2012 EDUCATIONAL BOOK - American Society of Clinical Oncology

Evaluation of Patients with Disseminated or
Locoregionally Advanced Thyroid Cancer:
A Primer for Medical Oncologists
By A. Dimitrios Colevas, MD, and Manisha H. Shah, MD
Overview: Historically, patients with thyroid cancers are
managed by endocrinologists, surgeons and radiation oncologists.
Due to recent progress in this field with advances in
treatment of thyroid cancer, medical oncologists are now
commonly involved in care of patients with advanced thyroid
TRADITIONALLY, TREATMENT of patients with differentiated
thyroid carcinomas (DTC), which includes
papillary, follicular, and Hurthle cell carcinomas, has been
highly constrained by the lack of effective treatment of
patients with metastatic or recurrent locoregional disease
after surgical treatments have been exhausted or are not
feasible. Treatments in this setting have been mostly limited
to external-beam radiation treatment focused on the area of
concern or systemic radioactive iodine (RAI) for patients
with rising serum thyroglobulin levels or evidence of iodineavid
evaluable metastases. Because there are no convincing
data on extending survival for patients with disease that is
evaluable only by thyroglobulin levels, endocrinologists and
nuclear medicine physicians have struggled with the selection
of patients for whom RAI is indicated. 1 Although some
advocate treatment with RAI for most patients with thyroglobulin
levels higher than 10 ng/mL, others support a more
focused approach of treatment for patients who are thought
to be at high risk for clinically relevant sequellae of progressive
disease, as disease volume can be reduced even in
patients with thyroglobulin-positive but imaging-negative
disease. 2,3 Therefore, patients referred to the medical oncologist
for RAI-refractory thyroid cancer have commonly received
RAI in the adjuvant setting and often with an
additional one or two doses of RAI in the metastatic setting,
defined by elevated thyroglobulin levels in the absence of
radiographically evaluable metastatic disease. Historically,
it was not uncommon to encounter patients with relatively
indolent disease who had received cumulative RAI doses
exceeding 600 mCi. More recently, because of an increased
awareness of long-term adverse events from RAI, such as
bone marrow suppression, salivary gland compromise, and
gonadal dysfunction, many patients treated with RAI, even
those with clinically indolent disease, are referred to the
medical oncologist with lower prior cumulative RAI doses, in
the range of 200–400 mCi.
Traditional cytotoxic chemotherapy has played a minimal
role in the treatment of patients with RAI-refractory thyroid
cancer. Despite reports or small retrospective experiential
reviews suggesting promise, especially in the induction
setting for patients with no prior cancer treatment, most
well-documented studies demonstrate little to no response to
conventional chemotherapy in patients with RAI-refractory
disease. 4,5 Doxorubicin is often cited as a standard of care on
the basis of a 37% response rate, but that rate was reported
in an oldstudy, and neither the time to progression nor the
methods used to determine responses were reported. 6 Subsequent
studies in patients with RAI-refractory disease have
yielded a 5% response rate. 7 Combination chemotherapy has
384
cancers. In this manuscript, we describe general principles in
management of patients with various types of thyroid cancers
including differentiated, medullary and anaplastic thyroid cancers.
been equally disappointing. In a small study in which the
combination of cisplatin and doxorubicin was compared with
doxorubicin alone, the combination had a numerically lower
response rate than single-agent doxorubicin. 8 There are
hints that newer combinations of cytotoxic chemotherapy
may be achieving better results. In a study of 14 patients
treated with gemcitabine plus oxaliplatin, a complete response
was achieved in one patient and a partial response
was achieved in seven. 9
The medical oncologist caring for patients with advanced
thyroid cancer should be familiar with alternatives to systemic
cytotoxic chemotherapy for patients who have received
RAI (Sidebar 1). Patients with locoregionally recurrent disease
following thyroidectomy and RAI should be considered
for surgery or external-beam radiation treatment. Occasionally,
patients benefit from other locoregional modalities,
such as the use of ethanol injection or radiofrequency ablation
for lymph nodes involved with clinically apparent recurrent
disease.
In patients with locoregionally recurrent or metastatic
disease, the medical oncologist should also ensure that
aggressive suppression of thyroid-stimulating hormone has
been achieved. Some data suggest that aggressive thyroid
stimulating hormone (TSH) suppression leads to improved
outcomes, although one large randomized controlled study of
TSH suppression compared with replacement in the adjuvant
setting after surgery did not demonstrate superiority of
suppression. 10,11 There is consensus among experts that, for
patients with known recurrent differentiated thyroid cancer
(as opposed to patients being treated in the adjuvant setting),
the target TSH level should be less than 0.1 mU/L.
For patients who have clinically meaningful progression
of disease during submaximal TSH suppression (TSH � 0.1
mU/L), the trade-off of side effects from more aggressive
TSH suppression must be weighed against the possibility of
antitumor benefit. The levothyroxine dose necessary to
achieve suppression is typically higher than 1.6 mcg/kg/day,
often cited in the literature as a minimal thyroid suppressive
dose for patients with benign thyroid conditions. One
study found that 2.56 mcg/kg/d was the average dose neces-
From the Stanford Cancer Institute, Stanford University, Palo Alto, CA; The Ohio State
University Comprehensive Cancer Center, Columbus, OH.
Authors’ disclosures of potential conflicts of interest are found at the end of this article.
Address reprint requests to Manisha H. Shah, MD, Ohio State University, 320 W. 10 th
Avenue, A438 Starling-Loving Hall, Columbus, OH 43210; email: manisha.shah@osumc.edu.
© 2012 by American Society of Clinical Oncology.
1092-9118/10/1-10