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Original Studies |
Clinical Endocrinology Branch (P.R.-P., P.M.Y., N.J.S.) and Division of Intramural Research (M.C.S.), National Institute of Diabetes, Digestive, and Kidney Diseases, and the Nuclear Medicine Department (J.C.R., W.C.B.), Warren G. Magnuson Clinical Center, National Institutes of Health, Bethesda, Maryland 20892
Address correspondence and requests for reprints to: Nicholas J. Sarlis, M.D., Ph.D., Investigator, Clinical Endocrinology Branch, National Institute of Diabetes, Digestive, and Kidney Diseases, National Institutes of Health, Building 10, Room 8D12C, 10 Center Drive, MSC 1758, Bethesda, Maryland 20892-1758. E-mail: njsarlis{at}helix.nih.gov
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Abstract |
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 Top Abstract IntroductionCase ReportMethod of Determination of...References |
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Introduction |
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TopAbstractIntroductionCase ReportMethod of Determination of...References |
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The iodine uptake by metastases in most cases of thyroid carcinomas is quite low, but is increased significantly under the stimulation of TSH during a hypothyroid period before 131I treatment (18). In cases of thyroid cancer metastases producing excess TH, the optimal way to effectively achieve a cytotoxic concentration of 131I per gram of tumor has not been defined (19, 20, 21). Approaches to this problem might include stimulation with: 1). endogenous TSH after short-term administration of an antithyroidal drug (22); 2) oral TRH (23); and 3) recombinant human TSH (rhTSH) (24, 25, 26) to optimize TSH levels for 131I scanning and therapy. In the past, bovine TSH had also been used toward the latter aim (27, 28, 29), but is no longer available. Finally, it is possible that at least some hypersecretory thyroid carcinomas may show sufficient iodine uptake at baseline to permit empirical high-dose 131I therapy (dose range, 150–200 mCi) without the need of additional stimulation by high TSH levels; however, the efficacy of such a therapeutic protocol has not been formally studied.
We herewith describe the use of rhTSH in the context of both pretreatment lesion dosimetry and 131I therapy for the management of hypersecretory metastases in an uncommon case of malignant struma ovarii. We also discuss the potential general role of combining rhTSH administration with pretreatment lesion dosimetric analysis in the treatment of thyroid cancer metastases that hypersecrete TH.
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Case Report |
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TopAbstractIntroductionCase ReportMethod of Determination of...References |
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A 46-yr-old woman presented with constipation and vague
abdominal pain. Computed tomography, performed with iodinated iv
radiographic contrast, showed a multicystic left lower abdominal mass,
as well as multiple hepatic masses. At laparotomy a 20 x 18
x 17-cm mass arising from the left ovary was removed; the tumor did
not invade surrounding tissues. The ovarian mass was a follicular
thyroid carcinoma associated with a small area of apparently normal
thyroid tissue. An intraoperative biopsy of one of the liver masses
showed metastatic well-differentiated follicular thyroid carcinoma.
Four weeks later, a total thyroidectomy was performed. Notably, an
iodine-containing preparation was used for skin cleansing prior to both
operative procedures. The resected thyroid gland had normal histology,
except for a 0.5-cm follicular adenoma; there was no evidence of
malignancy. After thyroidectomy, despite no supplemental TH therapy,
the patient remained clinically euthyroid; biochemically, there was
only a slight decrease in serum T4, which,
however, remained within the normal range, as well as an elevation in
serum TSH, which increased slightly above the upper limit of the normal
range (Table 1
). Despite the extensive
metastatic liver disease (occupying approximately 10% of the mass of
the organ), 131I was not administered due to the
concern that the suboptimal increase in serum TSH would preclude
effective therapy, as well as concerns about radiation-induced liver
toxicity. Six months later, the patient was referred to the National
Institutes of Health (NIH) for 131I
treatment.
