Management of treatment-related toxicities in advanced medullary thyroid
Marcia S. Brosea
, Keith C. Bibleb
, Laura Q.M. Chowc
, Jill Gilbertd
, Carolyn Grandea
Francis Wordene
, Robert Haddadf,⁎
aDepartment of Otorhinolaryngology, Head and Neck Surgery and the Abramson Cancer Center, University of Pennsylvania, United States
b Mayo Clinic-Rochester, United States
University of Washington, United States
d Vanderbilt University, United States
e University of Michigan, United States
Dana-Farber Cancer Institute, United States
Progress in the treatment of advanced medullary thyroid cancer (MTC) has resulted from the approval of 2 drugs
within the past 5 years, vandetanib and cabozantinib. These multikinase inhibitors (MKIs) possess overlapping
specificities for multiple kinase targets implicated in the progression of MTC. Both drugs are associated with
toxicities, including hypertension, hemorrhage/perforation, diarrhea and other gastrointestinal events, several
dermatologic events, and hypothyroidism. In addition, vandetanib is uniquely associated with QTc prolongation
through interaction with myocardial potassium channels, and cabozantinib is uniquely associated with hand-foot
skin reaction. Treatment-related toxicities occur frequently and can be severe or life-threatening, and patients
undergoing long-term treatment will likely experience adverse events (AEs). Here we offer specific practical
recommendations for managing AEs commonly occurring with vandetanib and cabozantinib. The recommended
approach relies on early recognition and palliation of symptoms, dose interruption, and dose reduction as ne￾cessary in order for the patient to maintain the highest tolerable dose for as long as possible and optimal quality
of life. Treatment guidelines do not specify a recommended sequence for treating with vandetanib and cabo￾zantinib; however, most patients will receive both drugs during their lifetime. The choice for first-line therapy is
individualized after a risk-benefit assessment and depends on physician preference and patient-related factors,
such as comorbid conditions. Because most generalist practices may not be familiar with the intricacies of agents
such as vandetanib and cabozantinib, we commend that patients with advanced MTC be managed and treated by
a thyroid cancer specialist with coordination of care within a multidisciplinary team.
Medullary thyroid cancer (MTC) is a rare neuroendocrine malig￾nancy that arises in the calcitonin-producing parafollicular cells (C
cells) of the thyroid [1,2]. A calcitonin level of > 1000 pg/mL suggests
the presence of advanced disease with distant metastasis, generally
occurring in the liver, lung, bone, lymph nodes, and brain [1–3]. Be￾cause of its rarity, the exact prevalence of advanced MTC is not known;
however, its incidence is estimated to be approximately 0.2 per 100,000
population [4]. Because 20% of cases of MTC are associated with
multiple endocrine neoplasia syndrome, all patients with MTC should
be screened for germline mutations in the rearranged during transfec￾tion (RET) proto-oncogene [5]. The 5-year survival rate of early-stage
(Stages I-III) disease is > 90% but only < 30% in advanced MTC [1].
Similarly, although surgery is potentially curative in early-stage MTC,
advanced MTC is not curable by surgery or currently available thera￾pies, defining a high unmet need in this patient population [1,2].
Multikinase inhibitors in the treatment of advanced medullary
thyroid cancer
Although treatment with multikinase inhibitors (MKIs) is not cura￾tive, they do have a role in treating advanced/metastatic MTC that is
symptomatic, progressive, and life-threatening. Two such inhibitors,
vandetanib (Caprelsa®; Sanofi Genzyme, Cambridge, MA) and cabo￾zantinib (Cometriq®; Exelixis, South San Francisco, CA) target multiple


Received 2 August 2017; Received in revised form 12 April 2018; Accepted 20 April 2018
⁎ Corresponding author at: Head and Neck Oncology Program, Dana Farber Cancer Institute, 450 Brookline Avenue, Boston, MA 02215, United States.
E-mail address: [email protected] (R. Haddad).
Cancer Treatment Reviews 66 (2018) 64–73
0305-7372/ © 2018 Published by Elsevier Ltd.
kinases and are recommended in published clinical guidelines for MTC
[1,2,6,7]. Additionally, both vandetanib and cabozantinib were ap￾proved based on results of pivotal phase III trials in MTC [6,7]. Im￾portantly, because these 2 trials enrolled different patient populations
and differed as to whether patients receiving placebo were allowed to
cross over upon disease progression, the results (Table 1) cannot be
directly compared but are provided only as summary information [8,9].
For example, the difference in median progression-free survival (PFS) in
these studies, best seen in the placebo arm, reflects a key difference in
trial eligibility: the cabozantinib EXAM study required radiographically
documented disease progression at enrollment, which resulted in a
sicker patient population with a placebo PFS of 4.0 months, whereas the
vandetanib ZETA study did not require radiographic progression and as
a result the placebo arm had a PFS of 19.3 months [8,9]. Furthermore,
crossover from placebo to vandetanib was allowed, confounding the
assessment of overall survival; the cabozantinib trial did not permit
crossover, potentially allowing for credible assessments of the effects on
overall survival [8,9].
The basis for multikinase inhibitor–associated toxicity
Vandetanib and cabozantinib are broad-spectrum MKIs with largely
overlapping kinase selectivities [6,7]. These drugs primarily target
vascular endothelial growth factor receptors (VEGFRs) but also target
many tyrosine kinases implicated in modifying MTC disease patho￾genesis, including mutated RET [6,7]. The efficacy and toxicities of
MKIs overlap and likely reflect target-binding affinities specific to each
drug. The kinase targets of vandetanib include VEGFR, RET, members
of the epidermal growth factor receptor (EGFR) family, BRK), TIE2, and
members of the ephrin receptor and SRC nonreceptor kinase families
[6]. In preclinical models, vandetanib reduced tumor-induced angio￾genesis and tumor vessel permeability, and inhibited tumor growth and
metastasis [6].
