Treatment of Scan-Negative, Thyroglobulin-Positive Metastatic Thyroid Cancer Using Radioiodine 131I and Recombinant Human Thyroid Stimulating Hormone
Amiel Z. Rudavsky and
Leonard M. Freeman
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
|
---|
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 260).

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.
|
|
Over the ensuing 2 1/2 yr, the patient developed multiple new and
expanding metastatic skeletal lesions that were treated with external
beam radiotherapy. Interval growth of the pulmonary nodules was noted.
An episode of hemoptysis in July 1994 was attributed to erosion of a
metastatic nodule through a bronchus. The thyroglobulin rose to 498
ng/mL by July 1993 and continued to increase thereafter. By May 1995
the patient was suffering from severe, diffuse bone pain, marked weight
loss, anorexia, anemia, leukopenia, debilitation, and extreme weakness
and spent much of his time in bed. A chest radiograph obtained on June
23, 1995 revealed interval enlargement of the metastatic pulmonary
nodules (Fig. 2
). On August 23, 1995 his white blood
cell count (WBC) was 3.2 x 103 per cc (normal
4.010.5 x 103 per cc), his red blood cell count
(RBC) was 2.87 x 106 per cc (normal 3.95.9 x
106 per cc), and his hematocrit (Hct) was 25.5% (normal
3650%).

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.
|
|
Because of the patients desperate condition, we requested permission
to use recombinant human TSH (rhTSH) to stimulate uptake in the
patients metastases in preparation for the administration of a large
therapeutic dose of 131I. With the cooperation of the
manufacturer (Genzyme Corporation, Cambridge, MA) and the Food and Drug
Administration, we obtained approval for the compassionate therapeutic
use of rhTSH under emergency use regulations. rhTSH is an
investigational drug currently being evaluated in clinical studies for
providing TSH stimulation for diagnostic 131I whole body
scanning of thyroid cancer.
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
patients 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
patients 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
|
---|
The evaluation and treatment of metastatic thyroid cancer in an
athyrotic patient is predicated on the ability of the lesions to
incorporate 131I. Both the scan and radioiodine therapy
must be performed after the patient has stopped thyroactive medications
for a sufficient time to raise endogenous TSH well into the hypothyroid
range (1). Larger doses of radioiodine reportedly increase the
possibility of detecting functional lesions on scan (2). A scanning
dose between 2 mCi and 5 mCi of 131I achieves a reasonable
compromise between sensitivity and the liability of "stunning"
thyroid metastases, thus impairing their ability to concentrate a
subsequent therapeutic dose of radioiodine (3).
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 patients 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 patients 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 patients total body radiation burden was
considerably below the estimated LD50 level of 400600
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
|
---|
-
Snyder III WH. 1996 Thyroid cancer. In: Rakel
RE, ed. Conns current therapy- 1996. Philadelphia: W.B. Saunders;
624627.
-
Waxman A, Ramanna L, Chapman N, et al. 1981 The
significance of I-131 scan dose in patients with thyroid cancer:
determination of ablation: concise communication. J Nucl Med. 22:861865.[Abstract]
-
Park HM. 1992 Stunned thyroid after high dose
I-131 imaging. Clin Nucl Med. 17:501502.[Medline]
-
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. 71:806814.[Medline]
-
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. 80:14881492.[Abstract]
-
Pacini F, Lippi F, Formica N, et al. 1987 Therapeutic doses of iodine-131 reveal undiagnosed metastases in
thyroid cancer patients with undetectable serum thyroglobulin. J
Nucl Med. 28:18881891.[Abstract]
-
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. 78:188196.[Abstract]