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Head, Neck, and Thyroid Cancer
Table 2: Molecular Treatment Approaches Currently in
declining over the past few years despite an increase in the incidence
Phase I/II Stages in Anaplastic Thyroid Cancer and/or
of well-differentiated thyroid tumors. The mean age at diagnosis is 55–65
Medullary Thyroid Cancer
years, and the incidence peaks in the sixth to seventh decade.
23
The
clinical presentation is usually a rapidly enlarging anterior neck mass,
Compound Target Thyroid
Cancer
with a doubling of tumor volume sometimes within a week, dysphagia,
Sorafenib RET, VEGFR1-3, PDGFR, FLT3, KIT, FGFR, RAF, BRAF ATC, MTC
dyspnea, and vocal cord paralysis.
24
ATC is usually locally advanced at
Sunitinib RET, VEGFR2, PDGFR, FLT3, KIT, FGFR ATC, MTC presentation, and 50% of patients show evidence of metastatic
Motesanib RET, VEGFR1-3, PDGFR, FLT3, KIT ATC, MTC
disease.
24
Median survival of patients with localized disease is eight
Axitinib VEGFR1-3, PDGFR, KIT ATC, MTC
months, and three months with metastatic disease.
25
The prognosis
Vandetanib RET, VEGFR2+3, EGFR MTC
seems to be determined by age, sex, size of the primary tumor,
Thalidomide Angiogenesis MTC
complete resection, and extent of the disease.
26,27
A prognostic index
Combretastatin A Angiogenesis ATC
was developed by Sugitani et al.
28
and is based on the most important
17-AAG Heat shock protein 90 MTC
risk factors: acute symptoms, tumor >5cm, presence of distant
CS 7017 Peroxisome proliferator-activated receptor-gamma ATC
SAHA Histone deacetylase MTC
metastasis, and white cell count >10,000/µl.
Pazopanib VEGFR1-3, PDGFR, KIT ATC, MTC
XL184 VEGFR2, MET and RET MTC
Most patients with ATC die within a few months after diagnosis,
PF-03814735 Aurora kinase ATC, MTC
primarily due to strangulation by local tumour invasion. Consequently,
(solid tumours) local disease control is of major importance and might potentially
Bortezomib Proteasome ATC, MTC
extend overall survival. From retrospective data analysis there is
ATC = anaplastic thyroid cancer; MTC = medullary thyroid cancer. evidence that a single treatment modality is insufficient to achieve
stable local control.
26,29
Long-term survival was observed only in
Molecular Treatment patients who were treated with a combined approach using surgery,
The only curative treatment in MTC is surgery. Novel treatment options radiation, and chemotherapy.
1,25,26,30
However, to date, the optimal
are mandatory for patients with either persistent or recurrent sequence of local treatment modalities has not been defined. Surgery
unresectable disease. Promising molecular targets identified in MTC are usually consists of a total thyroidectomy. Radiotherapy in more recent
the RET protein and the VEGF system.
4
Several RET kinase inhibitors series was applied as hyperfractionated radiotherapy, and
currently in clinical phase I/II trials are multikinase inhibitors and have chemotherapy was applied parallel to radiation as a radiosensitizer
additional inhibiting activity, most importantly against the VEGF receptor with doxorubicin or mitoxantrone.
1
Some studies continued
(see Table 2). Initial results from phase II trials with vandetanib, axitinib, chemotherapy after completion of local treatment.
31
By increasing
or motesanib show some partial responses and a large proportion of the local control rate, distant metastases gain more relevance for
prolonged disease stabilization.
4,5
The data available at present indicate overall survival.
that not all MTC could sufficiently be treated by targeting only RET. The
optimal duration of therapy is yet to be defined, and the impact of such The most commonly used chemotherapeutic drug in ATC is
a treatment on overall survival and prognosis is still unclear. doxorubicin either as monotherapy or in combination with cisplatin.
32–34
However, although some responses have been seen, an effect of
Currently, several pre-clinical and phase I/II trials have been launched to treatment on overall survival has not yet been proved.
35,36
New
investigate the combination of multikinase inhibitors and conventional chemotherapeutic agents such as paclitaxel, either alone or in
chemotherapy in various tumors, providing useful data on activity and combination, may increase response rates and survival. In a phase II
toxicity for the design of phase II studies for combinations of targeted study reported by Ain et al.,
37
paclitaxel monotherapy induced a
agents and conventional chemotherapy in MTC. Future experimental promising 53% response rate. Whether this high activity translates into
work has to delineate potential alterations in the downstream signaling increased survival remains unclear. More active drugs or drug
pathways of RET and identify further crucial molecular lesions as combinations are mandatory to achieve a significant improvement of
potential targets in RET-negative MTC. the still dismal clinical outcome.
Heat shock protein 90 is a chaperone that acts to stabilize growth factor Multimodality Treatment
receptors and cell signaling molecules. Its inhibition leads to RAF-1 The main causes of death in untreated ATC are local complications such
depletion and inhibition of MAPK activation. A current phase II study is as strangulation due to rapid tumour progression.
30,38
Multimodality
recruiting patients with locally unresectable differentiated thoracic treatment, including surgery, radiation, or radiochemotherapy and
cancer or MTC to be treated with 17-allylaminogeldanamycin (17AAG), a chemotherapy, can increase the local tumor control rate.
26,30,31,39–41
heat shock protein 90 inhibitor (see Figure 1). However, the optimal sequence of surgery, radiation, and chemotherapy
is still a matter of debate.
1
It is generally agreed that a complete
Anaplastic Thyroid Cancer resection of the local tumor either before or subsequent to
Prognosis and Current Treatment radiochemotherapy may improve the overall prognosis.
35,41,42
Although ATC accounts for only 1.6% of all thyroid cancers, it is
responsible for more than half of the 1,200 deaths attributed to thyroid In earlier series, surgery is commonly used as first-line treatment
cancer in the US each year.
23
Fortunately, the incidence of ATC has been in resectable cases, followed by either radiation or radio-
34 US ONCOLOGY
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