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Original Studies |
Department of Nuclear Medicine, University of Wuerzburg (M.L., M.L., H.H., U.M., C.R.), D-97080 Wuerzburg, Germany; and Genzyme Europe, 1411 DD Naarden, The Netherlands
Address all correspondence and requests for reprints to: Dr. M. Luster, Department of Nuclear Medicine, University of Wuerzburg, Josef-Schneider-Str. 2, D-97080 Wuerzburg, Germany. E-mail: luster{at}nuklearmedizin.uni-wuerzburg.de
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Abstract |
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 Top Abstract IntroductionSubjects and MethodsResultsDiscussionReferences |
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Introduction |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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As with use of radioiodine for diagnostic procedures, therapeutic applications of 131I in patients with DTC have required withdrawal of thyroid hormones for several weeks to raise endogenous TSH to levels associated with increased iodine uptake by thyroid tissue (>30 mU/L) (2, 3, 4). The resultant hypothyroidism, however, is often poorly tolerated and in some cases may even be fatal in patients in very poor physical condition (5, 6, 7, 8, 9). In addition, patients may be unable to generate endogenous TSH levels sufficient for stimulating 131I uptake. In some cases this may be due to pituitary insufficiency (secondary hypothyroidism) resulting from metastases to the brain (10, 11).
The use of recombinant human TSH (rhTSH) to increase serum levels of TSH as an alternative to discontinuation of thyroid hormones has proven to be an effective tool in the diagnostic follow-up of patients with DTC. Recent studies have demonstrated that rhTSH stimulates serum thyroglobulin (Tg) release from thyroid tissue and induces 131I uptake for scintigraphy (5, 6, 12, 13). More than 400 patients have been pretreated with rhTSH before administration of radioiodine for diagnostic scanning with no related serious adverse events reported to date. Results from the most recent phase III trial of rhTSH for follow-up scintigraphy in patients with DTC showed that whole body scans (WBS) performed after rhTSH demonstrated high concordance with scans performed after withdrawal of THST in detecting recurrent or residual disease (6). In addition, use of rhTSH, which allows continuation of thyroid hormones, was associated with significantly fewer side-effects and higher quality of life compared with THST withdrawal. This was largely due to prevention of hypothyroid symptoms, which are frequently very debilitating (6).
These studies, confirming the safety and efficacy of rhTSH in conjunction with 131I for diagnostic purposes, have led to increased interest in the use of rhTSH in preparation for ablative RIT in patients with recurrent DTC. Studies to date, however, have included a minority of patients with stage IV disease. Thus, it is important to establish a safety and efficacy profile of rhTSH/RIT in patients with advanced DTC. We describe the first 11 consecutive patients (16 treatments) referred to our center for use of rhTSH in conjunction with radioablative therapy. Patients described in this case series suffering from advanced recurrent DTC would otherwise not have been able to receive 131I therapy due to either an inability to tolerate discontinuation of thyroid hormones or ineffectiveness of THST withdrawal in raising endogenous TSH. The results of these compassionate use applications suggest that rhTSH may offer a promising alternative to THST withdrawal for therapeutic applications of 131I.
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Subjects and Methods |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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A total of 16 treatments with radioablative doses of
131I after exogenous TSH stimulation with rhTSH
(Thyrogen, Genzyme Transgenics Corp., Cambridge, MA) were
performed in 11 consecutive patients (6 women and 5 men) with advanced
recurrent and/or residual DTC. Patients were treated between March 1997
and October 1998 at the University of Wuerzburg (Wuerzburg, Germany),
with follow-up continuing for up to 10 months. The 11 patients
represented the total number of patients referred to the center for use
of rhTSH under euthyroid conditions during this period. The median age
was 57 yr (range, 15–85 yr). All patients had histologically proven
DTC (5 papillary, including 1 follicular variant, and 6 follicular),
with primary diagnosis established between 1985 and 1998. At the time
of referral, 10 of 11 patients were stage IV by tumor node
metastasis classification, including 1 patient (no. 5) who
developed pulmonary metastases after initial staging (Table 1
). Metastatic disease was distant in all
patients except 1 (no. 10), whose disease was limited to local lymph
node involvement.
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). The time
since last radioactive iodine treatment ranged from 4–58 months, with
a median of 15 months. Three patients had undergone external beam
therapy within 9 months before referral (no. 1, 2, and 7).
Referrals for use of rhTSH fell into two broad categories: 1) patients
unable to achieve sufficient serum TSH levels (defined as >30 mU/L)
(4) after THST withdrawal (four patients), a group that included two
patients with secondary hypothyroidism and one patient with a large
thyroid remnant after partial resection; and 2) patients in whom THST
withdrawal may cause life-threatening conditions due to poor physical
condition resulting from metastatic disease, advanced age (six
patients), or severe hypothyroid symptoms demonstrated during previous
thyroid hormone withdrawal (one patient; Table 1). Before treatment,
approval of compassionate use by the local ethics committee was
obtained, and all patients gave written informed consent.
