S P E C I A L F E A T U R E

C l i n i c a l C a s e S e m i n a r

Medullary Thyroid Cancer in the Era of Tyrosine

Kinase Inhibitors: To Treat or Not to Treat—and With
Which Drug—Those Are the Questions

Maria E. Cabanillas, Mimi I. Hu, and Camilo Jimenez

Department of Endocrine Neoplasia and Hormonal Disorders, The University of Texas MD Anderson

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Cancer Center, Houston, Texas 77030

Context: Medullary thyroid cancer (MTC) is a rare form of thyroid cancer comprising approximately
4% of all thyroid cancers. The majority of patients have a relatively good prognosis; however, a
subgroup of patients will require systemic therapy. Large phase III randomized trials led to the
approval of two drugs—vandetanib and cabozantinib—for progressive or symptomatic MTC. The
decision regarding which drug to initiate first is not entirely clear and is a common concern amongst
treating physicians.

Evidence Acquisition and Synthesis: A review of the literature in English was conducted, and data
were summarized and integrated into a decision matrix.

Conclusions: The decision regarding which drug to initiate first for progressive MTC should be based
on a careful review of the medical history, physical examination findings, medication list, electrocar-
diogram, laboratory results, and tumor characteristics. It is necessary to consider the relative contra-
indications when choosing which drug to initiate first. (J Clin Endocrinol Metab 99: 4390 – 4396, 2014)

Clinical Case diogram (EKG) was normal. The patient started potas-
sium and magnesium supplementation. The patient was
61-year-old man with a history of coronary artery
A disease complicated with cardiac arrest presented
with a right neck mass. Sonogram of the neck revealed a
considered a candidate for systemic therapy due to pro-
gressive disease.
This article reviews the elements in a patient’s disease
1-cm right thyroid nodule and bulky lymphadenopathy. and personal medical history that play a significant role in
Fine-needle aspiration confirmed a medullary thyroid can- the decision regarding which agent to initiate. A person-
cer (MTC). Germline RET testing was negative. Calci- alized treatment strategy is required in patients with pro-
tonin was 930 pg/mL (normal, ⬍5 pg/mL), and abdominal gressive MTC.
computed tomography scan was normal. The patient un-
derwent a total thyroidectomy with lymph node dissec-
tion. Sonogram of the neck 6 months after surgery was Background
normal and calcitonin was 247 pg/mL. One year later, the
patient presented with recurrent right neck lymphadenop- MTC accounts for approximately 4% of thyroid cancers.
athy and multiple liver metastases. The patient com- It is derived from the neuroendocrine “C” cells. These
plained of diarrhea (10 –13 bowel movements daily). Cal- tumors secrete calcitonin and carcinoembryonic antigen
citonin was 1835 pg/mL. The patient had hypokalemia, (CEA), which are sensitive biomarkers for the disease. Pa-
3.3 mEq/L (normal range, 3.5–5.0), and hypomag- tients present with a thyroid nodule with or without cer-
nesemia, 1.5 mg/dL (normal range, 1.8 –2.9). Electrocar- vical lymphadenopathy, and frequently with distant me-

ISSN Print 0021-972X ISSN Online 1945-7197 Abbreviations: AE, adverse event; CEA, carcinoembryonic antigen; DT, doubling time; EKG,
Printed in U.S.A. electrocardiogram; GI, gastrointestinal; MTC, medullary thyroid cancer; PFS, progression-
Copyright © 2014 by the Endocrine Society free survival; QTcF, corrected QT interval (Fridericia formula); TKI, tyrosine kinase inhibitor.
Received July 1, 2014. Accepted September 12, 2014.
First Published Online September 19, 2014

4390 jcem.endojournals.org J Clin Endocrinol Metab, December 2014, 99(12):4390 – 4396 doi: 10.1210/jc.2014-2811
doi: 10.1210/jc.2014-2811 jcem.endojournals.org 4391

tastases to the liver, lungs, and/or bone. Diarrhea and/or Systemic Therapy
flushing are present in approximately 30% of cases.
Only a select population of patients with metastatic MTC
Most patients with MTC have a relatively good prog-
should be considered for systemic therapy. The criteria for
nosis. Stage at diagnosis is highly predictive of overall sur-
initiating systemic therapy are clinically significant disease
vival. The 10-year survival rate is 96% among patients
progression (9) (within 12–14 mo), symptomatic tumor
with localized disease (tumor confined to the thyroid burden that cannot be managed with localized therapy, or
gland), compared to 76% in patients with regional disease tumor involvement that threatens organ function or vital
(extension beyond the thyroid directly into surrounding structures that cannot be managed with localized therapy
tissues or regional lymph nodes) (1). Distant metastases (10). It should be emphasized that rising tumor markers
are evident at presentation in 7–23% of patients; the me- alone are not sufficient evidence of progression to warrant