Cabozantinib shares some of these targets, including VEGFR family
members, RET, and TIE2, and also targets MET, KIT, TRKB, FLT3, AXL,
TYRO3, and ROS1 tyrosine kinases, among others [7]. Preclinical stu￾dies demonstrated that cabozantinib inhibits angiogenesis; disrupts
tumor vasculature; inhibits tumor cell migration, invasion, and pro￾liferation; and promotes tumor cell death [7,10].
Treating advanced medullary thyroid cancer: who we treat and
Care is needed in identifying patients with advanced MTC who are
candidates to receive MKIs. The patient population studied in the phase
III trial of vandetanib was composed of adults with measurable, un￾resectable, locally advanced or metastatic MTC (hereditary or sporadic)
whose disease was confirmed by tumor analysis or the presence of a
germline RET mutation; tumor progression was not required for en￾rollment. Patients were required to have a serum calcitonin level of
≥500 pg/mL. Patients with significant cardiac, hematopoietic, hepatic,
or renal dysfunction were excluded. Prior systemic therapy for MTC
(including chemotherapy or other MKIs) was allowed [9]. The popu￾lation enrolled in the phase III cabozantinib trial was similar in most
respects and included adults with histologically confirmed, un￾resectable, locally advanced or metastatic MTC. However, in contrast to
the vandetanib trial, documented radiographic disease progression
during the prior 14 months was required for the cabozantinib trial [8].
The use of MKIs is recommended conditionally in NCCN Clinical
Practice Guidelines in Oncology (NCCN Guidelines®) (Category 1 re￾commendation) and treatment guidelines of the American Thyroid
Association (Grade A recommendation). These guidelines indicate that
patients’ disease should be symptomatic or progressing before initiating
treatment; increasing levels of tumor markers alone are not sufficient
criteria [1,2]. An active surveillance approach is generally re￾commended for patients with stable, slowly progressing, or indolent
disease that is not symptomatic or likely to cause immediate symptoms
or complications [1]. Therefore, a risk-benefit assessment should be
performed for each patient with MTC to determine if and when to in￾itiate MKI treatment [1,2,6].
Patient-specific factors to consider include overall disease burden,
locations and pace of disease progression, patient age and comorbid
conditions (e.g., preexisting QTc prolongation or hepatic impairment),
and importantly, patient preference. Because treatment guidelines do
not have a recommended sequence for treating with MKIs, the choice of
agent—vandetanib or cabozantinib—is individualized [1,2]. Indeed,
most patients will receive both agents, administered separately, during
their lifetime, and therefore, the preference for first-line agent varies by
physician and will depend on patient-related factors. Many patients in
clinical practice are likely to have comorbid conditions that would have
excluded them from clinical trials, which must be taken into account. In
some cases these patients are more challenging to manage with respect
to potential toxicities. The distinct pharmacokinetic properties and
drug-drug interactions of vandetanib and cabozantinib are important to
know for both choosing an initial therapy and managing toxicities
(Table 2) [6,7].
Dosing considerations
Because patients may undergo long-term treatment with vandetanib
and/or cabozantinib, most will experience MKI-associated adverse
events (AEs) [8,9]. Therefore, providers need to have a strong under￾standing of how to manage AEs and a practice setting that will allow
expeditious recognition of AEs in order to optimize management. The
rationale for early recognition and optimal management of AEs is to
improve tolerance and adherence to the treatment regimen, while mi￾tigating potential risks, in an effort to optimize clinical outcomes and
afford patients an acceptable quality of life [11]. The general man￾agement approach relies first upon palliation of symptoms where
Table 1
Selected efficacy and safety results in the multinational, pivotal, phase III trials
of vandetanib and cabozantinib in advanced medullary thyroid cancer [7,8].
(Note. Data do not provide direct comparisons due to differences in study design
and patient populations.)
Parameter Vandetanib—ZETA trial Cabozantinib—EXAM trial
Median PFS vs
HR (95% CI)
Not reached (vs 19.3
0.46 (0.31–0.69)
< 0.001
11.2 mo (vs 4.0 mo)
0.28 (0.19–0.40)
< 0.001
OR (95% CI)
5.48 (2.99–10.79)
< 0.001
(OR not given)
< 0.001
Disease control
OR (95% CI)
2.64 (1.48–4.69)
(OR not given)
Biochemical response
Calcitonin level
69% of patients
OR, 72.9 (26.2–303.2)
< 0.001
−45%, mean
+57% (mean, placebo)
< 0.001
Biochemical response
CEA level
52% of patients
OR, 52.0 (16.0–320.3)
< 0.001
−24%, mean
+89% (mean, placebo)
< 0.001
AEs (all grades) in
≥30% of
Diarrhea, rash, nausea,
Diarrhea, PPE, decreased
appetite, decreased weight,
nausea, fatigue
Discontinuations for
12% 16%
Dose reductions for
35% 79%
AE, adverse event; CEA, carcinoembryonic antigen; CI, confidence interval;
EXAM, Efficacy of XL184 (Cabozantinib) in Advanced Medullary Thyroid
Cancer; HR, hazard ratio; OR, odds ratio; ORR, objective response rate (all
partial responses); PFS, progression-free survival; PPE, palmar-plantar ery￾throdysesthesia; RECIST, Response Evaluation Criteria in Solid Tumors; ZETA,
Zactima Efficacy in Thyroid Cancer Assessment.
