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Treatment of Scan-Negative, Thyroglobulin-Positive Metastatic Thyroid Cancer Using Radioiodine ¹³¹I and Recombinant Human Thyroid Stimulating Hormone

Departments of Nuclear Medicine (A.Z.R., L.M.F.), Medicine (A.Z.R.) and Radiology (L.M.F.), Montefiore Medical Center and The Albert Einstein College of Medicine of Yeshiva University, Bronx, New York 10467

Address all correspondence and requests for reprints to: Amiel Z. Rudavsky, M.D., Department of Nuclear Medicine, Montefiore Medical Center, 111 East 210 Street, Bronx, New York 10467.

	Introduction

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A 54-year-old apparently healthy male dentist experienced the onset of polyuria and polydipsia in November 1988. An endocrinologist diagnosed diabetes mellitus, subsequently controlled with diet and oral hypoglycemic agents. Thyroid nodules were discovered at this examination; sonograms and radioiodine scans demonstrated a multinodular goiter with several nonfunctioning nodules. Fine needle aspiration biopsy of a right lower pole dominant "cold" nodule revealed cellular atypia. A total thyroidectomy was performed in March, 1989; the pathological diagnosis was "follicular variant of papillary carcinoma of the thyroid, multifocal". Preoperative chest radiographs and computed tomography disclosed diffuse nodularity in both lung fields. A 5 mCi ¹³¹I total body scan (TBS) obtained in April 1989, before starting levothyroxine replacement therapy, revealed uptake in the thyroid bed and multiple foci of activity in both lung fields. The patient received an oral therapeutic dose of approximately 170 mCi of ¹³¹I on April 18, 1989, and treatment with TSH suppressive doses of levothyroxine was subsequently instituted. In November 1989, following appropriate suspension of suppressive therapy, diagnostic studies using 5 mCi of ¹³¹I revealed that the 48h uptake in the thyroid bed was less than 0.1% and that there was no detectable extrathyroidal activity, despite the continued demonstration of diffuse metastatic nodules on chest radiographs. Subsequent 5 mCi ¹³¹I TBS, performed in April 1990, December 1990, and September 1991 again failed to show uptake in any lung metastases. In December 1992, after discontinuing levothyroxine for several weeks in preparation for a TBS, the patient noted a palpable, movable mass in the inferior cervical region extending below the level of the suprasternal notch, which proved to be well-differentiated "pure papillary carcinoma". The TBS was negative (Fig. 1). A magnetic resonance study (MRI) revealed metastatic disease in the fifth cervical and several thoracic vertebrae. A ^99mTc methylene diphosphonate bone scan demonstrated multiple foci of minimally increased activity in the cervical spine, thoracic spine, left sacroiliac region, and left femur. Biopsy of the latter lesion showed follicular architecture with some papillary elements. The thyroglobulin was elevated to 82 ng/mL (normal 2–60).

View larger version (120K): [in this window] [in a new window]   Figure 1. 131I Total body scan performed on December 6, 1992 showing absence of uptake in known sites of metastatic disease (lungs, chest wall, cervical and thoracic vertebrae, sacrum, left femur). Endogenous TSH at the time of this scan was 24.6 mu/mL.

View larger version (131K): [in this window] [in a new window]   Figure 2. Chest radiograph taken on June 23, 1995 showing large and small metastatic nodules diffusely scattered throughout both lung fields.

After obtaining Institutional Review Board authorization and detailed informed consent, we administered to the patient 0.9 mg rhTSH im on September 5 and 6, 1995. Immediately before receiving rhTSH, the patient’s TSH was less than 0.050 mu/mL. It rose to more than 50 mu/mL and 46.1 mu/mL, respectively, on the days following the rhTSH injections despite continuation of TSH suppressive doses of levothyroxine. His thyroglobulin on September 5, 1995, before rhTSH administration, was 7,800 ng/mL. The patient was hospitalized, and an oral dose of 515 mCi ¹³¹I was administered on September 7, 1995. He vomited about 5% of the dose several hours later. The patient’s hospital course was complicated by pneumonia, characterized by a 92% granulocytosis with a WBC of 4.2 x 10³ per cc, and demonstrated on chest radiographs. The pneumonia cleared with appropriate antibiotic treatment. By hospital discharge on September 22, 1995 the patient had experienced considerable amelioration of bone pain. A TBS obtained on September 14, 1995 revealed uptake of the therapeutic dose in both lungs and in essentially all skeletal lesions (Fig. 3). Post-treatment radiation measurements indicated that the patient had sustained a total body radiation dose of about 240 rads. Over the next few months the patient experienced further improvement with weight gain, resolution of bone pain, resumption of independent ambulation (without a cane or walker), and return of energy. By January 1996 his thyroglobulin had decreased to 1924 ng/mL. His anemia responded to a course of human recombinant erythropoietin therapy, and his leukopenia resolved. In January 1996 his WBC was 3.9 x 10³ per cc, his RBC was 3.9 x 10⁶ per cc, and his Hct was 34.2%, and he resumed his full-time dental practice. In February 1996 repeat radiographs and bone scans demonstrated healing or stabilization of the skeletal lesions (Fig. 4); the pulmonary nodules also remained stable. In March 1996, deviation of the tongue to the right was noted. A soft tissue mass at the base of the skull was demonstrated on MRI and treated with external beam radiotherapy. The patient continues to pursue his thriving dental practice and demanding social schedule.