Methods
Before treatment, baseline serum Tg, TSH, free T4 (fT4), and free T3 (fT3) levels were obtained for all patients to confirm TSH suppression and to rule out overdosage of levothyroxine. All patients received levothyroxine (1.5–2.5 µg/kg BW) to achieve TSH levels less than 0.1 mU/L. Interference of Tg autoantibodies was ruled out by Tg recovery rates within normal limits for all patients. Serum TSH, fT3, fT4, and Tg were measured using commercially available kits (DYNO-test TSH 1, Brahms, Berlin, Germany; Amerlex-MAB fT3 Kit, fT4 Kit, Demeditec, Kiel, Germany; DYNO-test Tg-S, Brahms).
Under the treatment protocol, all patients received an im dose of 0.9
mg rhTSH on 2 consecutive days followed by oral application (capsule)
of 131I on day 3 (Fig. 1) (11). This rhTSH dosing regimen has
been shown to be safe and effective in stimulating
131I uptake in DTC patients receiving radioactive
iodine (RAI) for diagnostic procedures (6). 131I
activities ranged from 27–200 mCi (1–7.4 GBq), adjusted on an
individual basis based on age, indication, and presence of metastases.
Doses of 131I administered at the referral center
are typically 27–81 mCi (1–3 GBq) for remnant ablation and 135–189
mCi (5–7 GBq) for distant metastases based on German Society of
Nuclear Medicine guidelines (4). Patients with documented or clinically
suspected brain or spinal cord metastases (no. 1, 2, 4, and 7) received
steroid treatment (8 mg dexamethasone, orally, twice daily or 80 mg
prednisone, orally, daily) to prevent peritumoral edema resulting in
manifestation or aggravation of neurological compression symptoms.
Steroid doses were based on those routinely used in patients with brain
or spinal cord metastases receiving external beam therapy (14). All
patients were continued on thyroid hormones at TSH-suppressive levels
throughout the treatment and follow-up periods.
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Posttherapy follow-up occurring 2–10 months (mean, 4.3 months) after treatment with rhTSH and RIT included regular measurement of serum Tg and an additional WBS performed in conjunction with rhTSH in six cases. Scintigrams were interpreted by two experienced investigators. Criteria for progressive, stable, and decreased tumor burden were based on number and relative RAI uptake of the lesions. Additional standard diagnostic procedures (e.g. ultrasound of the neck region and chest x-ray) were performed in all patients. More specific radiographic assessments (computed tomography scan and magnetic resonance imaging) were conducted in selected cases. Follow-up Tg and WBS assessments were not performed in three patients who died within 2 months after RIT. Patients were hospitalized in a special unit (according to German Radiation Protection Laws) and monitored for adverse events, including symptoms of hypothyroidism, by experienced medical personnel throughout the treatment and follow-up period.
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Results |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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and Fig. 2). Decreases in Tg of this magnitude
were considered to represent partial remission in this analysis. In
Fig. 2, the course of the Tg levels for all 11 patients is plotted on a
logarithmic scale. As shown, the median Tg level dropped (665 ng/mL
pretreatment vs. 177 ng/mL posttreatment) despite the fact
that in 1 case a marked increase in Tg level was observed. Only 3
patients had more than 1 treatment course.
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show decreased
tumor burden in one of five patients who were in partial remission as
determined by Tg levels. In an additional three patients, comparison of
follow-up WBS with pretreatment scans or clinical investigation
indicated decreased tumor burden (patient 3) or disease stabilization
(patients 6 and 11) despite increased or unchanged Tg levels. Three
patients (no. 2, 4, and 7) died within 2 months after radioiodine
therapy due to progressive tumor growth, including two patients who had
received external beam therapy within 9 months of referral.
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Analysis of serum TSH levels showed sharp increases in all patients
after rhTSH injections (on days 1 and 2) to more than 80 mU/L on day 3
(data not shown). The maximum Tg level also was increased from the
baseline, indicating Tg release from the thyroid cancer tissue, in the
majority of cases (Table 2). fT4 levels were
slightly elevated in most of the patients, consistent with compliance
with levothyroxine intake; fT3 levels remained
within normal limits (data not shown).
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Discussion |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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All four patients referred for compassionate use of rhTSH due to insufficient endogenous TSH stimulation were shown to have increased TSH levels after rhTSH injections, and two of four had an increased maximum Tg level consistent with Tg release after TSH stimulation.
Of significance, particularly for patients referred for their inability to tolerate discontinuation of thyroid hormones, no adverse events associated with the treatment were reported. This included a patient who had required hospitalization due to severe gastritis after thyroid hormone withdrawal during previous radioiodine treatments. As expected, none of the eight patients in this series surviving to the 2-month follow-up developed any major adverse events; only minor side-effects such as headache (two patients) were seen. Although three patients died 6–8 weeks after 131I therapy, mortality was closely related to an a priori dramatic course of the disease (15). The possibility that tumor growth was accelerated by rhTSH in these patients cannot be ruled out; however, to date there have been no reports of rhTSH-stimulated progression of cancer in patients with DTC. Furthermore, the use of rhTSH theoretically results in a shorter period of TSH elevation compared with the more prolonged period of increased endogenous TSH following thyroid hormone withdrawal, minimizing the potential for TSH-stimulated growth.