M.S. Brose et al. Cancer Treatment Reviews 66 (2018) 64–73
possible with over-the-counter or prescription medications (e.g.,
treating hypertension, remediating mucocutaneous toxicities, respon￾sively adjusting the levothyroxine dosage) [9,11]. Then, if not suc￾cessful, dose interruption can be used [11]. Dose reductions are the
final choice, with the goal of maintaining the highest tolerable and
presumably, therefore, effective dose for the patient for as long as
The approved recommended starting dose of vandetanib is 300 mg/
day; 200 mg/day is the starting dose only if the creatinine clearance
level is < 50 mL/min. The starting dose should also be reduced in pa￾tients with mild hepatic impairment, and vandetanib is not re￾commended for patients with moderate or severe hepatic impairment
(serum bilirubin of > 1.5 times the upper limit of normal) [6]. The
starting dose can be increased if there is concomitant use of strong
CYP3A4 inducers and should be decreased (and grapefruit juice
avoided) with concomitant strong CYP3A4 inhibitors; however, in
practice this calibration can be difficult [6].
During treatment, the dose for both MKIs should be reduced as
needed to manage toxicities, while still achieving minimal levels re￾quired for therapeutic effect. For vandetanib, the dose is decreased from
300 mg/day to 200 mg/day, then to 100 mg/day, if needed for
grade ≥ 3 AEs that cannot otherwise be expeditiously remediated as
discussed below [6]. These lower doses may be sufficient to allow
disease control, because stable disease was achieved with 200 or
100 mg/day of vandetanib in a phase I dose-escalation study [12] and
dose adjustment was part of the strategy in the phase III (ZETA) study
[9]. A recently completed phase IV trial evaluated the efficacy of a 150-
mg daily dose [13].
If severe AEs occur, treatment must be interrupted. A boxed warning
mandates that vandetanib be withheld for QTc prolongation of > 500
ms, then resumed at a reduced dose when the QTc interval is < 450 ms
[6]. Importantly, QTc prolongation is not an issue specific to vande￾tanib; treatment interruption is also required for QTc prolongation with
other MKIs. Vandetanib therapy should also be interrupted for other
grade ≥ 3 AEs, and resumed at a reduced dose when the toxicity re￾solves or improves to grade 1 in response to palliative interventions [6].
The pharmacokinetic properties of vandetanib should be considered
when deciding on treatment interruption (Table 2). Importantly, be￾cause dose reduction of vandetanib alone will not quickly attenuate AEs
due to its slow elimination (half-life, 19 days), consideration of dose
interruption should be made quickly to palliate severe toxicities [6].
The recommended starting dose of cabozantinib as per the package
insert is 140 mg/day, or 80 mg/day if the patient has mild-to-moderate
hepatic impairment (Child-Pugh score A or B) [7]. See Table 2 re￾garding increased exposure necessitating dose reduction for hepatic
impairment [7]. However, many experienced MTC providers start in￾stead at 80 or 60 mg/day due to frequent and prohibitively severe AEs
seen at higher dosages [14]. The cabozantinib dosage can be reduced
from 140 mg/day to 100 mg/day, then to 80 or 60 mg/day, as needed to
address AEs [7]. Alternatively, if well tolerated at a starting dosage of
60 or 80 mg/day, the dosage of cabozantinib can be escalated as tol￾erated. A phase IV trial is currently evaluating the efficacy of 60 mg/
day dosing [15]. With concomitant treatment with strong CYP3A4 in￾hibitors, reduce the cabozantinib dose in 40-mg increments [7]; many
patients require further reduction to 20 mg/day. Treatment should be
interrupted for grade 2 “intolerable” AEs, grade ≥ 3 AEs, or grade 4
hematologic AEs [7] but only after it is established that the AEs cannot
be palliated using other interventions. Cabozantinib may then be re￾sumed at a reduced dose when the toxicity resolves or improves to
grade 1 [7].
General considerations
MKI treatment should be “personalized,” with response to toxicities
in 2 ways: (1) supplemental palliative therapies to expeditiously and
responsively address emerging toxicities, and (2) dosage interruptions
or reductions if necessary to manage toxicities. However, every effort
should be made to optimize tolerance and maintain the highest dosage
level that is reasonably tolerable in each patient. Toxicities are frequent
and can be severe and sometimes even life-threatening. Therefore,
providers initiating MKI therapy must have sufficient experience and
resources to manage emergent issues in a timely fashion.
Table 2
Select pharmacokinetic properties and drug-drug interactions of vandetanib and cabozantinib [5,6].
Parameter Vandetanib Cabozantinib
Peak plasma concentration Median 6 h (range, 4–10 h) Range 2–5 h
Steady state At 3 mo At 15 days
t1/2 19 days 55 h
Effects of food (high-fat meal) N/A Cmax increased by 41%
AUC increased by 57%
Elimination 44% in feces
25% in urine
54% in feces
27% in urine
Moderate renal impairment AUC increased by 39% No effect
Severe renal impairment AUC increased by 41% Unknown
Mild hepatic impairment No effect AUC increased by 81%
Moderate hepatic impairment Not recommended (moderate or severe impairment) AUC increased by 63%
Metabolism Via CYP3A4 Via CYP3A4
Drug-drug interactions
Strong CYP3A4 inducers AUC decreased by 40% AUC decreased by 77%
Strong CYP 3A4 inhibitors No effect AUC increased by 38%
Other CYP450 substrates No effect on midazolam AUC (CYP3A4 substrate) No effect on rosiglitazone AUC (CYP2C8 substrate)
P-glycoprotein transporter substrates AUC of digoxin increased by 23% Potential for increased exposure to other substrates
Other transporters Metformin AUC increased by 74% (OCT2 transporter substrate) Potential for increased exposure to cabozantinib with MRP2 inhibitors
Gastric pH (PPI/H2 blocker) No effect No effect
AUC, area under the concentration-time curve; t1.2, plasma half-life; CYP450, cytochrome P450; MRP2, multidrug resistance protein 2; N/A, not available; OCT2,
organic cation transporter 2; PPI, proton-pump inhibitor. a See the text under the heading Dosing Considerations for more information about the effects of pharmacokinetics on toxicities.