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dian overall survival of these patients is about 3 years (2). initiation of systemic therapy. In patients with severe, in-
A substantial number of patients with distant metastases tractable diarrhea due to MTC, systemic therapy may de-
may have indolent disease that remains quiescent or slow crease tumor burden and improve symptoms. However, in
growing over years of routine observation. some instances, these therapies also may worsen diarrhea.
Postoperative calcitonin and CEA doubling times Therefore, a decision to start chemotherapy based solely
(DTs) are predictors of aggressive tumor behavior. Pa- on diarrhea should be made by physicians who are expe-
tients who have a calcitonin DT of more than 1 year have rienced in managing MTC-related diarrhea.
a 95% 10-year survival rate and a 73% 5-year recurrence- Until 2011, there were no effective agents approved for
advanced MTC. Vandetanib and cabozantinib are anti-
free survival. In contrast, patients whose calcitonin DT is
angiogenic, multikinase inhibitors recently approved by
less than or equal to 1 year have 10-year survival rates and
the Food and Drug Administration (FDA) for symptom-
5-year recurrence-free survival rates of 18 and 20%, re-
atic or progressive MTC. The choice of drug may be dic-
spectively (3). Calculation of DT is helpful and is recom-
tated by certain findings on the history, examination, lab-
mended for identifying high-risk patients who should be oratory, and EKG findings and the behavior of the tumor,
monitored more frequently for tumor progression (4). which are explained further below. It should be pointed
out that if a patient is not a good candidate for vandetanib
or cabozantinib, a clinical trial or other commercially
Initial Treatment and Follow-up available TKIs may be considered (10).

Currently, the only curative treatment for MTC is surgery. Vandetanib

However, when cervical lymph node metastases are pres- Vandetanib is an oral multikinase inhibitor of RET,
ent at the time of initial surgery, the cure rate is low, and VEGFR2 and -3, and EGFR, approved in 2011 for symp-
90% of patients will demonstrate residual disease, either tomatic and/or progressive MTC in patients with unre-
radiologically or biochemically (5). Patients who have per- sectable or metastatic disease. The recommended starting
sistent neck disease can be observed or managed with re- dosage is 300 mg by mouth once daily, and the drug can
peat surgery if progression is proven over time. Many pa- be taken with or without food.
tients with distant metastases have indolent disease that Vandetanib’s approval was based on a phase III, ran-
may not require systemic treatment for many years. Lo- domized, double-blinded, placebo-controlled trial that
calized therapy with external beam radiation may be con- demonstrated a progression-free survival (PFS) advantage
sidered to palliate painful bone metastases or to prevent in MTC patients treated with vandetanib (PFS estimated
at 30 months) when compared with placebo (PFS ⫽ 19
other skeletal-related events (eg, spinal cord compression,
months; P ⬍ .0001) (11). The overall response rate to
fracture). We and others have observed that tyrosine ki-
vandetanib was 44%. Progression before enrollment was
nase inhibitors (TKIs) may offer limited efficacy in thyroid
not an entry criterion, which may have contributed to the
cancer patients with bony metastases (6, 7). Therefore,
long PFS found in the placebo group. Crossover from pla-
progressive or symptomatic bone disease treatments, such cebo to the treatment arm due to tumor progression was
as radiation therapy and/or an antiresorptive (intravenous permitted.
bisphosphonate or RANK-ligand inhibitor), need to be Vandetanib can be prescribed only by physicians who
considered if feasible. Embolization or cryoablation of have completed the Vandetanib Risk Evaluation and Mit-
metastatic disease in the liver or bone may be beneficial in igation Strategy (REMS) program because of a black box
some cases as a means of decreasing tumor burden, alle- warning for prolongation of the QT interval, torsades de
viating pain, or treating refractory diarrhea (8). pointes, and sudden death in clinical trials. Routine EKGs,
4392 Cabanillas et al MTC—Who to Treat and With Which Drug J Clin Endocrinol Metab, December 2014, 99(12):4390 – 4396