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). Serum thyroglobulin (Tg)
was highly elevated, consistent with the large mass of metastatic
disease in the liver (Table 1). This was in the absence of serum
anti-Tg antibodies, which actually remained negative at all time points
during the patient’s evaluation. The patient’s thyroid function
indices were measured using the following methods:
T4, competitive electrochemiluminescent
immunoassay; and TSH, two-site "sandwich" electrochemiluminescent
immunoassay. The T4 and TSH assays were performed
on an Elecys 2010 immunoassay analyzer (Roche Diagnostics,
Indianapolis, IN). Serum Tg was measured using the OptiQuant
Thyroglobulin RIA kit (Kronus, San Clemente, CA; assay
performed at Mayo Medical Labs, Rochester, MN). The baseline uptake of
radioiodine (either 123I or
131I) by the metastases was not assessed at that
point. Urinary free iodine daily excretion was 45 µg/day (normal
range, 100–460 µg/day). |
Method of Determination of the "Minimal Effective" 131I Therapy Dose (Using rhTSH and Lesion Dosimetry) |
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TopAbstractIntroductionCase ReportMethod of Determination of...References |
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. Serum T3 reached
a maximum level of 310 ng/mL from a baseline of 157 ng/mL 48 h
after the second rhTSH dose (normal range, 75–170 ng/mL), whereas
T4 increased from a baseline of 5.2 µg/dL to
6.7 µg/dL 72 h after the second rhTSH dose (normal range,
4.5–11.0 µg/dL).
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). Regions of interest were drawn around
the perimeter of each lesion to determine the µCi of
131I that each contained. Background activity was
determined by drawing regions of interest in the hepatic parenchyma
outside the areas of the lesions. The turnover and half-life
(t1/2) of 131I in each
lesion was obtained by fitting a single exponential function to the
24–168 h data.
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The data analysis showed that the hepatic metastases accumulated 78%
of the administered 131I at 24 h posttracer
administration, accounting for almost all of the whole body retention
of the radionuclide. After 24 h, the biological half-life
(t1/2 biol) of 131I
activity in the whole body was longer than 55 days, so that there was
extremely avid retention of iodine by the hepatic lesions with minimal
secretion and/or release of 131I. The percent
131I uptake and volumes of the various lesions
are shown in Fig. 3. The percent
131I uptake in the lesions varied from 1.8 to
12.2%, with an average of 4.5% per lesion. In Fig. 3, lesions 3, 4,
and 7 were analyzed in combination and had a cumulative uptake of
23.6%. Lesion volumes ranged from 7–62 mL, with an average of 24 mL
per lesion. Again, in Fig. 3, lesions 3, 4, and 7 were considered in
combination and had a cumulative volume of 94.5 mL. The total volume of
metastatic lesions was 396.7 mL, which accounted for approximately
11.8% of the mass of the liver (3373 mL). There was a strong
correlation between percent 131I uptake and
lesion volume (r = +0.87, P < 0.001), which
implied that the various metastatic foci had similar avidity for
131I. Percent 131I uptake
corrected for the mass of each lesion, assuming average tissue density
of 1 g/mL, varied from 0.07%/g tissue to 0.34%/g tissue, with an
average of 0.13%/g tissue per lesion (P > 0.05 for
differerences among these values by Student’s t test). The
biological half-life (t1/2 biol) of
131I in the various lesions ranged from 9.8 days
to infinite time. The corresponding effective half-life (t1/2
eff) of 131I was subsequently
calculated using the formula 1/t1/2 eff =
(1/t1/2 biol) + (1/t1/2
phys), where t1/2 phys represents the
physical half-life of 131I (8.04 days). The
t1/2 eff ranged from 4.4–8.04 days, with an
average of 6.2 days. For 6 of the 17 lesions, the t1/2
biol was extremely long and, thus, the t1/2
eff was practically identical to t1/2
phys. These values of both t1/2 eff
and t1/2 biol were exceptionally high in
comparison with those observed in most thyroid carcinomas (41, 42),
reflecting a high retention and very lengthy time of residence of
131I within the metastases in our case. From
these data, the values of: 1) rad/µCi of 131I
administered, and 2i) µCi needed to deliver 8000 rad were calculated
for each lesion. As shown in Fig. 4, if
65 mCi were administered, 15 of the 17 lesions would receive a
radiation dose of at least 8000 rad. The predicted radiation doses to
the lesions ranged from 6,300–27,000 rad.