M.S. Brose et al. Cancer Treatment Reviews 66 (2018) 64–73
Because most generalist providers who may be called upon to ad￾dress patient issues may be unfamiliar with the intricacies of agents
such as vandetanib and cabozantinib, they cannot reasonably be relied
upon to provide optimal guidance. Consequently, more tailored and
informed guidance to patients is preferable and can be facilitated using
several approaches. Patients receiving MKIs can first be provided with
instructional materials about AEs requiring intervention. Ideally, pa￾tients are given easy access to assistance through provider contact tel￾ephone numbers to have questions addressed in a timely fashion as AEs
emerge. If a provider cannot accommodate this access, consideration
should be given to referring the patient to a more specialized center
with more robust capabilities.
Recommendations for managing treatment-related toxicities
Adverse events — Vandetanib
The most common AEs of any severity associated with vandetanib
therapy are diarrhea, rash, nausea, hypertension, headache, fatigue,
decreased appetite, acne, dry skin, dermatitis acneiform, asthenia, vo￾miting, and QTc prolongation. Serious grade ≥ 3 toxicities commonly
associated with vandetanib include diarrhea, hypertension, QTc pro￾longation, fatigue, decreased appetite, rash, and asthenia (Table 3)
Adverse events — Cabozantinib
Cabozantinib shares some of the most frequent toxicities reported
for vandetanib, for example, diarrhea, decreased appetite, nausea, fa￾tigue, and hypertension. Cabozantinib is also commonly associated
with unique AEs, such as PPE/hand-foot skin reaction (HFS), dysgeusia,
and stomatitis. Cabozantinib is also associated with a broad range of
serious (grade ≥ 3) AEs: diarrhea, PPE/HFS, fatigue, hypertension,
asthenia, decreased weight, decreased appetite, dysphagia, hemor￾rhage, and mucosal inflammation (Table 3) [8].
QT prolongation with vandetanib
Treatment with vandetanib has been associated with an important
nonreceptor kinase–directed effect, a concentration-dependent pro￾longation of the QTc interval. This potential serious complication re￾sults from the drug’s interactions with the myocardial potassium ion
channel involved in cardiac repolarization [6,16]. In the phase III study
of vandetanib, QTc prolongation occurred in 14% of patients, and in 8%
of patients this event was of grade 3 or 4 severity [9]. QTc prolonga￾tion > 500 ms was not reported in the phase III study of cabozantinib
[8]. Vandetanib has also been associated with Torsades de pointes,
ventricular tachycardia, and sudden death [6]; however, these events
were not reported in the vandetanib phase III trial and no clear linkage
was made between sudden death events and QTc [9]. Vandetanib is
contraindicated in patients with the following: congenital long QT
syndrome; a pretherapy QTc interval of > 450 ms (> 480 ms in the
European Union); a history of Torsades de pointes, bradyarrhythmias,
or uncompensated heart failure; and hypocalcemia, hypokalemia, or
hypomagnesemia. Treatment with vandetanib should be discontinued if
a patient develops a QTc interval of > 500 ms and held until it returns
to < 450 ms, at which time vandetanib should be resumed at a reduced
dose. Importantly, because of the 19-day half-life of vandetanib, a
prolonged QT interval may not resolve quickly [6].
An electrocardiogram (ECG), serum electrolyte (potassium, calcium,
and magnesium) levels, and thyroid-stimulating hormone (TSH) levels
should be obtained at baseline, at 2–4 weeks and 8–12 weeks after in￾itiating treatment, and every 3 months thereafter (and more frequently
in patients with diarrhea). These assessments should also be conducted
after any reduction or interruption of the vandetanib dose lasting
for > 2 weeks. Preexisting hypocalcemia, hypokalemia, or hypo￾magnesemia should be corrected before starting treatment. Finally,
vandetanib should not be used concomitantly with agents known to
prolong the QT interval (e.g., amiodarone, chloroquine, clarithromycin,
granisetron, and methadone, among others). A clinical algorithm for
managing patients receiving vandetanib is shown in Table 4 [6].
Because of the potential for serious complications, providers must
be certified through the CAPRELSA Risk Evaluation and Mitigation
Strategy (REMS) Program prior to prescribing vandetanib [6,17]. Al￾though restricted distribution and REMS education for providers may
be perceived by some as a disincentive, this information is necessary to
optimize choice of therapy: QTc prolongation and advanced MTC are
both life-threatening, and the risks and benefits of vandetanib must be
carefully weighed. Moreover, in the authors’ experience, QTc pro￾longation is largely also a generalizable “class effect” and occurs to
varying degrees in response to therapy with all VEGFR-targeted MKIs.
Hypertension and cardiovascular toxicity
Providers who manage patients with advanced MTC should recall
that the high prevalence of cardiovascular disease in the general po￾pulation is likely to be reflected in their own patients [18]. A range of
cardiovascular issues, including hypertension and vascular toxic effects,
are recognized class effects of drugs that inhibit VEGF signaling.
Hypertension was reported at similar rates in the phase III trials of
vandetanib and cabozantinib [8,9]. Thirty-two percent of patients
treated with vandetanib experienced hypertension of all grades, and
hypertension was serious (grade ≥ 3) in 9% of patients [9].
Table 3
Selected most common adverse events and serious adverse events observed in
phase III studies of vandetanib and cabozantinib [7,8].