review of concomitant medications that may prolong the other RET mutations treated with cabozantinib (61 vs 36
QT interval, and correction of electrolyte abnormalities wk). Of interest, patients with RAS mutations treated with
(hypocalcemia, hypokalemia, hypomagnesemia) are re- cabozantinib exhibit longer PFS when compared with
quired during treatment. Patients with a history of long those treated with placebo (47 vs 8 wk; hazard ratio, 0.15;
QT syndrome, baseline rate-corrected QT (using the Frid- 95% confidence interval, 0.02, 1.10) (13). Although these
ericia formula; QTcF) of ⬎ 450 milliseconds, or uncor- results are suggestive, we cannot recommend the use of
rectable electrolyte disturbances should not be treated these drugs based on RET status. In fact, some patients
with this drug. without RET mutations have benefited from vandetanib
and cabozantinib.
Cabozantinib In vitro data showed that RET V804M and V804L

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Cabozantinib is a multikinase inhibitor of VEGFR2, mutations confer resistance to vandetanib (14). Although
RET, and c-MET, approved in 2012 for the treatment of cabozantinib could be considered a better therapeutic op-
patients with progressive, metastatic MTC. The recom- tion for these patients, clinical confirmation is required;
mended starting dosage is 140 mg by mouth once a day. thus, vandetanib could still be offered to patients with
Our recommendation is to start one (100 mg) or two (60 MTC with RET 804 mutations.
mg) dose levels lower than the recommended starting dose
because the full dose is associated with a greater degree of Adverse events (AEs) associated with vandetanib
toxicity and can be difficult to tolerate. The dose can then and cabozantinib
be titrated up sequentially to the full dose, if a response is Although TKIs generally are better tolerated than cy-
not achieved and the patient tolerates a dosing level well. totoxic chemotherapy, many patients develop side effects.
Conversely, cabozantinib can be decreased further to 40 These drugs are continued until the patient exhibits ra-
mg if patients experience grade 2 or intolerable toxicities diological progression or develops intolerable AEs asso-
that cannot be managed medically. Our clinical experience ciated with the drug. Tables 1 and 2 show the most com-
has been that responses are seen even at dose levels below mon AEs associated with vandetanib and cabozantinib.
40 mg. Patients should be instructed to take the drug on an The most common AEs associated with vandetanib are
empty stomach. The label carries a black box warning for diarrhea, rash, acne, fatigue, nausea, hypertension, head-
ache, vomiting, QT prolongation, and photosensitivity.
perforations, fistulas, and hemorrhage; therefore, this
The most common laboratory abnormalities are hypocal-
drug should be used with caution or avoided in patients
cemia, liver enzyme elevations, hypoglycemia, hypothy-
with a history of neck/mediastinal irradiation or injury to
roidism, and increase in creatinine. Rare but serious AEs
the gastrointestinal (GI) mucosa.
include Stevens-Johnson syndrome, interstitial lung dis-
In contrast to clinical trials of vandetanib, trials eval-
uating cabozantinib in MTC required patients to demon-
strate radiological progression before enrollment. The Table 1. Common AEs Associated with Vandetanib
and Cabozantinib in Order of Frequency (19, 20)
drug’s approval was based on the phase III randomized,
double-blind, placebo-controlled trial that demonstrated Vandetanib Cabozantinib
a PFS advantage among MTC patients treated with cabo- Diarrhea, 57% Diarrhea, 63%
zantinib (PFS, 11.2 mo) when compared with placebo Rash, 53% Stomatitis, 51%
(PFS, 4 mo; P ⬍ .0001) (12). Overall response rate was Dermatitis acneiform/acne, 35% Hand-foot skin reaction,50%
Nausea, 33% Weight loss, 48%
28%. Hypertension, 33% Decreased appetite, 46%
Headache, 26% Nausea, 43%
Effectiveness of vandetanib and cabozantinib and Fatigue, 24% Fatigue, 41%
Decreased appetite, 21% Dysgeusia, 34%
patient’s mutational status
Abdominal pain, 21% Hair color changes/graying,
In the phase III vandetanib trial, patients with sporadic 34%
MTC harboring a somatic RET M918T mutation had a Dry skin, 15% Hypertension, 33%
higher response rate to vandetanib (54.5%; 55 of 101) Vomiting, 15% Constipation, 27%
QT prolongation, 14%a Abdominal pain, 27%
than patients without this mutation (32%; 33 of 103) (11). Photosensitivity reaction, 13% Vomiting, 24%
In the phase III cabozantinib trial, patients with somatic/ Dysphonia, 20%
germline RET mutations treated with cabozantinib ex- Pruritus, 11% Headache, 18%
Dyspepsia, 11% Dysphagia, 13%
hibited longer PFS when compared with those treated with Proteinuria, 10% Dyspepsia, 11%
placebo (60 vs 20 wk; hazard ratio, 0.23; 95% confidence Depression, 10%
interval, 0.14, 0.38). PFS was longer in patients with so- a
Sixty-nine percent had QTc prolongation ⬎ 450 ms and 7% had QTc
matic/germline M918T mutation than in patients with ⬎ 500 ms using the Fridericia correction.
doi: 10.1210/jc.2014-2811 jcem.endojournals.org 4393