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Administration of 131I therapy and follow-up evaluation of therapeutic efficacy
Prior to the administration of the therapy dose of 131I, the patient was placed on metoprolol (150 mg/day) to avoid the development of clinically important thyrotoxic symptoms, in case posttreatment hyperthyroidism would develop due to release of preformed TH stored in the tumor. rhTSH was administered as before, and the 131I therapy dose (65 mCi) was administered 24 h after the second rhTSH dose. It is important to note that, as of yet, the United States Food and Drug Administration has not approved the use of rhTSH for the treatment of thyroid carcinoma. Hence, we obtained approval by the NIH Institutional Review Board for the administration of a therapeutic dose of 131I post-rhTSH. Our patient was included in a single-case protocol, and rhTSH was administered on a "compassionate exemption" basis. The pattern of serum TSH and Tg responses to rhTSH stimulation was similar to those observed after the first series of injections during dosimetry (data not shown). The posttherapy 131I uptake by the lesions was also calculated, and the value was similar to the one observed before therapy (72% uptake at 48 h). A posttherapy WBS identified no additional metastatic lesions. The patient received a blood radiation dose of 120.2 rad.
The patient’s course after the administration of therapy under
rhTSH stimulation was uneventful. Although she experienced mild
transient nausea, she did not develop radiation hepatitis (by either
symptoms and signs of hepatic damage or increase in serum transaminase
levels), thyrotoxicosis, or bone marrow suppression. She was maintained
on a suppressive dose of TH. Four months after
131I therapy, and under TH suppression therapy,
the patient’s serum Tg values were 2380 ng/mL, indicative of residual
metastatic disease. Six months after the first
131I therapy, the patient was reevaluated by MRI
of the liver, which showed significant reduction in the size of the
metastatic lesions (Figs. 5 and 6). The patient’s TH therapy was
withdrawn in preparation for a follow-up tracer dose (approximately 5
mCi) 131I diagnostic WBS, whole body dosimetry,
and repeat 131I high-dose therapy. At that point,
there was still evidence of a minimal degree of TH secretion by the
tumor, as 6 weeks after discontinuation of levothyroxine therapy the
patient’s serum T4 was still detectable at 1.6
µg/dL (normal range, 4.5–11.0 µg/dL). The corresponding serum TSH
was elevated, although not markedly so, at 31.3 µU/mL (normal range,
0.43–4.6 µU/mL). In fact, a more significant increase in serum TSH
would be expected in the complete absence of hormonal secretion by the
tumor. The serum Tg level was 26,025 ng/mL under the above conditions
and was now considerably decreased compared to that seen before the
first 131I treatment [70,700 ng/mL with a TSH
level of 41.0 µU/mL (under rhTSH stimulation)]. A tracer dose
131I diagnostic WBS confirmed the existence of
multiple hepatic metastases, without abnormalities in any other organs.
Following whole body and blood dosimetry, the patient received her
second 131I treatment with the maximally safe
dose of 297 mCi. A posttherapy WBS was positive only for hepatic
metastases. Our current treatment plan includes the repeat
administration of maximally safe 131I doses
following pretreatment whole body dosimetry under hypothyroid
conditions to eradicate the remaining hepatic metastatic disease.