Vandetanib Cabozantinib
Most common AEs (all grades) occurring in ≥10% of patients
Adverse event % Adverse event %
Diarrhea 56 Diarrhea 63
Rash 45 PPE 50
Nausea 33 Decreased weight 48
Hypertension 32 Decreased appetite 46
Headache 26 Nausea 43
Fatigue 24 Fatigue 41
Decreased appetite 21 Dysgeusia 34
Acne 20 Hair color changes 34
Dry skin 15 Hypertension 33
Dermatitis acneiform 15 Stomatitis 29
Asthenia 14 Constipation 27
Vomiting 14 Hemorrhage 25
ECG QT prolongation 14 Vomiting 24
Abdominal pain 14 Mucosal inflammation 23
Insomnia 13 Asthenia 21
Nasopharyngitis 11 Rash 19
Cough 10 Oropharyngeal pain 18
Decreased weight 10 Dyspepsia 11
Serious adverse events (grade ≥ 3) occurring in ≥ 3% of patients
Diarrhea 11 Diarrhea 16
Hypertension 9 PPE 13
QTc prolongation 8 Fatigue 9
Fatigue 6 Hypertension 8
Decreased appetite 4 Asthenia 6
Rash 4 Decreased weight 5
Asthenia 3 Decreased appetite 5
Dysphagia 4
Hemorrhage 3
Mucosal inflammation 3
PPE, palmar-plantar erythrodysesthesia. a See the text under the headings Adverse Events for more information about
specific AEs in this table.
In the phase III study of cabozantinib, 33% of patients experienced
hypertension of all grades and 8% of patients had serious hypertension
(grade ≥ 3) [8]. The cabozantinib label notes that 96% of patients ex￾perienced some degree of blood pressure (BP) elevation (prehyperten￾sion or overt hypertension [i.e., systolic pressure of ≥120 mm Hg or
diastolic pressure of ≥80 mm Hg]), although no patient developed
malignant hypertension [7].
Therapy with vandetanib or cabozantinib should not be initiated
unless the patient’s baseline systolic BP is consistently < 150 mm Hg.
With respect to monitoring BP, hypertension may develop within a
week of initiating treatment [18]. BP should be monitored and phar￾macologic therapies continued for preexisting hypertension. Amlodi￾pine or other calcium channel blockers are least harmful and most ef￾fective as initial new therapy; adding angiotensin-converting enzyme
inhibitors, angiotensin II receptor blockers, or diuretics should be
considered if initial management is ineffective. Pharmacologic thera￾pies should be started promptly, with the goal of maintaining a systolic
BP of < 150 mm Hg; in our experience, this is almost always possible.
However, in rare instances, MKI therapy may need to be transiently
interrupted or even permanently discontinued in the event of severe or
intractable hypertension (most likely in a patient with preexisting hy￾pertension) to avoid serious neurologic or cardiac complications such as
cardiomyopathy [6,7,16]. Yearly echocardiograms should be con￾sidered in patients on any VEGFR-inhibiting MKI for ≥1 year.
Diarrhea and other gastrointestinal toxicities
Diarrhea is a common AE reported with MKIs, including vandetanib
and cabozantinib, and is apparently related to the targeting of both
VEGFR and EGFR expressed on the mucosal epithelium of the gastro￾intestinal (GI) tract [19,20]. Diarrhea is also common in patients with
advanced MTC and metastatic disease in the liver, as a result of hy￾persecretion of calcitonin and other tumor-derived hormones, causing
increased GI motility [2]. Because diarrhea is a key symptom of MTC,
treatment-related diarrhea may be exacerbated by the underlying dis￾ease and may even worsen in response to therapy. Although treating the
disease with an MKI and lowering calcitonin levels sometimes lessens
diarrhea, this is not always the case. Other common GI effects asso￾ciated with vandetanib and cabozantinib include nausea, dyspepsia,
abdominal pain, and decreased appetite (Table 3) [6–9].
Diarrhea was the most common AE reported in the phase III trial of
vandetanib (Table 3). Fifty-six percent of patients experienced diarrhea
of all grades, although diarrhea was generally of grade 1 or 2; severe
(grade ≥ 3) diarrhea occurred in 11% of patients. Study investigators
reported that diarrhea was generally manageable with supportive care
Similarly, 63% of patients in the phase III trial of cabozantinib ex￾perienced diarrhea of all grades and diarrhea was severe (grade ≥ 3) in
16% of patients (Table 3). Diarrhea was managed with supportive care
and dose reductions or interruptions, similar to what we find in our
respective practices [8]. Every effort should be made to control MTC￾related diarrhea before initiating an MKI. Agents that have proven ef￾fective include loperamide and diphenoxylate/atropine, and patients
should be counseled to expect and manage diarrhea by first using these
agents daily as opposed to waiting for events to occur [11]. If diarrhea
is not controlled, daily low doses of codeine or tincture of opium can
alleviate symptoms and prevent the need for a dose reduction of ca￾bozantinib.
Detailed therapeutic approaches to the management of diarrhea and
dyspepsia are shown in Table 5 [6,7,11,17,20–23]. If diarrhea occurs in
patients receiving MKIs, ECGs and testing of serum electrolyte levels
should be used to carefully monitor patients to enable early detection of
QT prolongation that may result from dehydration and electrolyte de￾pletion [6]. Patients should be counseled to contact their provider
whenever diarrhea occurs and screened for number of bowel move￾ments at every follow-up visit. Based on the provider’s assessment,
appropriate grading and intervention can be determined. For grade ≥ 3
diarrhea, therapy should be interrupted and resumed at a reduced dose
Table 4
Confirm pathology for MTCa X
ECG – Must have QTcF ≤ 450 msb XX X X
Documentation of cardiac historyc X
Laboratory data – Magnesium, Calcium,
Potassium, TSHd
Medication reviewe X X XXXXXX
Radiology staging scans X X X X
Clinic appointment X X X X X X X X
ECG, electrocardiogram; MTC, medullary thyroid cancer; TSH, thyroid-stimulating hormone. a Vandetanib is a kinase inhibitor indicated for the treatment of symptomatic or progressive MTC in patients with unresectable locally advanced or metastatic
disease. b Vandetanib should not be given to patients with a QTcF of > 450 ms.
