2012 EDUCATIONAL BOOK - American Society of Clinical Oncology

APPROACHES TO ADVANCED THYROID CANCERS
Drug Administration (FDA) for use in progressive and
symptomatic metastatic MTC in 2011.
Other RET-inhibitory small molecules have also shown
promise in MTC, including XL184 (cabozantinib), 11 which
has also been subject to a recent randomized phase III trial
in MTC that has yielded apparently promising results,
but that has not yet been published. Furthermore, VEGFinhibitory
TKIs also appear to have activity in MTC and are
the subject of further study in advanced MTC. 2 It should
also be noted that cytotoxic chemotherapy has shown some
activity in MTC, albeit perhaps more modest in extent than
seen in response to TKI therapy. 12-14
As noted above in the case of DTC, potential risks and
benefits of candidate systemic therapeutic approaches
should be carefully considered before their initiation in
patients with MTC because many such patients will have
indolent disease courses most often not requiring systemic
therapies.
Systemic Therapeutic Approaches to Advanced ATC
Cytotoxic chemotherapy remains the most effective, albeit
marginally so, approach to treating advanced ATC. The two
classes of agents with highest activity overall in ATC are
anthracyclines and antimicrotubule inhibitors, with the
greatest amount of data available in the case of paclitaxel. In
particular, the CATCHIT trial demonstrated single-agent
paclitaxel to produce a transient response rate of 53% in
ATC—but the requirement for confirmation of response had
to be shortened to 2 weeks to yield this result 15 ; to be sure,
responses to most any systemic therapy in advanced ATC
tend to be very brief. The related taxane docetaxel has
also shown some activity in ATC. 16 EPC2407 (Crolibulin;
EpiCept Corporation, Tarrytown, NY) have also shown
some promise in ATC, 17,18 with a phase II trial of EPC2407
combined with cisplatin now ongoing (clinicaltrials.gov identifier
NCT01240590).
Doxorubicin, approved by the U.S FDA for use in advanced
thyroid cancer in the 1970s, has been used as a single
agent in thyroid cancer, as well as combined with cisplatin,
with somewhat better outcomes resulting from the twoagent
combination. 19
Although results from evaluation of TKIs in ATC have
been disappointing overall, imatinib monotherapy was recent
reported to induce responses in several patients with
ATC. 20 Further, the combination of the TKI pazopanib with
Authors’ Disclosures of Potential Conflicts of Interest
Author
Michael E. Menefee*
Robert C. Smallridge*
Keith C. Bible*
*No relevant relationships to disclose.
Employment or
Leadership
Positions
Consultant or
Advisory Role
1. Siegel R, Naishadham D, Jemal A. Cancer statistics, 2012. CA Cancer
J Clin. 2012;62:10-29.
2. Harris PJ, Bible KC. Emerging therapeutics for advanced thyroid
malignancies: rationale and targeted approaches. Expert Opin Investig Drugs.
2011;20:1357-1275.
3. Bible KC, Suman VJ, Molina JR, et al. Efficacy of pazopanib in
paclitaxel has produced sufficiently encouraging preclinical
results to be subject to evaluation in a randomized Radiation
Oncology Treatment Group (RTOG) of intensity-modulated
radiotherapy plus paclitaxel with or without pazopanib
(clinicaltrials.gov identifier NCT01236547). Yet additional
agents and combinations are actively being evaluated in
advanced ATC. 2
Also of potential promise in ATC is the application of
systemic therapies in conjunction with the initial treatment
of neck-confined disease—especially when systemic therapy
is combined with radiation therapy. In applying this approach,
several groups have observed unexpectedly favorable
outcomes and survival, 21,22 suggesting that it may be
fruitful in patients with good performance status seeking an
aggressive approach to their initial therapy.
Conclusion
Historically, progress had been slow in developing more
effective systemic approaches to treating advanced thyroid
cancers. This situation has recently begun to change with
the elaboration of an increasing amount of information
related to the molecular pathways contributing to thyroid
cancer pathogenesis, thereby resulting in the identification
of an ever-increasing array of candidate therapeutic molecular
targets that has already begun to lead to therapeutic
advances in thyroid cancers. In particular, the RET kinase
inhibitor vandetanib has been identified as sufficiently
promising to merit its approval by the U.S. FDA for use in
metastatic progressive and symptomatic medullary thyroid
cancer, because it has been shown to delay time to progression
and to induce a high rate of clinical response in MTC.
Additionally, VEGF-R–inhibitory multi-targeted kinase inhibitors
including sunitinib, sorafenib, axitinib, and pazopanib
have demonstrated high rates of durable clinical
responses in DTC, prompting their application as a new
“standard of care” in treating patients with metastatic
RAI-refractory DTC. Although therapeutic progress in ATC
has been slow, emerging evidence suggests promise in the
early application of cytotoxic chemotherapy in conjunction
with other up-front therapies (e.g., radiation therapy and
surgery) for locoregionally confined ATC. Nevertheless, despite
considerable recent progress, further basic advances
and therapeutic progress related to thyroid cancers are still
very much needed, especially for patients with rapidly
progressive metastatic disease.
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Ownership Honoraria
REFERENCES
Research
Funding
Expert
Testimony
Other
Remuneration
progressive, radioiodine-refractory, metastatic differentiated thyroid cancers:
results of a phase 2 consortium study. Lancet Oncol. 2010;11:962-972.
4. Kloos RT, Ringel MD, Knopp MV, et al. Phase II trial of sorafenib in
metastatic thyroid cancer. J Clin Oncol. 2009;27:1675-1684.
5. Gupta-Abramson V, Troxel AB, Nellore A, et al. Phase II trial of
sorafenib in advanced thyroid cancer. J Clin Oncol. 2008;26:4714-4719.
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