Recombinant human thyroid stimulating hormone in 2008: focus on thyroid cancer management
OncoTargets and Therapy
Recombinant human thyroid stimulating hormone in 2008: focus on thyroid cancer management
Ann Gramza 1
Kathr yn G Schuff 0
0 Division of Endocrinology, Oregon Health and Science University , Portland, OR USA
1 Division of Medical Oncology, Oregon Health and Science University , Portland, OR USA
Radioiodine (RAI) ablation following thyroidectomy is standard of care treatment for patients with intermediate or high risk differentiated thyroid cancer. Traditionally, this has been achieved by forgoing thyroid hormone replacement postoperatively, allowing endogenous thyroid stimulating hormone (TSH) levels to rise. This rise in TSH provides the stimulus for RAI uptake by the thyroid remnant, but is associated with clinical hypothyroidism and its associated morbidities. Recombinant human TSH (rhTSH, thyrotropin alfa [Thyrogen®], Genzyme Corporation, Cambridge, MA, USA) was developed to provide TSH stimulation without withdrawal of thyroid hormone and clinical hypothyroidism. Phase III studies reported equivalent detection of recurrent or residual disease when rhTSH was used compared with thyroid hormone withdrawal (THW). These trials led to its approval as an adjunctive diagnostic tool for serum thyroglobulin (Tg) testing with or without RAI imaging in the surveillance of patients with differentiated thyroid cancer. Recently, rhTSH was given an indication for adjunctive preparation for thyroid remnant ablation after phase III studies demonstrated comparable outcomes for rhTSH preparation when compared with THW. Importantly, rhTSH stimulation has been found to be safe, well tolerated, and to result in improved quality of life. Here, we review the efficacy and tolerability studies leading to the approval for the use of rhTSH in well-differentiated thyroid cancer management.
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2) Diagnostic scanning to detect residual/recurrent disease
and 3) Treatment of residual/recurrent disease. Radioiodine
administration following thyroidectomy (“remnant ablation”)
is performed to reduce the risk of thyroid cancer recurrence
and improve the accuracy of surveillance strategies. The
two goals of treatment are to destroy micrometastatic or
residual disease, and ablate remaining normal thyroid tissue
to facilitate RAI scanning and use of Tg as a tumor marker.
No prospective studies have been done to address the
question of which patients benefit from this treatment strategy.
However, based on large retrospective series, the published
consensus guidelines from both the European Thyroid
Association (ETA) and American Thyroid Association
(ATA) recommend RAI ablation for patients with higher
stage disease and recommend considering ablation in lower
risk patients with tumors larger than 1 or 1.5 cm
(Cooper
et al 2006; Pacini et al 2006b)
.
The use of RAI for all three purposes relies on the
ability of both normal and malignant thyroid tissue to transport
iodine for synthesis of thyroglobulin, triiodothyronine and
thyroxine in response to TSH. An overview of the
procedures for thyroid remnant ablation and diagnostic scanning
are shown in Figure 1 and 2, respectively. TSH stimulation
historically has been achieved by discontinuation of thyroid
hormone replacement for 5 to 6 weeks, (thyroid hormone
withdrawal, THW), allowing endogenous TSH levels to rise
(Figure 1a and 1b). The optimal TSH level for ablation is felt
to be 30 mU/L, based on a study that demonstrated that
low TSH levels were more likely to be associated with low
iodine uptake, which was more robust on reevaluation with
a higher TSH
(Edmonds et al 1977)
. In addition to high TSH
levels, iodine depletion, such as with a low iodine diet for 1
to 2 weeks, is important for optimal RAI uptake. If desired
to assist in treatment decisions, diagnostic RAI whole body
scans (WBS) are performed with a tracer dose of 74 to 185
MBq (2–5 mCi) 131I and the diagnostic scan obtained 48 to
72 hours later as shown in Figure 1b. Radioiodine at a dose
of 1.1 to 3.7 GBq (30–100 mCi) is administered for remnant
ablation, with higher doses if residual disease is known or
suspected or the tumor has unfavorable histology or if
treatment of metastatic disease is planned. The patient is placed
back on levothyroxine suppressive therapy, as appropriate,
and approximately 1 week after the treatment dose of RAI, a
post-therapy WBS is performed to better assess for residual
or metastatic disease. Substitution of rhTSH stimulation for
TSH stimulation by THW for diagnostic evaluations (shown
in Figure 2b and reviewed by Cooper et al (2006) or for
thyroid remnant ablation (shown in Figures 1c and 1d), has
been published by a number of centers, allowing patients to
remain on levothyroxine therapy and avoid the symptoms
of hypothyroidism
(Robbins et al 2001; Pacini et al 2002;
Robbins et al 2002b; Barbaro et al 2003; Barbaro et al 2006;
Pacini et al 2006a; Pilli et al 2007; Rosario et al 2008; Taieb
et al 2008; Tuttle et al 2008)
. Over the last 3 years,
thyrotropin alfa (Thyrog (...truncated)