c Vandetanib should not be given to patients who have a history of Torsades de pointes, bradyarrhythmias, uncompensated heart failure, or congenital long QT
d To reduce the risk of QT prolongation: serum potassium levels should be maintained at ≥4 mEq/L (within normal range); serum magnesium and calcium levels
should be kept within normal range.
e Drugs that prolong the QT interval or are associated with Torsades de pointes should be avoided in combination with vandetanib. These include: antiarrhythmic
drugs (including, but not limited to, amiodarone, disopyramide, procainamide, sotalol, and dofetilide) and other drugs (including, but not limited to, chloroquine,
clarithromycin, dolasetron, granisetron, haloperidol, methadone, moxifloxacin, and pimozide).
after the diarrhea improves [17]. If severe diarrhea threatening to cause
dehydration occurs, outpatient intravenous hydration may occasionally
be required, and ECG and, especially, testing of serum electrolyte levels
should be used to carefully monitor patients to enable early detection
and remediation of potentially serious resulting AEs [20].
Management strategies for diarrhea include dose adjustment or in￾terruption and symptomatic treatment with pharmacologic agents
(Table 5) [11,21]. In patients without baseline (ie, disease-related
diarrhea), new-onset diarrhea is generally mild (grade 1) with vande￾tanib and more frequently moderate (grade 2) with cabozantinib; mild
and moderate diarrhea are well controlled with adherence to loper￾amide [20]. Recommended dietary adjustments (e.g., probiotics and
avoidance of high fiber foods) alone are often insufficient.
Mucosal inflammation and stomatitis/oral pain with cabozantinib
Cabozantinib and other MKIs are also associated with mucosal in-
flammation and stomatitis/oral pain that is specifically related to in￾hibition of VEGFR/EGFR [19]. In the phase III trial of cabozantinib in
advanced MTC, 29% of patients reported stomatitis of all grades (1.9%
grade ≥ 3) and 23% of patients reported mucositis (3% grade ≥ 3) [8].
The cabozantinib prescribing information indicates that 36% of patients
experienced oral pain of any severity [7]. Oral AEs generally occur
within 2–4 weeks of initiating therapy. Supportive measures to manage
oral pain include sucralfate elixir, salt water and sodium bicarbonate,
and/or lidocaine-containing oral rinses [11]. Some patients also gain
symptomatic relief from pure Aloe vera extract oral rinses and avoid￾ance of acidic and spicy foods and many flavored toothpastes. Mucosal
inflammation–related AEs were not reported in the phase III study of
vandetanib and are not addressed in the prescribing information [6,9].
Dermatologic adverse events
MKIs are associated with a wide variety of cutaneous AEs appar￾ently related at least in part to inhibition of both VEGFR and EGFR
[19]. Patients receiving vandetanib in the phase III trial experienced
rash (45%), acne (20%), dry skin (15%), and dermatitis acneiform
(15%). These AEs were generally grade 1 or 2 in severity; however, rash
Table 5
Recommendations for prophylaxis and management of diarrhea and dyspepsia with multikinase inhibitors [5,6,10,16,19–22].
General – grade 1/2 • Provider should be informed when patient is experiencing grade 1/2 diarrhea
• Use pharmacologic/dietary interventions initially (see below)
• Dose reductions/interruptions generally are not needed
• Manage proactively to avoid chronic diarrhea that can lead to dehydration and electrolyte imbalances
General – grade ≥ 3 • Withhold treatment while trying other options to control diarrhea
• Resume treatment when diarrhea declines to grade 1 or “tolerable” grade 2
• Reduce dose, depending on full assessment of dietary habits and adherence to antidiarrheal medications, etc.
Patient education • Educate patients prior to and throughout treatment about onset and management of diarrhea and dietary restrictions
• Patients should be advised to alert the healthcare team about changes in bowel habits
Patient monitoring • Actively monitor and manage hydration and electrolyte status
• Evaluate new or changes in abdominal pain, emesis, or inability to pass stool for risk of GI perforation, especially in patients with a history of
diverticulitis/diverticulosis or prior colitis
• Assess for Clostridium difficile infection and other infection if diarrhea increased unexpectedly
Dietary • Treatment may cause changes in taste and affect eating habits
• Avoid caffeine, dairy, and greasy foods (worsen GI distress)
• Avoid high fiber foods
• Patients should keep food diaries to identify patient-specific adverse foods
• Optimal hydration is the mainstay of responding to diarrhea (other than antidiarrheal agents)
Supplementation • Replace lost calcium with supplementation
Treatment • Generally symptomatic
● Provide antimotility agent at onset of diarrhea, rather than waiting to see if dietary changes are effective
● Loperamide (Imodium®) 2–4 mg with or without food, followed by 2 mg every 4 h or after each loose stool
• Consider standing dose of loperamide titrated to 12 pills/day for worsening diarrhea
● Note. This maximum number of pills per day is not in accordance with the directions on the loperamide packaging. Educate around dose maximums
for adherence to schedule
• Loperamide 2 mg prophylactically 30 min before the scheduled dose, in patients who experienced diarrhea with previous doses
• Diphenoxylate/atropine (Lomotil®), with a similar dose escalation if loperamide is ineffective
Other medications • Tincture of opium or other opiates (e.g., codeine) may also be added to palliate severe diarrhea
• Bile acid sequestrants can also palliate MKI-induced diarrhea
• Cholestyramine may be helpful in some patients
● Note. Start at 4 g/day and titrate up to 4 g/tid
● Must be taken ≥4 h before/after thyroid hormone
General • Dose reduction rarely needed
• Epigastric pain may affect appetite and lead to (sometimes severe) weight loss
Patient education • Educate patients prior to/throughout treatment about dietary restrictions
• Patients should be advised to alert the healthcare team about onset of new GI distress
Administration • Vandetanib may be taken with or without food
• Instruct patients not to eat for ≥2 h before and ≥1 h after cabozantinib
Dietary • Follow recommendations for diarrhea
• Minimize intake of gas-producing foods
• Avoid carbonated drinks
Supplementation • Supplement with lactinex (Lactobacillus) granules or alternate with a probiotic for 2–4 wk to control increasing gas, discomfort, and change in gut flora
Treatment • If dietary changes/supplementation are ineffective, follow with a proton pump inhibitor, bid: 2 h before or after MKI dosing
• Sucralfate suspension, an anti-ulcer medication, taken daily may also be helpful
• Some patients may better-tolerate MKIs if taken after eating rather than on an empty stomach
bid, twice daily; GI, gastrointestinal; tid, 3 times daily. a See the text under the heading Diarrhea and Other Gastrointestinal Toxicities for more information about GI toxicities.