Table 2. Lab Abnormalities Associated with safety being the top priority. Figure 1 illustrates the pri-
Vandetanib and Cabozantinib in Order of Frequency mary and secondary considerations that should be taken
into account before deciding which drug to start first.
Vandetanib Cabozantinib Vandetanib carries a black box warning because of QT
Calcium decreased, 57% AST increased, 86% interval prolongation, torsade de pointes, and sudden
ALT increased, 51% ALT increased, 86%
Glucose decreased, 24% Alkaline phosphatase increased,
death, which have been observed in clinical trials. In the
52% phase III vandetanib trial, QT prolongation was reported
Creatinine increased, 16% Calcium decreased, 52% in 14% of patients randomized to vandetanib and in 1%
Bilirubin increased, 13% Phosphorus decreased, 28% of patients randomized to placebo. Vandetanib should not
Magnesium decreased, 7% Bilirubin increased, 25%
Potassium decreased, 6% Magnesium decreased, 19% be given to patients with a history of torsades de pointes,

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Potassium increased, 6% Potassium decreased, 18% congenital long QT syndrome, bradyarrhythmias, or un-
Neutropenia, 10% Sodium decreased, 10% compensated heart failure. Vandetanib should not be
Thrombocytopenia, 9% Neutropenia, 35%
Thrombocytopenia, 35% started in patients whose corrected QT interval (QTcF,
TSH increased, 57% Fridericia formula) is greater than 450 milliseconds and
Abbreviations: ALT, alanine aminotransferase; AST, aspartate
should be used with caution in patients taking antiarrhyth-
aminotransferase. mic drugs or drugs that cause QT prolongation. Patients
should be made aware of all drugs that must be avoided
while taking vandetanib.
ease, ischemic cerebrovascular events, hemorrhage, heart One purpose of the REMS program for vandetanib is to
failure, and reversible posterior leukoencephalopathy
ensure that patients are monitored for QT prolongation.
syndrome. Only 2.5% of patients treated with vandetanib
EKGs should be obtained on patients at baseline, at 2– 4
on the phase III clinical trial were reported to have a fatal
weeks, at 8 –12 weeks, and then every 3 months during
AE (15).
treatment with vandetanib. Electrolytes should be moni-
The most common AEs associated with cabozantinib
tored closely because hypokalemia, hypocalcemia, and
are diarrhea, stomatitis, hand-foot skin reaction, weight
hypomagnesemia may cause QT prolongation. These elec-
loss, decreased appetite, nausea, fatigue, dysgeusia, gray-
trolyte abnormalities are common in thyroid cancer pa-
ing of the hair, hypertension, constipation, abdominal
tients who may have hypoparathyroidism as a complica-
pain, vomiting, dysphonia, and headaches. Common lab-
tion of neck surgery, diarrhea attributable to MTC, and/or
oratory abnormalities include elevation of liver enzymes,
diarrhea due to drug toxicity. Drugs that prolong the QT
hypocalcemia, hypophosphatemia, elevation in alkaline
interval should be avoided. These include commonly used
phosphatase, hyperbilirubinemia, neutropenia, thrombo-
drugs such as some antibiotics, antiemetics (ie, 5-HT3 an-
cytopenia, hypothyroidism, and low magnesium, potas-
tagonists and dopamine D2 antagonists), and antidepres-
sium, and sodium. Rare but serious AEs include perfora-
sants. A complete list can be found at www.crediblemeds.org.
tion and fistula, hemorrhage, thromboembolic events,
In the rare patients who develop ectopic Cushing’s syndrome
poor wound healing, osteonecrosis of the jaw, and revers-
due to MTC, the use of vandetanib should be undertaken cau-
ible posterior leukoencephalopathy syndrome. Six per-
tiously due to the associated electrolyte and cardiac distur-
cent of patients treated with cabozantinib on the phase III
bances. Consideration should be given to referring such a pa-
clinical trial experienced a fatal adverse reaction (16). A
tient to a center with extensive experience in caring for these
complete list of AEs for both drugs can be found in the
package inserts (15, 16). patients. Cushing’s patients exhibit hypokalemia that places
Because neither drug is curative, long-term use is re- them at risk for a prolonged QT and torsades de pointes. A few
quired and can lead to diminished quality of life. Aggres- reports have described successful control of ectopic Cushing’s
sive, conscientious management of AEs is required to syndrome with vandetanib (17, 18); nevertheless, some patients
maintain patient compliance, optimize therapy, and avoid may not respond to it (authors’ experience), and it is potentially
potentially life-threatening consequences. dangerous to give this drug to a patient at risk of hypokalemia.
Because it is currently not possible to predict which MTC pa-
tients would respond to vandetanib, it is important to stabilize
the Cushing’s syndrome and/or correct it in a definitive manner
Choice of TKI
(bilateral adrenalectomy) before initiating vandetanib treat-
Oftentimes the choice of an approved agent to initiate is ment.Ifthisisnotpossible,cabozantinibmaybeabetteroption.
unclear. However, a patient-centered approach should be Cabozantinib carries a black box warning for perfora-
taken with careful consideration of the patient’s medical tions, fistulas, and hemorrhage. The medical history
history, physical examination, and baseline tests—with should include questions regarding any history of hemop-
4394 Cabanillas et al MTC—Who to Treat and With Which Drug J Clin Endocrinol Metab, December 2014, 99(12):4390 – 4396

