VOLUME

30

NUMBER

JANUARY

10

2012

JOURNAL OF CLINICAL ONCOLOGY

Progress in Molecular Targeted Therapy for Thyroid

Cancer: Vandetanib in Medullary Thyroid Cancer
Benjamin Solomon and Danny Rischin, Peter MacCallum Cancer Centre, East Melbourne, Victoria, Australia
See accompanying articles on pages 134 and 200

Thyroid cancer, the most common endocrine neoplasm, is increasing in incidence and will account for an estimated 48,020 new
cases and 1,740 deaths in the United States in 2011.1 Most thyroid
cancers arise from thyroid follicular cells. These include differentiated
thyroid cancers (DTCs)papillary thyroid cancer (which accounts
for 80% of all thyroid tumors) and follicular thyroid cancer (approximately 15% of thyroid tumors)as well as the less common anaplastic thyroid cancer.2,3 Medullary thyroid cancer (MTC) is a tumor of
the calcitonin-producing parafollicular or C cells of the thyroid and
comprises 2% to 3% of all thyroid cancers.2,3 MTC occurs in familial
forms as part of the multiple endocrine neoplasia syndromes
(MEN2A or MEN2B) and familial MTC in 20% to 30% of cases but
more commonly is apparently sporadic. Although the majority of
thyroid cancers, other than anaplastic thyroid cancer, are effectively
treated with surgery (combined with radioiodine and thyroidstimulating hormone suppression in high-risk DTC), treatment options with cytotoxic chemotherapy or radiotherapy for patients who
develop unresectable recurrent or metastatic MTC or noniodine-avid
DTC have been minimally effective.
Several recurrent mutations or gene rearrangements have been
identified in both DTC and MTC and seem to be important in the
pathogenesis of thyroid cancers. The first of these, recognized more
than two decades ago, was a gene rearrangement involving the protooncogene RET (rearranged during transformation) in papillary thyroid cancer (so-called RET/PTC gene rearrangements).4 The novel
gene fusion results in aberrant expression and activation of the RET
kinase in thyroid follicular tissue, which leads to the development of
papillary thyroid cancer. Since then, several RET/PTC variants have
been identified in 10% to 20% of sporadic papillary tumors in adults,
but in up to 50% to 80% of papillary tumors that arise in childhood or
after exposure to ionizing radiation (for example, by fallout from the
Chernobyl nuclear accident).5 Activating mutations in RET are present in the germline of virtually all patients with hereditary MTC. These
mutations may present as part of the MEN2A, familial MTC, or
MEN2B syndromes in which there is a genotypic/phenotypic correlation between the type of RET mutation and clinical features such as age
of onset and clinical aggressiveness of thyroid tumors, the incidence of
pheochromocytoma or hyperparathyroidism, and the presence of
developmental abnormalities, mucosal neuromas, and intestinal ganglioneuromas.6 RET mutations are also found in at least 50% of
sporadic MTCs.6,7 Activating mutations in BRAF (in particular the
V600E mutation) have been identified in approximately 50% of papJournal of Clinical Oncology, Vol 30, No 2 (January 10), 2012: pp 119-133

illary thyroid cancers and correlate with poor outcome.8,9 RAS mutations, particularly those that involve NRAS and HRAS, are found in
10% to 20% of papillary thyroid cancers (usually in the follicular
variant) and 40% to 50% of follicular thyroid cancers.10 Translocations that result in a fusion between PAX8 and the peroxisome
proliferator-activated receptor gene are found in 30% to 40% of
follicular thyroid cancers.10,11 Although characterization of these genetic events in thyroid cancer may have diagnostic and prognostic
implications, it also provides an opportunity to develop therapies that
are targeted at these potential molecular drivers.
In the article that accompanies this editorial, Wells et al12 report
the results of a phase III randomized trial using vandetanib (Caprelsa,
ZD6474; AstraZeneca, Wilmington, DE), an orally available smallmolecule inhibitor of RET as well as the vascular endothelial growth
factor receptor 2 (VEGFR2) and epidermal growth factor receptor, in
patients with locally advanced or metastatic MTC. After the observation
of responses to vandetanib in patients with hereditary MTC,13,14 a
double-blind, placebo-controlled, phase III study was initiated in
which patients with locally advanced or metastatic MTC were randomly assigned in a 2:1 ratio to receive 300 mg of vandetanib daily or
a placebo. Remarkably, Wells et al12 were able to accrue 331 patients
with this uncommon neoplasm from 23 countries during a period of
less than 1 year. Most patients (90%) had sporadic MTC and 95% had
metastatic disease. Although 51 patients (23 who received vandetanib
and 28 in the placebo group) received open-label vandetanib before
progression was documented on a central reading of scans, the study
achieved its primary end point with prolongation of progression-free
survival (PFS) on the basis of independently reviewed imaging in
patients who were treated with vandetanib compared with those who
received the placebo (hazard ratio, 0.46; 95% CI, 0.31 to 0.69; P
.001). The median PFS with the placebo was 19.3 months and was not
reached in the vandetanib group (but was estimated at 30.5 months).
Objective responses were seen in 45% of patients who were treated
with vandetanib, with disease control rates of 87% with vandetanib
compared with 71% in patients treated with the placebo. Biochemical
responses with falling calcitonin and carcinoembryonic antigen levels
were seen in 69% and 52% of patients who were treated with vandetanib, respectively. With a median follow-up of 24 months, no differences were seen in overall survival, and although the survival analysis is
to be repeated once 50% of patients have died, this end point may be
confounded by cross-over.
2011 by American Society of Clinical Oncology

