels. Two others patients (nos 11, 13) have progressive disease despite multiple courses of ¹³¹I and additional local treatments (Table 2). The fifth patient (no. 2) had a single (spinal) metastasis for which she received surgery, external beam radiotherapy, and a total of 524 mCi ¹³¹I, but with an incomplete response (Table 2).

Among the eight patients (nos 1, 3, 4, 5, 7, 9, 10, 12) whose bone metastases were discovered by ¹³¹I scanning, five are in an apparent remission after an average cumulative ¹³¹I dose of 303 mCi and no additional therapy. ¹³¹I uptake has disappeared in these five patients (Figs 1–3). Tg level has fallen markedly in two patients (from 511 to 1.7 ng/ml in patient no. 1 (Fig. 1) and from 22 to 4 ng/ml in patient no. 5 (Fig. 2)), and is undetectable in the other three patients (nos 3, 4, and 7 (Fig. 3)). Another patient (no. 12) had an excellent response and is continuing ¹³¹I therapy. She has a slight residual ¹³¹I uptake at a single site, while the other bone and lung ¹³¹I foci have disappeared, and the off-T4 Tg level has fallen from 194 to 10.9 ng/ml. One of the other two patients (patient no. 9) has a progressive disease with new bone metastases despite ¹³¹I therapy and local treatments, and died 63 months after the discovery of bone metastases. The other patient (no. 10), who had focal ¹³¹I uptake in the left femur, refused additional therapy because MRI showed a normal femur. She finally accepted therapy 18 months later because of a rise in Tg levels on L-T4 therapy. At this time, the ¹³¹I scan showed multiple bone metastases which were also clearly visible on MRI, and the off-T4 Tg level which had increased from 180 to 2234 ng/ml. Disease is now progressing despite ¹³¹I therapy.

View larger version (154K): [in this window] [in a new window]   Figure 1 131I whole-body scans of patient no.1 (all scans are anterior views). The first scan (left) was obtained at the time of 131I thyroid remnant ablation (100 mCi, off-T4 Tg 519 ng/ml). In addition to the uptake in the thyroid bed area, focal 131I uptake is visible on the right humerus, the right occipital area, and the left acetabulum (arrowheads). There is also a faint pulmonary uptake. Complementary radiological studies were negative, except for the metastasis of the right humerus (5 mm on MRI). The second scan was recorded 5 months later during a second course of 131I therapy (100 mCi, Tg = 233 ng/ml). Some 131I uptake is still visible on the right humerus, the right occipital area, and the left acetabulum. This scan also revealed an uptake on the manubrium (arrowhead), which was masked by the uptake in the thyroid bed during initial therapy. Diffuse lung uptake is now clearly visible. This third scan was obtained at 36 months, at the time of the fifth and last course of 131I therapy (100 mCi, Tg = 11.5 ng/ml). 131I uptake at metastatic sites disappeared (the activity in the right pelvis corresponds to the bladder). The last scan was obtained with a diagnostic 131I activity (5 mCi) after rhTSH stimulation, 18 months after the last course of 131I therapy. No abnormal 131I uptake was seen. Stimulated Tg = 1.7 ng/ml.

View larger version (147K): [in this window] [in a new window]   Figure 2 Whole-body scans of patient no. 5 (all scans are posterior views). The first scan (left) was obtained at the time of 131I remnant ablation (100 mCi, off-T4 Tg = 22 ng/ml). In addition to an uptake in the thyroid bed area (masked), focal 131I uptake is visible on the spine at levels T6 and L2 (arrowheads), on the inner border of the right scapula (arrow), and on the left iliac bone (curved arrow). The precise location of the 131I foci was possible by combining 131I scanning with 99mTc-HMDP bone scanning (shown next to the 131I scan), using simultaneous dual-tracer imaging. Bone scan per se is negative (the faint focus at level T6 is probably due to Compton scatter from 131I in the technetium-99m window, as also seen at the level of the thyroid remnant). The 131I scan on the right was obtained at 21 months, at the time of the third course of 131I therapy (off-T4 Tg = 4.2 ng/ml; TSH = 50 µIU/ml). This scan shows the absence of residual 131I uptake at metastatic sites (physiological uptake is seen corresponding to the stomach). A fourth course of 131I therapy (3.7 GBq) was given 1 year later confirming the absence of residual 131I uptake. The patient keeps a slightly elevated Tg level under stimulation (off-T4 Tg = 4 ng/ml; TSH = 59 µIU/ml).

View larger version (147K): [in this window] [in a new window]   Figure 3 Whole-body scans of patient no. 7 (all scans are posterior views). The first scan (left) was obtained at the time of 131I remnant ablation (100 mCi, off-T4 Tg = 7.4 ng/ml). In addition to an uptake in the thyroid bed area (masked), two foci of 131I uptake are visible on the spine at the level of T11 and L3 (arrowheads). The precise location of 131I foci was obtained by combining 131I scanning and 99mTc-HMDP bone scanning using simultaneous dual-tracer planar imaging and SPECT. The whole-body bone scan (shown next to the 131I scan) is negative. The faint uptake in the upper thoracic spine is due to Compton scatter in the technetium-99m window from 131I present in the thyroid remnant. The second 131I scan was recorded 6 months later during the second course of 131I therapy (150 mCi, off-T4 Tg 1 ng/ml). 131I uptake at metastatic sites had disappeared (physiological uptake is seen in stomach and transverse colon).