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Figure 1. Top panel, Relative contraindications to consider when choosing vandetanib or cabozantinib for progressive or symptomatic MTC. A
careful review of the medical history, patient medications, EKG, and tumor characteristics should be performed to determine which drug to start in
patients who qualify for systemic therapy for MTC. Vandetanib should be avoided in patients who are at risk of prolonged QT interval as a result of
personal cardiac history, difficulty in managing hypocalcemia, or use of certain medications that cannot be substituted. Cabozantinib should be
avoided in patients with a history of peptic ulcer disease, diverticulitis, or a tumor invading the trachea, esophagus, or major vessels due to the risk
of perforation or fistula. In these patients, vandetanib should be used with caution. Bottom panel, Factors that may be taken into consideration
when a patient has no relative contraindications to either vandetanib or cabozantinib (see top panel). A careful review of the medication list,
tumor characteristics, and patient characteristics is important when selecting which drug to initiate in patients with MTC, especially if the patient
has no contraindications to either drug. Concomitant use of CYP3A4 inhibitor drugs may increase the plasma concentration of cabozantinib,
whereas CYP3A4 inducers may decrease the plasma concentration of vandetanib. A list of CYP3A4 inhibitors and inducers can be found at
www.medicine.iupui.edu/clinpharm/ddis/. Cabozantinib is the only drug proven to be effective in patients with progressive MTC; therefore, the
rate of progression may be important when selecting which drug to initiate. Low body mass index and a patient’s willingness to protect him- or
herself from sun exposure are additional factors to be considered. Cabozantinib causes weight loss, whereas vandetanib may cause weight gain.
Photosensitivity is an adverse effect of vandetanib. h/o, history of; PUD, peptic ulcer disease; QTcF, rate-corrected QT interval using the Fridericia
formula; EBRT, external beam radiation therapy.
doi: 10.1210/jc.2014-2811 jcem.endojournals.org 4395

tysis, diverticulitis, chronic inflammatory GI disease fatigue, the cabozantinib dose was reduced from 140 to
(Crohn’s disease or ulcerative colitis), active peptic ulcer 100 mg/d. The authors wish to emphasize that the selec-
disease, or radiation to the neck or mediastinum because tion of cabozantinib was based on careful consideration of
these patients may have a higher risk of GI perforation, the patient’s overall clinical picture. As described in this
hemorrhage, and tracheoesophageal fistula. article, the final selection of the agent to initiate in patients
Invasion of the tumor into the trachea, bronchus, or with progressive MTC is a patient-centered approach that
esophagus may increase the risk of fistula formation. Tu- must weigh potential risks and benefits of the treatment
mors that encase major vessels or invade the GI mucosa, selected.
cholecystitis, cholangitis, and appendicitis are associated
with a high risk of bleeding or GI perforation. All patients Conclusions