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Malignant struma ovarii is a rare disease representing approximately 5%–10% of all strumae (3, 4, 5, 6, 7) and 5% of ovarian malignant germ cell tumors (45). Due to its rarity and relatively good overall prognosis, its treatment has been debated, with some cases being treated with surgery alone (3, 4, 5, 6, 7, 8, 9, 46). Only a small proportion of malignant strumae metastasize; hence, there are only 31 cases of metastatic struma documented in the literature (3, 4, 5, 6, 7, 8, 9, 14, 15, 16, 17). Metastatic disease from malignant struma ovarii has been managed with various modalities other than 131I, including ip chromic 32P phosphate (2) or radioactive colloidal gold (12), external beam radiotherapy (2, 3, 6), and extensive surgical debulking (47). However, since metastatic struma ovarii resembles metastatic thyroid carcinoma, a similar treatment protocol has been proposed for both. This includes surgical removal of the ovarian tumor and the thyroid gland, 131I ablative therapy, and suppressive TH therapy thereafter (13, 14, 15, 16, 17). Total thyroidectomy is advocated to enable effective 131I ablative treatment of the tumor and to facilitate follow-up with serial 131I diagnostic WBSs and serum Tg measurements. It also permits exclusion of a primary thyroid carcinoma.
In the case presented here, the metastatic deposits from the malignant struma ovarii were functional because they were able to produce TH. Hypersecretory thyroid cancer is uncommon, but may occasionally lead to overt thyrotoxicosis (20, 21, 22). When thyrotoxicosis is evident, distant metastases coexist in 83% of cases (20, 21). In our case, the highly functional metastases had pathological features of follicular carcinoma, in agreement with the reported pathology in most cases of thyroid carcinomas associated with production of high amounts of TH (21), but in direct contrast with most malignant strumae that present pathologically with features of papillary thyroid carcinoma (7). Hypersecretory thyroid cancer metastases are defined as the absence of hypothyroidism following thyroidectomy and/or the suppression of 131I uptake by the normal thyroid remnant in the presence of demonstrable uptake by the metastatic lesions (20). Using the above criteria, in a review of 40 cases with metastatic thyroid carcinoma and thyrotoxicosis, only 25 cases have been reported as harboring functional metastases (21). Notably, estimates of the iodine-concentrating efficiency of highly functioning thyroid cancer metastases (in percent uptake/g of tissue) have been reported at 10% of that of normal thyroid tissue. Therefore, thyrotoxicosis or euthyroidism after thyroidectomy usually result from large metastases, which could reach a cumulative weight of 2–3 kg (20), in direct similarity to our case where the total volume of metastatic disease was rather high (396.7 mL).
Interestingly, most functional thyroid cancer metastases produce predominantly T3. The potential underlying mechanisms responsible for this effect could be either preferential T3 production or accelerated peripheral conversion of T4 to T3 (21). Another possibility could also include a "defect" in the structure of intratumoral Tg with rapid removal of the molecule from the iodination site. Likewise, our patient presented with such a "T3 predominance," which was further accentuated after rhTSH stimulation.
Our case raises the challenging issue of how to optimally treat thyroid cancer metastases that are hormonally active. Although most thyroid cancer patients are currently treated with "standard" fixed amounts of 131I (19, 48, 49, 50, 51), it should be recognized that this approach has been used because it is simple and for most patients has proven to be effective and relatively safe. Patients with widespread or multiple metastases, however, present a more difficult challenge, and one approach is to administer the largest possible amount of 131I that will be safe for the patient based on estimates of blood, whole body, and lung radiation (43, 44). This "maximal safe dose" method, however, does not guarantee that the treatment will be effective. Nor does it guarantee that patients will receive an amount of 131I that is not excessive for effective treatment of their tumor. For adequately addressing these two questions, one needs to determine the radiation dose that will actually be received by the tumor, an estimate that requires lesion dosimetry (i.e. measurement of 131I uptake and retention), as well as the volume of the tumor (35, 36, 37, 41, 52). Maxon et al. (34, 37) have shown that absorbed radiation doses greater than 8000 rad to metastatic thyroid cancer lesions are likely to eradicate them. Although lesion dosimetry is currently not widely available, as few centers have expertise in its performance, 131I therapy based on lesion dosimetry has several benefits over therapy using "standard" arbitrary 131I amounts. These benefits include: 1) minimization of whole body radiation exposure (53); 2) increased probability that the lesion will be eradicated (37); and 3) help with decision-making whether to withhold theatment when the radiation dose to the lesion(s) is too low for effective therapy (i.e. <3500 rad) (34). With regard to the contribution of lesion dosimetry to therapeutic efficacy in our case, we believe that it added a significant benefit as serum Tg levels declined substantially after 131I therapy. We consider the clinical response in this case to be an "extensive partial response" by oncological criteria. In our case, the need for aggressive treatment with the administration of a maximally safe dose of 131I during the first 131I therapy is substantiated by the extent and multifocality of the metastatic disease, as well as the indeterminate prognosis at presentation [because of the rarity of the tumor features (i.e. metastatic hypersecretory thyroid cancer arising from a struma ovarii) with multiple hepatic metastases].