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Editorials

The activity of vandetanib in MTC is in keeping with that seen

with other multitargeted tyrosine kinases that are directed at RET,
including sorafenib,15 sunitinib,16 motesanib,17 and cabozantinib,18
in patients with MTC who have been treated in phase I and II studies.
Notably, all of these agents are also potent inhibitors of VEGFR2,
which raises the possibility that inhibition of VEGF receptor signaling
may contribute to the responses that have been observed in MTC.
Intriguingly, there have been reports of patients with MTC responding to axitinib,19 a VEGFR inhibitor that purportedly does
not inhibit RET at clinically achievable doses.20 Another phase III
study in which patients with MTC were randomly assigned to receive
cabozantinib (an oral inhibitor of RET as well as VEGFR2 and MET)
or a placebo has recently completed accrual. Responses to cabozantinib were seen in 49% (17 of 35) of patients with MTC who were
treated on the expansion cohort of a preceding phase I study, including some responses in patients who were previously treated with
vandetanib or sunitinib.18
The investigators made a commendable effort to determine the
relationship between RET genotype and response to vandetanib.12
Tissue was obtained for RET genotyping from 297 of the 298 patients
with sporadic MTC. Mutations in RET were identified in 155 patients
(52%), no RET mutations were identified in 8 patients (2.7%), and
mutation status was determined to be unknown in 135 patients
(45.3%). The last category is large because of the stringent criteria that
were associated with the definition of no RET mutation: a patient had
to have sufficient DNA available and be negative by allele-specific
polymerase chain reaction for M918T and by sequencing each of
exons 10, 11, and 13 to 16 of RET to be considered negative. A response
rate of 46.4% (13 of 28) was seen in patients with hereditary MTC
similar to the 51.8% (57 of 110) in RET mutationpositive sporadic
MTC. The M918T mutation, a tyrosine kinase domain mutation with
potent transforming activity in vitro, was the most frequent mutation
found in 92% (142 of 155) of the patients with RET mutationpositive
sporadic MTC. It is the most common mutation found in MEN2B
and in sporadic MTC and has been associated with poor prognosis in
both settings.6,7,21-23 The response rate in patients with sporadic MTC
and M918T mutations who were treated with vandetanib was 54.5%
(55 of 101) compared with the 32% (33 of 103) response rate seen in
the patients who were negative for mutations or for whom mutation
status was unknown. The remarkable response rate seen in patients
with MTC and RET mutations is directly comparable with response
rates seen in recent studies of targeted agents studied in genotypically
selected populations, such as vemurafenib in melanoma with BRAF
V600E mutations (51%)24 or crizotinib in ALK-rearranged non
small-cell lung cancer (57%).25
However, despite the impressive response rate and prolongation
in PFS, can we be sure that patients who are treated with vandetanib
are truly living better, longer? Improvements in PFS may not be
meaningful if they are not accompanied by improvements in symptoms and health-related quality of life. Although the authors report a
delay in time to worsening of pain in patients who received vandetanib
(Appendix),12 no other patient-reported outcomes, including effects
on other tumor-related symptoms or quality of life, are reported.
Hence, it is difficult to determine the extent to which the beneficial
effects of vandetanib on tumor-related symptoms and delays in tumor
progression were counterbalanced by drug-related adverse effects.
Frequently observed adverse effects related to vandetanib included
diarrhea (56% v 26%), rash (45% v 11%), nausea (33% v 16%),
120