M.S. Brose et al. Cancer Treatment Reviews 66 (2018) 64–73
of grade ≥ 3 severity occurred in 4% of patients [9]. Severe cutaneous
reactions, such as Stevens-Johnson syndrome and toxic epidermal ne￾crolysis, have been reported with vandetanib but were not observed in
clinical trials [6,9]. If severe skin reactions cannot be managed with the
use of systemic corticosteroids, vandetanib should be permanently
discontinued [6]. Less severe reactions may be managed with the use of
topical analgesics (e.g., lidocaine) and supportive care, and are less
likely to occur if skin hydration is optimized preemptively [11].
In the phase III trial of cabozantinib, PPE/HFS of any severity oc￾curred in half of patients and was serious (grade ≥ 3) in 13% [8]. Be￾cause the onset of PPE/HFS may occur as early as a few weeks into
treatment with MKIs, preemptive measures are warranted [7,8,11].
Other dermatologic effects include rash, dry skin, alopecia, erythema,
and hyperkeratosis [7,8].
Recommendations for the management of dermatologic toxicities
are presented in Table 6 [6,7,11,17]. PPE severity may be immediately
improved on initiation of ibuprofen every 8 h for an extended period.
Importantly, because in most cases PPE progresses through grades 1
and 2 to grade 3, early intervention can prevent more severe toxicity
requiring dose interruption or reduction. Selective use of glucocorticoid
lotions, such as 0.05% triamcinolone cream, can also be helpful in
palliating hand skin irritation [11].When unresponsive to aggressive
and proactive skin care, skin toxicities are managed by withholding
cabozantinib for grade 3 (or intolerable grade 2) events and then re￾suming treatment at a reduced dose when the toxicity resolves to grade
1 [7].
Importantly, patients may experience photosensitivity and derma￾tologic AEs that may be triggered by sun exposure (photosensitivity
dermatitis) [6]. Therefore, patients must be counseled on the im￾portance of avoiding sun exposure, with liberal use of ultraviolet-pro￾tective clothing and sunblock [11]. Similar to its effect on other drug￾related AEs, the 19-day half-life of vandetanib delays the resolution of
dermatologic toxicities [6]. Therefore, patients must avoid sun ex￾posure and continue to use sunscreen for up to 4 months after dis￾continuing vandetanib [6].
Hemorrhage, perforation, fistulas, and wound healing
A range of potentially serious GI tract AEs occur with the anti￾angiogenic activity of MKIs that target VEGFR. These include not only
the oral AEs discussed previously but also hemorrhage, as well as in￾testinal perforation and GI and non-GI (i.e., tracheal or esophageal)
fistulas [6,7,19]. Although serious bleeding and intestinal perforation
were not reported in the phase III study, vandetanib is associated with
both mild and moderate bleeding events in 14% of patients and in￾testinal perforation in a small number of patients (0.4%) [6,9]. In our
experience, the risk of intestinal perforation with MKIs is higher in
patients with a history of bowel liabilities, such as colitis or diverticu￾litis.
The cabozantinib prescribing information carries a boxed warning
for VEGFR-related GI and other hemorrhage [7]. Severe, and occa￾sionally fatal, hemorrhage has been reported in 3% of patients receiving
cabozantinib. A similar rate of serious GI perforations (3%) and a low
rate (1%) of fistula formation (including 1 fatal) also have been re￾ported in patients receiving cabozantinib, and fatal non-GI fistulas in
the trachea/esophagus have also occurred [7].
Because of the potential for these serious—and possibly life-threa￾tening—events, patients with a recent history of hemorrhage or sig￾nificant hemoptysis should not be treated with cabozantinib and pa￾tients being treated should be carefully monitored for any symptoms of
perforation or fistula [7,8]. With the use of MKI therapy, perforation is
more likely to occur at sites of prior surgery (ie, anastomotic sites) or
previous irradiation [11]. Treatment should be discontinued if per￾foration occurs, and the patient should be monitored closely for any
need for reparative surgery. Impaired would healing is a related com￾plication stemming from decreased perfusion [11,19]. Caution dictates
that MKI therapy be interrupted ideally ≥2–4 weeks before undergoing
major surgery (and ≥10 days before any surgery), depending on half￾life and be resumed postsurgery based on clinical judgment of adequate
wound healing. It should be noted that patients who have required
emergent surgery, which would have prevented prior dose interruption,
have not had major bleeding complications [11].