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should be aware of these potentially life-threatening risks.
Consideration of vandetanib is appropriate among pa- In summary, a significant number of patients with residual
tients at high risk of developing these complications. or recurrent MTC have indolent disease, characterized by
Cabozantinib has no specific monitoring guidelines; how- stable or slowly rising calcitonin and/or CEA levels, and
ever, guidance on how to monitor patients on TKIs can be can be actively surveyed for progression at appropriate
found elsewhere (19). intervals. Given the toxicity profile of currently available
If a patient has no contraindications for vandetanib and chemotherapeutic agents for MTC, the lack of curative
cabozantinib, other clinical factors may be considered intent, and the need for chronic use for disease control,
(Figure 1, bottom panel). For example, patients with rap- systemic chemotherapeutic agents, such as vandetanib or
idly progressive disease may be considered for cabozan- cabozantinib, should not be initiated in patients with in-
tinib because the clinical trial that led to its FDA approval dolent MTC, regardless of the presence of metastatic dis-
required progression, with one-third of enrolled patients ease. For patients who meet the indication for treatment
having rapid progression (within 6 months before study (progressive or symptomatic MTC without viable surgical
entry) (12), whereas the vandetanib trial did not. Photo- or targeted treatment options), it is extremely important
sensitivity is a common side effect of vandetanib, and pa- for a clinician to recognize that a patient-centered ap-
proach should be taken concerning which drug to initiate,
tients who are unable or unwilling to avoid unprotected
which includes a careful review of the patient’s medical
sun exposure may have less risk of phototoxicity on cabo-
history, physical examination, concomitant medications,
zantinib. Hand-foot skin reaction is a common side effect
EKG and laboratory results, and tumor characteristics.
of cabozantinib. For patients whose jobs mostly comprise
Careful monitoring of patients on these drugs is important
the use of their hands (eg, musicians), vandetanib may be
in order to keep patients safe, manage AEs efficiently and
preferred. In addition, cabozantinib is associated with
proactively, and determine when the drug is no longer
weight loss, whereas vandetanib is associated with weight
effective.
gain (20). Therefore, with a patient who is losing weight
as a result of cancer, vandetanib may be considered as a
first-line agent over cabozantinib. A review of the medi- Acknowledgments
cation list should be conducted to determine whether the
We thank Kathryn Hale for her editorial services.
patient is taking a CYP3A4 inhibitor or inducer. Concom-
itant use of CYP3A4 inhibitors may increase toxicity to Address all correspondence and requests for reprints to:
cabozantinib by increasing plasma concentrations of the Maria E. Cabanillas, MD, Department of Endocrine Neoplasia
drug. CYP3A4 inducers can decrease the plasma concen- and Hormonal Disorders, The University of Texas MD Ander-
son Cancer Center, 1515 Holcombe Boulevard, Unit 1461,
tration of vandetanib, making the drug less efficacious. A
Houston, TX 77030. E-mail: [email protected].
complete and frequently updated list can be found at This work was supported by the National Institutes of Health/
www.medicine.iupui.edu/clinpharm/ddis/. National Cancer Institute under award number P30CA016672.
Disclosure Summary: M.E.C. has received research funding
and consulting fees from Exelixis and consulting fees from Astra
Zeneca. M.I.H. has received research support from AstraZen-
Clinical Case Continued eca. C.J. has nothing to disclose.
Because of the electrolyte disturbances and history of car-
diac arrest in our patient, cabozantinib was chosen. After References
2 months of therapy, diarrhea improved (two or three
1. Roman S, Lin R, Sosa JA. Prognosis of medullary thyroid carcinoma:
bowel movements daily), and a 28% tumor size reduction demographic, clinical, and pathologic predictors of survival in 1252
was noted. Calcitonin was decreased to 53 pg/mL. Due to cases. Cancer. 2006;107:2134 –2142.
4396 Cabanillas et al MTC—Who to Treat and With Which Drug J Clin Endocrinol Metab, December 2014, 99(12):4390 – 4396