2011 by American Society of Clinical Oncology

hypertension (32% v 5%), and headache (26% v 9%). Thirty-five

percent of patients required dose reductions and 12% of patients
discontinued vandetanib because of toxicity. Particularly concerning
is the grade 3 QTc prolongation that was seen in 8% of patients who
were treated with vandetanib. In most previous studies with vandetanib, these changes were asymptomatic. In contrast, in the present
study, in which there was typically a long duration of treatment with
vandetanib at a dose of 300 mg daily, there was one sudden death and
one death from cardiopulmonary arrest in patients who were receiving vandetanib.26 As a consequence, the US Food and Drug Administration placed a boxed warning regarding QT prolongation, torsades
de pointes, and sudden death in the prescribing information for vandetanib and has required a restricted distribution program (risk evaluation and mitigation strategy) with prescriber education focused on
patient selection, ECG and electrolyte monitoring, and awareness of
drug interactions with other drugs that may prolong the QT interval.26
The potential toxicity associated with long-term administration
of vandetanib highlights the importance of appropriate selection of
patients for treatment with this agent. The relatively indolent tempo of
disease in some patients with MTC who were enrolled onto this trial,
which did not require demonstration of progression before entry, is
evident from the time to progression of 19.3 months in patients who
received the placebo. The risk:benefit ratio of treatment is likely to be
unfavorable in asymptomatic patients or patients with a low disease
burden who experience slow progression. These patients may be appropriately monitored while not receiving therapy by assessment of
the tempo of disease radiologically and through measurement of calcitonin doubling time.27 In contrast, patients who are symptomatic,
have a high disease burden, or have rapidly progressing disease stand
to benefit the most from treatment with vandetanib.
The study by Wells et al12 establishes the efficacy of vandetanib in
patients with locally advanced or metastatic MTC and has led to the
registration of the first treatment for this indication. It places MTC
alongside tumor types such as melanoma, clear-cell carcinoma of the
kidney, and GI stromal tumors, for which the dismal efficacy of conventional cytotoxic chemotherapy contrasts with the remarkable efficacy of tyrosine kinase inhibitors. However, it also highlights a
number of key issues to be considered in the design and choice of end
points in future phase III trials in unresectable or metastatic thyroid
cancer. With regard to vandetanib in MTC, unanswered questions
remain about whether the benefit in PFS will translate into improved
overall survival, whether this treatment improves quality of life and/or
decreases symptom burden, what the optimal timing of this treatment
is, what the activity of vandetanib in RET mutationnegative MTC is,
how much the VEGFR and epidermal growth factor receptor targeting
effects of vandetanib contribute to its activity in MTC, whether the use
of lower doses of vandetanib will mitigate toxicities but maintain
efficacy, and what mechanisms are responsible for acquired resistance
to vandetanib. Finally, the shift away from clinical trials in all-comers
with thyroid cancer toward studies such as this one that involve clinically and genotypically defined subsets of patients with thyroid cancer
will allow more efficient interrogation of other potential molecular
targets in thyroid malignancies.
AUTHORS DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST

Although all authors completed the disclosure declaration, the following

author(s) indicated a financial or other interest that is relevant to the subject
matter under consideration in this article. Certain relationships marked
with a U are those for which no compensation was received; those
JOURNAL OF CLINICAL ONCOLOGY

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Editorials

relationships marked with a C were compensated. For a detailed

description of the disclosure categories, or for more information about
ASCOs conflict of interest policy, please refer to the Author Disclosure
Declaration and the Disclosures of Potential Conflicts of Interest section in
Information for Contributors.
Employment or Leadership Position: None Consultant or Advisory
Role: Benjamin Solomon, AstraZeneca (C), Pfizer (C); Danny Rischin,
Amgen (C) Stock Ownership: None Honoraria: Danny Rischin,
GlaxoSmithKline Research Funding: Benjamin Solomon, Pfizer Expert
Testimony: None Other Remuneration: None
AUTHOR CONTRIBUTIONS

Manuscript writing: All authors

Final approval of manuscript: All authors
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DOI: 10.1200/JCO.2011.37.8638; published online ahead of print at

www.jco.org on October 24, 2011

Role of Nonclinical Factors in the Receipt of

High-Quality Systemic Adjuvant Breast
Cancer Treatment
Jennifer J. Griggs, University of Michigan Hospital and Health Systems, Ann Arbor, MI
See accompanying article on page 142

Disparities in the quality of breast cancer care and outcomes

among black women and among those of lower socioeconomic status
(SES) have been documented in multiple studies over nearly three
decades.1 Little is known about the quality of care and breast cancer
www.jco.org

outcomes among Latinas, but higher case-fatality rates have been

observed when compared with non-Hispanic whites.2 Although some
studies of breast cancer prognosis among Hispanic women have indicated survival rates that are equivalent to those among non-Hispanic
2011 by American Society of Clinical Oncology

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