The additional value of whole body and blood dosimetry performed along with lesional dosimetry is to allow delivery of a dose of 131I that is within safety limits (43, 44). In our case, we wanted to minimize the probability of the following potential side effects of 131I therapy: 1) acute radiation-induced hepatitis (30, 31, 32, 33), and 2) release of pools of stored TH from the destruction of hormonally active bulky metastases, which could lead to thyroid storm. Another potential side effect of the treatment could be the unpredictable release of radioactive iodoproteins from the tumor with long half-life, which could lead to radiation toxicity to the bone marrow (41, 54). This is an idiosyncratic event, for which whole body and blood dosimetry could not be of predictive value. With regard to the possibility of radiation hepatitis, most data has been gathered by studies investigating the tolerance of the liver to external beam irradiation. The safety limit for radiation delivered to the whole organ is approx. 3700 rad (30, 31, 32, 33, 55), although other studies have shown that hepatic exposures of up to 10,000 rad could be tolerated if the dose is delivered internally rather than by external beam (56, 57). Although we did not calculate the whole organ exposure of our patient’s liver following administration of 65 mCi, it was estimated that this would be far below 10,000 rad. In fact, this assumption was proven true post hoc, as no evidence of radiation hepatitis was seen after treatment (no signs and symptoms of liver damage and absence of increase in serum transaminase levels).
In our case, no "baseline" value for uptake of 131I by the hepatic metastases was documented. In fact, because these lesions were highly functional and presented with a markedly prolonged t1/2 biol for 131I, it remains indeterminate whether the administration of rhTSH led to a significantly increased iodine uptake over baseline. An 131I treatment protocol involving whole body and lesional dosimetry, but without the use of rhTSH, may have also been effective in inducing a measurable therapeutic effect. Although rhTSH has been shown to be effective in increasing 131I uptake in diagnostic WBSs of thyroid carcinoma patients (58, 59), and, in certain instances, has also been used for treatment with 131I (24, 25, 26), it is impossible to validate our assumption that rhTSH increased 131I uptake in our case. Intuitively, however, we believe that our approach involving rhTSH administration resulted in an increased therapeutic effect.
In summary, our patient presented with bulky, hormonally active liver metastases with a high 131I uptake/g of tissue and a markedly prolonged 131I t1/2 biol (and consequently very long t1/2 eff). Hence, treating our patient with a "standard" 131I dose could have been either unsafe or suboptimal. Whole body and lesion dosimetry assured the delivery of an effective and safe dose. In addition, the inability of our patient to raise her endogenous TSH levels was overcome by using rhTSH, aiming to stimulate 131I uptake.
To our knowledge, this is the first case in which rhTSH administration was used in conjunction with lesion dosimetry to ensure efficacious treatment of hormonally active (highly functional) thyroid carcinoma metastases. The same therapeutic approach could be potentially be of general use for the treatment of patients with hypersecretory metastatic thyroid cancer.
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Acknowledgments |
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Footnotes |
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Received June 18, 1999.
Revised September 9, 1999.
Accepted September 16, 1999.
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References |
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TopAbstractIntroductionCase ReportMethod of Determination of...References |
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gberg T. 1997 "Malignant struma ovarii" with peritoneal dissemination. Histopathology. 31:289–290.[CrossRef][Medline]
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