Several issues regarding use of steroids to prevent peritumoral edema in patients with central nervous system (CNS) metastases treated with rhTSH/RIT in this case series deserve comment. To our knowledge, there is no well designed randomized clinical trial showing the effect of steroids in patients with DTC. The use and dosage of steroids in the present series were based on routine use of glucocorticoids in patients with brain or spinal cord lesions treated by external beam therapy (13). Overall experience with rhTSH in DTC patients has shown that 4 of 55 patients with CNS metastases have had peritumoral edema after rhTSH injection (Dr. A. Dreijer, personal communication, Genzyme Corp., Cambridge, MA). Steroid coverage in this situation has been suggested by others (16, 17). In the present series, none of the four patients with CNS metastases receiving steroids had evidence of peritumoral edema after rhTSH treatment, although three of these patients died within 2 months of receiving treatment due to rapidly progressive disease.
Possible interactions between steroids and iodide transport across membranes, including renal tubular transport, have been suggested by in vitro studies on animal cells showing dexamethasone-induced down-regulation of the sodium iodide symporter resulting in suppressed iodide accumulation (18). However, it remains unclear whether these results are applicable to in vivo use of radioiodine in humans or whether the effectiveness of 131I therapy would be altered.
It should be noted that several of the patients had received other therapies within a few months of entry in the trial. However, two of the three patients (no. 2 and 7) who had received external beam therapy within 9 months before rhTSH died within 2 months of entry; the third patient who had received external beam therapy to spinal metastases demonstrated improvement in brain lesions (no. 1). In addition, although some patients had received recent RIT, these treatments were unlikely to result in significant detectable therapeutic effects after a latency period of 4 months or more, taking into account the aggressiveness of most of the tumors treated. Thus, improvements observed in this case series were considered to have most likely resulted from the current treatment.
Our standard procedure is to perform follow-up diagnostic WBS 4–6 months after RIT. However, given the desperate situation of a few of our patients, follow-up scans were performed as soon as 2 months after rhTSH/RIT to allow more frequent treatments in the hope of achieving better therapeutic results. This approach cannot be considered beneficial for every patient on the basis of the data presented.
Although the results of our investigation are encouraging, they must be considered preliminary because of the relatively small number of patients. However, the positive results are consistent with the few reports to date by other groups noting successful use of rhTSH in patients with advanced metastatic DTC in conjunction with radioablative therapy (11, 19). The experiences with these patients raise several critical issues related to the use of rhTSH as an alternative to THST withdrawal in therapeutic settings.
Discontinuation of levothyroxine imposes a risk of life-threatening side-effects in patients with DTC. Because patients for whom ablative 131I therapy is indicated often suffer from an aggressive course of the disease, physicians are particularly reluctant to discontinue TSH-suppressive medication in these patients, as hypothyroidism is known to potentiate the tumor-related morbidity (5, 6, 7, 8, 9). The data presented here suggest that rhTSH enables us to offer high dose radioiodine therapy, a well tolerated and often effective therapy, to these patients. By avoiding the patient discomfort and risk of potentially fatal side-effects associated with hypothyroidism, the use of rhTSH has the potential to extend the application of radioablative therapy to patients with severe DTC who in the past would have been considered too critically ill to undergo thyroid hormone withdrawal to receive this therapy. This will necessitate critical evaluation of the overall life expectancy of each patient and will probably be a subject of future medical debate.
Even with the possible expanded use of RIT with rhTSH, such therapy will continue to be contraindicated in patients in whom radioiodine uptake cannot be demonstrated. This situation often results from the dedifferentiation of the tumor cells. rhTSH does not by itself induce 131I uptake in dedifferentiated tumor cells and does not influence biological redifferentiation. A new approach for this clinical setting involves use of retinoic acid to promote differentiation. Although preliminary results of retinoid monotherapy are somewhat conflicting, the combination of vitamin A derivatives and rhTSH appears promising (20, 21).
Another critical issue related to use of rhTSH with radioiodine ablative therapy requiring further investigation is dosing of 131I under euthyroid conditions. Dosimetry was not performed on the patients in this series. Preliminary results from a multicentric study (6) show that the whole body retention of radioiodine 48 h after rhTSH and 131I (administered during continuation of thyroid hormones) is significantly lower compared to retention after withdrawal of thyroid hormones (22). This can be explained by the higher renal excretion of iodine in euthyroid patients (rhTSH) compared with those who are hypothyroid. The resultant increased retention of radioiodine under hypothyroid conditions is obvious when comparing scans performed during THST withdrawal, which have significantly increased background activity compared with scans performed during continuation of thyroid hormones with rhTSH. Consistent with this, preliminary results from the above cited study (6) show that the 48-h uptake in the neck in the hypothyroid state may be higher than that in the euthyroid state. A dosimetric study is now ongoing to determine the correct dosing of 131I when rhTSH is used. The results of this study are expected to contribute to the further refinement of protocols for the use of rhTSH with 131I for the therapeutic benefit for patients with DTC.
Received September 13, 1999.
Revised July 1, 2000.
Accepted July 6, 2000.
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