2. Boostrom SY, Grant CS, Thompson GB, et al. Need for a revised with locally advanced or metastatic medullary thyroid cancer: a
staging consensus in medullary thyroid carcinoma. Arch Surg. 2009; randomized, double-blind phase III trial. J Clin Oncol. 2012;30:
144:663– 669. 134 –141.
3. Meijer JA, le Cessie S, van den Hout WB, et al. Calcitonin and 12. Elisei R, Schlumberger MJ, Müller SP, et al. Cabozantinib in pro-
carcinoembryonic antigen doubling times as prognostic factors in gressive medullary thyroid cancer. J Clin Oncol. 2013;31:3639 –
medullary thyroid carcinoma: a structured meta-analysis. Clin En- 3646.
docrinol (Oxf). 2010;72:534 –542. 13. Sherman SI, Cohen EE, Schoffski P, et al. Efficacy of cabozantinib
4. Calcitonin and carcinoembryonic antigen (CEA) doubling time cal- (Cabo) in medullary thyroid cancer (MTC) patients with RAS or
culator. American Thyroid Association. http://www.thyroid.org/ RET mutations: Results from a phase III study. In: Proceedings from
thyroid-physicians-professionals/calculators/thyroid-cancer- the American Society of Clinical Oncology; May 31–June 4, 2013;
carcinoma. Accessed August 11, 2014. Chicago, IL. Abstract 6000.
5. Machens A, Schneyer U, Holzhausen HJ, Dralle H. Prospects of 14. Carlomagno F, Guida T, Anaganti S, et al. Disease associated mu-
remission in medullary thyroid carcinoma according to basal calci- tations at valine 804 in the RET receptor tyrosine kinase confer

Downloaded from https://academic.oup.com/jcem/article-abstract/99/12/4390/2833890 by guest on 02 March 2020

tonin level. J Clin Endocrinol Metab. 2005;90:2029 –2034. resistance to selective kinase inhibitors. Oncogene. 2004;23:6056 –
6. Schneider TC, Abdulrahman RM, Corssmit EP, Morreau H, Smit 6063.
JW, Kapiteijn E. Long-term analysis of the efficacy and tolerability 15. Caprelsa (vandetanib) [package insert]. Wilmington, DE: AstraZen-
of sorafenib in advanced radio-iodine refractory differentiated thy- eca Pharmaceuticals; 2013.
roid carcinoma: final results of a phase II trial. Eur J Endocrinol. 16. Cometriq (cabozantinib) [package insert]. South San Francisco, CA:
2012;167:643– 650. Exelixis Pharmaceuticals Inc; 2012.
7. Cabanillas ME, Waguespack SG, Bronstein Y, et al. Treatment with 17. Baudry C, Paepegaey AC, Groussin L. Reversal of Cushing’s syn-
tyrosine kinase inhibitors for patients with differentiated thyroid drome by vandetanib in medullary thyroid carcinoma. N Engl
cancer: the M. D. Anderson experience. J Clin Endocrinol Metab. J Med. 2013;369:584 –586.
2010;95:2588 –2595. 18. Nella AA, Lodish MB, Fox E, et al. Vandetanib successfully controls
8. Fromigué J, De Baere T, Baudin E, Dromain C, Leboulleux S, medullary thyroid cancer-related Cushing syndrome in an adoles-
Schlumberger M. Chemoembolization for liver metastases from cent patient. J Clin Endocrinol Metab. 2014:99:3055–3059.
medullary thyroid carcinoma. J Clin Endocrinol Metab. 2006;91: 19. Carhill AA, Cabanillas ME, Jimenez C, et al. The noninvestigational
2496 –2499. use of tyrosine kinase inhibitors in thyroid cancer: establishing a
9. Eisenhauer EA, Therasse P, Bogaerts J, et al. New response evalu- standard for patient safety and monitoring. J Clin Endocrinol
ation criteria in solid tumours: revised RECIST guideline (version Metab. 2013;98:31– 42.
1.1). Eur J Cancer. 2009;45:228 –247. 20. Massicotte MH, Borget I, Broutin S, et al. Body composition vari-
10. Tuttle RM, Haddad R, Ball DW, et al. NCCN clinical practice ation and impact of low skeletal muscle mass in patients with ad-
guidelines in oncology: thyroid carcinoma. J Natl Compr Canc vanced medullary thyroid carcinoma treated with vandetanib: re-
Netw. 2014;1.2014. sults from a placebo-controlled study. J Clin Endocrinol Metab.
11. Wells SA Jr, Robinson BG, Gagel RF, et al. Vandetanib in patients 2013;98:2401–2408.