DƯỢC LÍ Goodman & Gilman's The Pharmacological Basis of Therapeutics 12th, 2010

Chemotherapy in Thyroid Cancer
Advanced and metastatic poorly differentiated papillary and follicular
thyroid cancer often does not concentrate iodine sufficient for
therapy with 131 I (Kloos, 2008). There have been significant
advances in targeted chemotherapy for thyroid cancer (Sherman,
2009). Recent advances in the molecular genetics of thyroid cancer
have resulted in the identification of oncogenic mutations in the
BRAF and RAS genes, known to activate the MAPK signaling pathway.
Medullary thyroid carcinoma is associated with mutations in
the RET gene, which also enhance MAPK signaling. These findings
have led to a number of successful clinical trials in poorly differentiated
papillary and follicular thyroid cancer and medullary thyroid
cancer. Treatment with inhibitors of receptor tyrosine kinases, vascular
endothelial growth factor (VEGF), and the VEGF receptor have
produced partial response rates in the range of 30%. Agents studied
include axitinib, gefitinib, imatinib, motesanib, sorafenib, sunitinib,
and vandetanib (Sipos and Shah, 2010). Single agents in poorly differentiated
thyroid cancer have most commonly produced disease
stabilization, although combining agents to target multiple growthpromoting
pathways may improve the disease response.
CLINICAL SUMMARY
Replacement therapy for hypothyroidism typically
uses oral L-thyroxine given once daily. The goals of
therapy are to restore the serum TSH concentration to
the mid-normal or low-normal range, and to relieve
the signs and symptoms of hypothyroidism. In
patients with central hypothyroidism, the biochemical
goal is to restore the serum-free T 4
to the upper half of
the normal range. Based on the long t 1/2
of thyroxine,
at least 6-8 weeks are required before a new steadystate
level is reached following initiation of therapy or
adjustment of dose. Special cases of hypothyroidism
include patients following surgical resection of differentiated
thyroid carcinoma and pregnancy. In the former
setting, the goal is to suppress the TSH level to
below normal, thereby removing the potential effect
of TSH to stimulate proliferation of the cancer cells.
In pregnant patients, the standard replacement dose is
usually increased. Realizing the effects of even relatively
mild hypothyroidism on neurological development
of the fetus and miscarriage, it is especially
important to monitor thyroid function tests carefully
during pregnancy.
Options available for treating hyperthyroid
patients include anti-thyroid drugs (e.g., propylthiouracil
and methimazole), radioactive iodine ablation,
and surgery. The preferred therapy differs among
endocrinologists and geographic regions as well as
patient characteristics. Special circumstances, such as
the presence of coexisting ophthalmopathy in patients
with Graves’ disease, also may influence the choice of
therapy; radioactive iodine may aggravate the ophthalmopathy.
Although younger patients with hyperthyroidism
often can be treated effectively with radioactive
iodine, medical therapy with anti-thyroid drugs to
reduce the levels of thyroid hormone has been the preferred
approach. The potential for increased toxicity of
anti-thyroid drugs in children and pregnant women may
influence this choice. In older patients or those with
cardiac disease, radioactive iodine usually is recommended
after the patient has been rendered euthyroid
with anti-thyroid medication. Surgery remains an
option for those who cannot tolerate anti-thyroid drugs
or decline radioactive iodine. Surgery is also the most
rapid way to treat hyperthyroidism permanently. The
initial treatment for thyroid cancer is surgical, usually
a total or near-total thyroidectomy. Radioiodine treatment
to ablate remnant thyroid tissue or to identify
metastatic spread can be done after withdrawal of thyroxine
replacement and elevation of endogenous TSH
or treatment with recombinant human TSH in patients
who are having a total body scan and serum thyroglobulin
measurement to determine the presence of residual
tissue. Treatment of metastatic disease with
radioiodine is performed after thyroxine withdrawal
and elevation of endogenous TSH.
BIBLIOGRAPHY
Abalovich M, Amino N, Barbour LA, et al. Management of thyroid
dysfunction during pregnancy and postpartum: An
Endocrine Society Clinical Practice Guideline. J Clin
Endocrinol Metab, 2007, 92:S1–47.
Aizawa Y, Yoshida K, Kaise N, et al. The development of transient
hypothyroidism after iodine-131 treatment in hyperthyroid
patients with Graves’ disease: Prevalence, mechanism and
prognosis. Clin Endocrinol (Oxf), 1997, 46:1–5.
Anderson GW, Schoonover CM, Jones SA. Control of thyroid
hormone action in the developing rat brain. Thyroid, 2003,
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Astwood EB. Chemotherapy of hyperthyroidism. Harvey Lect,
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Atzmon G, Barzilai N, Hollowell JG, et al. Extreme longevity is
associated with increased serum thyrotropin. J Clin
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Azizi F, Bahrainian M, Khamseh ME, Khoshniat M. Intellectual
development and thyroid function in children who were breastfed
by thyrotoxic mothers taking methimazole. J Pediatr
Endocrinol Metab, 2003, 16:1239–1243.
Bach-Huynh TG, Nayak B, Loh J, et al. Timing of levothyroxine
administration affects serum thyrotropin concentration.
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CHAPTER 39
THYROID AND ANTI-THYROID DRUGS