	Discussion

Top Abstract Introduction Patients and methods Results Discussion References

Our main finding is that a substantial percentage of bone metastases can now be discovered early on the ¹³¹I scan, when tumor burden is still limited. A complete response to iodine therapy can be achieved at this early stage. In 8 out of the 16 cases in this series (50%), the bone metastases were first revealed by ¹³¹I scanning. Complementary radiological studies were performed in all eight patients (MRI in six, CT in two, bone scan in seven). These imaging studies were negative in seven (cf. Table 2). In the remaining patient (patient no. 1), MRI showed a single metastasis. FDG-PET scan was not ordered on a routine basis in these patients (performed only in patient no. 10, in whom it proved negative). A study by Ito et al.(2007) showed that the sensitivity of FDG-PET is similar to that of bone scanning, but with higher specificity.

At the time of ¹³¹I ablation, the off-T4 Tg level in four patients with radiologically undetectable metastases was below 40 ng/ml, a value that some authors have proposed as a sign of possible distant metastasis (Schlumberger et al. 1996, Schlumberger 1998). In the absence of ablation therapy, early detection of bone metastases in these patients would not have been possible.

Several factors may have contributed to early detection of bone metastases, including trends toward earlier discovery and management of thyroid cancer and more frequent use of total thyroidectomy and ¹³¹I ablation (Schlumberger 1998, Mazzaferri & Kloos 2001, Cooper et al. 2006, Pacini et al. 2006). Scanning made after a therapy dose of ¹³¹I is highly sensitive so that a scan should always be obtained when a therapy dose has been administered. Improved sensitivity of gamma cameras may also be a factor.

We used dual-isotope acquisition of ¹³¹I and ^99mTc-HMDP bone scanning as internal landmarks. The correlation with anatomy can now be rendered easier by combining single-photon emission computed tomography and the computed tomography (¹³¹I-SPECT/CT) images were obtained with an integrated system ‘hybrid instruments’ (Krausz & Israel 2006).

Among the 13 patients with functioning bone metastases, 12 were diagnosed during initial management (clinical work-up or ¹³¹I scanning) and one was diagnosed 6 months later. None of the other patients developed functioning bone metastases, in keeping with our previous findings on functioning pulmonary metastases (Hindie et al. 2003). These results suggest that post-surgery adjuvant ¹³¹I therapy can be useful not only for early diagnosis of distant functioning metastases but possibly also for preventing late metastatic events.

Excellent responses to ¹³¹I therapy were obtained, without the need for additional treatment, in six of the eight patients in whom bone metastases were first discovered by ¹³¹I scanning. ¹³¹I uptake disappeared in five of these patients, while the other patient had slight residual ¹³¹I uptake at a single site (the other bone and lung metastases cleared). These results confirm the prognostic importance of early diagnosis of bone metastases of thyroid cancer (Marcocci et al. 1989, Pittas et al. 2000, Bernier et al. 2001, Petrich et al. 2001, Haq & Harmer 2005, Durante et al. 2006). The only patient who had delayed repeat ¹³¹I therapy progressed; MRI became positive and the Tg level increased tenfold. Therefore, when the whole-body ¹³¹I scan points to the presence of bone metastases – even if other imaging methods (MRI, CT, etc.) are negative and the Tg level is only moderately elevated – repeat ¹³¹I therapy should not be postponed; only at this early stage of tiny metastases is there a chance of cure.

In these patients with functional metastases that had no structural correlate on cross-sectional imaging, it is possible that the thyroid cancer metastases are actually bone marrow metastases rather than ‘bone’ metastases per se. Since ¹³¹I passes through the bone marrow and the blood stream, and since bone marrow metastases by definition must be quite small, it is likely that ¹³¹I treatment would be more effective in this setting. The 5 mm lesion seen on the MRI inthe humerus of patient no. was actually in the bone marrow and not in the bone parenchyma.

Antiangiogenic drugs and other targeted treatments may constitute a new therapeutic approach in patients who progress despite ¹³¹I therapy. A number of molecules are under investigation (Baudin & Schlumberger 2007). Yet, none has emerged as providing a definite benefit on survival with acceptable toxicity.

This study suggests that post-surgical ¹³¹I ablation can contribute to early detection of bone metastases, at a time when the Tg level may be only moderately elevated, when other radiological studies are negative, and when the disease is potentially curable by ¹³¹I therapy.

	Funding

 
A part of the costs for this work was supported by ‘Cisbio International’. There is no conflict of interest related to this study.

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