View larger version (106K): [in this window] [in a new window]   Figure 3. 131I Total body scan performed on September 14, 1995, seven days following oral 131I therapy preceded by the parenteral administration of rhTSH. Note uptake in both lungs and in bony metastases (thoracic and lumbar spine, both femurs, sacrum, both ilia, left lower rib cage).

View larger version (88K): [in this window] [in a new window]   Figure 4. Left: Radiograph taken on June 23, 1995 showing destruction of right ischium by metastatic disease. Right: Radiograph taken on April 19, 1996 (about 7 months after 131I treatment) showing bone regeneration in the right ischium.

	Discussion

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Thyroglobulin determinations have also been shown to be useful in evaluating such patients (4). Recent reports described patients with markedly elevated thyroglobulins whose diagnostic scans failed to demonstrate activity in metastases but who were treated empirically with ¹³¹I (5, 6). Several patients experienced a marked drop in their thyroglobulin and significant clinical improvement, including partial or complete resolution of metastases. Scans following the therapeutic dose of radioiodine demonstrated significant uptake in the metastatic lesions.

Unfortunately, certain patients with metastatic thyroid cancer cannot stop taking their TSH suppressive medication without risking severe adverse clinical consequences. Recent clinical trials have suggested that administration of rhTSH in preparation for a diagnostic ¹³¹I TBS may obviate the need to withdraw patients from thyroid replacement medication for this procedure (7).

This report describes the successful use of rhTSH in preparation for treatment of metastatic thyroid carcinoma with a large dose of ¹³¹I. Because of the previous rapid appearance of a metastatic lesion when levothyroxine was discontinued, we were reluctant to withdraw thyroactive medication. We felt that the administration of rhTSH was the only remaining opportunity to effectively treat this desperately ill patient. The patient tolerated the administration of rhTSH without incident. Following parenteral rhTSH the patient’s TSH rose to levels comparable to those attained after discontinuation of thyroid replacement in athyrotic patients. We administered a large dose of ¹³¹I because such doses have been reported to successfully treat metastatic thyroid cancer in patients without demonstrable uptake on conventional TBS but who had marked elevation of their thyroglobulin. Though no uptake of ¹³¹I had been demonstrated on this patient’s 5 mCi diagnostic scans, activity in multiple metastatic lesions was demonstrated on a scan obtained following administration of a large therapeutic dose of ¹³¹I. Calculations were not used for dose determination for two reasons. Pre-treatment dosimetry requires prior administration of a diagnostic dose; we did not seek or receive authorization for diagnostic use of rhTSH as part of the compassionate therapeutic use protocol. Moreover, we were less concerned about possible adverse long-term effects than with slowing the apparently inexorable progression of disease. Post-dose radiation measurements suggested that the patient’s total body radiation burden was considerably below the estimated LD₅₀ level of 400–600 rads. The patient experienced a meaningful clinical remission, and his thyroglobulin decreased significantly.

We have presented the first report of the successful use of rhTSH in the treatment of metastatic thyroid cancer. Controlled clinical studies are warranted to evaluate the safety and efficacy of rhTSH in the ¹³¹I therapy of metastatic thyroid cancer.

	Acknowledgments

 
We gratefully acknowledge the assistance of Ms. Deirdre Maxted and Witske Kingma, M.D., of the Genzyme Corporation and of Ira Greifer, M.D., of The Albert Einstein College of Medicine in obtaining the rhTSH used in this patient. We thank Sherman L. Heller, Ph.D., for performing the radiation measurements and calculations, and Drs. B. Fish and R. Silverglied for the Fig. 4 radiographs.

Received July 11, 1996.

Revised August 12, 1996.

Accepted September 13, 1996.

	References

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3. Park HM. 1992 Stunned thyroid after high dose I-131 imaging. Clin Nucl Med. 17:501–502.[Medline]
4. Ashcraft NW, Van Herle AJ. 1981 The comparative value of serum thyroglobulin measurements and iodine-131 total body scans in the follow-up of patients with treated differentiated thyroid cancer. Am J Med. 71:806–814.[CrossRef][Medline]
5. Pineda JD, Lee T, Ain K, Reynolds JC, Robbins J. 1985 Iodine-131 therapy for thyroid cancer patients with elevated thyroglobulin and negative diagnostic scan. J Clin Endocrinol Metab. 80:1488–1492.[Abstract/Free Full Text]
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7. Meier CA, Braverman LE, Ebner SA, et al. 1994 Diagnostic use of recombinant human thyrotropin in patients with thyroid carcinoma (Phase I/II study). J Clin Endocrinol Metab. 78:188–196.[Abstract]

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