2012 EDUCATIONAL BOOK - American Society of Clinical Oncology

gov identifier NCT00984282), with other TKI trials also
ongoing and planned in RAI-refractory metastatic DTC.
Another antiangiogenic strategy that has been successful,
but less well studied, has been the use of immunomodulatory
agents (IMiDs). The effects of the IMiDs in thyroid
cancer may extend beyond their impact on angiogenesis.
Thalidomide, 7 and more recently the thalidomide analog
lenalidomide, 8 have produced clinical benefit in patients
with DTC, with response rates ranging between 18% and
22% and stable disease between 32% and 44%. The IMiDs
are another therapeutic option in the limited, although
rapidly expanding, armamentarium against DTC.
The paradigm indicating that cytotoxic therapies are
ineffective in DTC has also been changing. For example, the
combination of gemcitabine and oxaliplatin (GEMOX) was
recently reported to produce a 57% response rate, with 7%
complete responses 9 ; these results rival or are superior to
outcomes reported from the use of TKIs in DTC. Hence,
newer cytotoxic agents and combinations such as GEMOX
KEY POINTS
● Vandetanib, an orally bioavailable inhibitor of the
RET kinase that is constitutively activated in medullary
thyroid cancer (MTC), has been approved by the
U.S. Food and Drug Administration for use in treating
progressive and symptomatic metastatic MTC; it
has been shown to delay time to progression compared
with placebo in a randomized phase III trial.
● Vascular endothelial growth factor receptor
(VEGF-R) inhibitory and antiangiogenic agents including
sorafenib, sunitinib, axitinib, and pazopanib
have shown high response rates in treating advanced
differentiated thyroid cancers (DTCs) in multiple
phase II trials, and are now commonly used in treating
patients with progressive radioiodine (RAI)refractory
metastatic DTC.
● In the decision to initiate systemic therapies in metastatic
and progressive DTC or MTC, considerable
restraint should be exercised, as many patients will
have slowly progressive disease not requiring active
systemic therapy. Alternatives for focal palliation of
areas of threatening disease (especially in the neck
and in bone) should first be prominently considered
before initiation of systemic therapies. Moreover, the
risk imposed by the disease versus by the systemic
approaches under consideration should be carefully
weighed.
● Application of systemic therapies earlier in the course
of anaplastic thyroid cancer (ATC) has begun to show
promise, especially when used in conjunction with
initial surgical and radiation therapies.
● Although considerable recent progress has been
made in better understanding candidate therapeutic
targets and approaches to treating advanced thyroid
cancers, additional and more effective systemic therapies
for these cancers remain sorely needed.
390
Table 1. Selected Therapeutics for Advanced Thyroid Cancers
Histotype Agent Molecular Target(s)
Differentiated thyroid
cancer
Medullary thyroid
cancer
Anaplastic thyroid
cancer
Axitinib6 Kinases, including VEGF-R
Gemcitabine/oxaliplatin9 DNA
Lenalidomide8 Incompletely defined
Pazopanib3 Kinases, including VEGF-R
Thalidomide7 Incompletely defined
Sorafenib4,5 Kinases, including VEGF-R
Sunitinib23 Kinases, including VEGF-R
Vandetanib10 Kinases, including RET
Cabozantinib11 Kinases, including RET, MET,
VEGF-R
Crolibulin17,18 Microtubules
Docetaxel16 Microtubules
Doxorubicin � cisplatin19 Topoisomerase II/DNA
Paclitaxel15 Microtubules
Abbreviation: VEGF-R, vascular endothelial growth factor receptor.
MENEFEE ET AL
provide an alternative approach to TKIs to consider in
patients with RAI-refractory DTC.
Although there has been considerable progress in developing
therapies for patients with rapidly progressive and
imminently threatening radioactive iodine-insensitive DTC,
most patients with DTC (even those with metastatic disease)
are subject to overall indolent disease courses. As a
result, there should be prominent consideration of focal
palliation of locally threatening disease (especially in the
neck and in bone) before initiation of systemic therapies.
Moreover, the risks imposed by the disease versus those
imposed by contemplated systemic therapies must be carefully
weighed so as to ensure that the initiation of systemic
therapy is in a particular patient’s best interests. Almost all
patients receiving treatment with TKIs will experience
adverse effects, with fatigue, diarrhea, induced hypertension,
and cutaneous toxicities overall quite common, and
with serious adverse effects also encountered in a minority
of patients. Similarly, the application of cytotoxic chemotherapy
is often associated with nausea, cytopenias, and
other adverse effects that have potential to adversely affect
patient quality of life and impose risks to patient welfare.
Overall, judicious application of available systemic therapies
is therefore required in advanced DTC.
Systemic Therapeutic Approaches to Advanced MTC
As noted earlier herein, MTC has proven to be an excellent
model system in the development and study of novel therapeutics
in thyroid cancer. In particular, MTC is commonly
heritable and characterized by constitutive activation of the
RET kinase—triggered by a germ-line mutation in the case
of heritable MTC, and alternatively by tumor-specific mutation
in the case of sporadic MTC. RET activation drives
proliferation in affected parafollicular “C”-cells within the
thyroid, contributing thereby to MTC pathogenesis and
serving as a specific mutational therapeutic molecular target
in MTC.
The RET inhibitor vandetanib has been evaluated in
phase II trials and in a randomized phase III trial compared
with placebo, with results indicating a high response rate
and improved progression-free survival in patients receiving
vandetanib compared with those receiving placebo (as a
result of the cross-over trial design; however, the effects of
vandetanib on overall survival are not reliably assessable). 10
As a result, vandetanib was approved by the U.S. Food and