Fatigue is common during treatment with MKIs and was reported
in ≤ 40% of patients in the clinical trials of vandetanib (24% all grades,
6% severe) and cabozantinib (41% all grades, 9% severe) [8,9]. Fatigue
may be self-limited, occurring during the first few months of treatment
and resolving thereafter [11]; however, it is generally persistent and
may be severe and even disabling. Patients should be evaluated for
underlying factors that may contribute to fatigue, including emotional
distress/depression, loss of muscle mass, diarrhea, dehydration, pain,
poor nutrition, fluid/electrolyte imbalance, hypothyroidism, and other
comorbid conditions [11,24]. Approaches to the management of fatigue
include adjusting the patient’s daily schedule, taking the MKI in the
evening to minimize daytime fatigue, incorporating caffeine (unless
diarrhea is a problem), exercising (especially weight-bearing exercises
to maintain muscle mass), and monitoring levels of electrolytes and
TSH. However, dose reductions are sometimes required [11].
MKIs may exacerbate hypothyroidism. At least 90% of patients in
the phase III studies of vandetanib and cabozantinib had prior thyr￾oidectomy; 49% of patients receiving vandetanib and 57% of patients
receiving cabozantinib had increasing TSH levels and required an in￾crease in thyroid replacement therapy [6–9]. Therefore, TSH and T4
levels should be monitored at 2–4 weeks after starting therapy, at
8–12 weeks, and every 3 months thereafter. Thyroid replacement
therapy should be adjusted as needed if rising TSH levels indicate
worsening hypothyroidism [6].
Additional considerations when managing toxicities
Where feasible, patients with advanced MTC should be managed
and treated by a thyroid cancer specialist with experience in MTC and
within a multidisciplinary team, with coordination of care as needed
with other specialties—endocrinology, medical oncology, radiation
oncology, interventional radiology, pathology, dermatology, and even
palliative care. In the community setting, local oncologists may reach
out to experts at tertiary care centers for consultation as needed to
support local care of these patients. Certain patients will require special
consideration when deciding whether and when to treat with MKIs.
These include patients who are elderly or frail (i.e., with ECOG per￾formance status > 2), have low body weight, have comorbid condi￾tions that predispose them to risks associated with MKIs, have had
surgery or radiation therapy or are surgical candidates, and who are
receiving concomitant agents that have drug-drug interactions with
vandetanib and cabozantinib (e.g., strong CYP3A4 inducers).
Patient counseling and education are important for a successful
M.S. Brose et al. Cancer Treatment Reviews 66 (2018) 64–73
patient-centered treatment plan, with patient capacity and competence
to make decisions of paramount importance. The risks of MTC and risks
of therapy must be very carefully weighed within the context of each
patient’s goals of care. When deciding if and when to initiate treatment,
the patient must understand and be willing to accept the possible
toxicities of treatment and also, conversely, the risks of watchful
waiting. Patient education can help to overcome the fear of toxicities
that may deter timely treatment. Close communication between the
physician, nurse, and patient can facilitate detecting symptoms of
toxicity when they first appear, allowing for proactive management,
with the goals of maintaining optimal adherence and tolerance to
achieve the best possible clinical outcomes.
Conclusion and future directions
Clinical guidelines in advanced MTC do not address the specific
choice of MKI when initiating systemic therapy, and the treatment path
forward to address disease progression while on vandetanib or cabo￾zantinib therapy is not clear. Solitary progressing lesions can be treated
with local measures, such as radiofrequency ablation, cryoablation,
surgery, or radiotherapy, possibly allowing continuation of MKI therapy
beyond progression and extending clinical benefit [1].
For generalized progression, the authors recommend switching to
the alternative approved MKI, from vandetanib to cabozantinib or vice
versa. Beyond this, additional responses may be attainable with “cy￾cling back” to repeat treatment with an agent that was previously used
Table 6
Recommendations for prophylaxis and management of palmar-plantar erythrodysesthesia/hand-foot skin reaction (PPE/HFS) and other skin toxicities related
treatment with vandetanib and cabozantinib [5,6,10,16].
Prior to initiating treatment • Baseline examination for preexisting hyperkeratosis
• Patient education on prevention and management
• Maintain skin hydration: frequent (bid) use of fragrance-free/hypoallergenic emollients/creams on hands, feet, and other
areas of dry skin
• Control calluses with manicure/pedicure
• Aid exfoliation of calluses: keratolytic agent (20–40% urea-based creams) bid
• Protect pressure points and tender areas of feet: soft/comfortable shoes, insole cushions, and shock-absorbing soles
Throughout treatment (all grades) • Continue recommendations made above
• Monitor patient weekly during the first 6 wk of treatment
• Avoid hot water
• Dry hands completely after washing
• Wear thick cotton gloves and socks, including at night after applying emollients to prevent further injury and retain moisture
• Soak feet in cool water with magnesium sulfate to reduce pain and soften calluses
• Avoid sun exposure, because MKIs are photosensitizers
• Avoid unprotected cold exposure, especially of hands and feet
By severity Initial Subsequent approaches, as needed
Grade 1 (mild): minimal skin changes or
dermatitis (e.g., erythema) without pain • Continue all recommendations as above
• 2-wk follow-up
• Ibuprofen 600 mg tid
• Consider topical therapy for symptomatic relief
• No dose modification
Grade 2 (moderate): skin changes (e.g., peeling,
blisters, bleeding, edema) or pain, not
interfering with function
• Continue recommendations for “throughout treatment”
and ibuprofen 600 mg tid as above
• 1-wk follow-up
• Clobetasol or triamcinolone 0.05% cream qid applied to
erythematous areas (avoiding face, axilla, breasts, and
• Topical analgesic (e.g., lidocaine 2%) for pain
• Grade 2 not addressed in prescribing information
• If not improved with palliative measures, dose interruption
for intolerable grade 2 PPE or grade 3 PPE until
improvement to grade 1
• Can rechallenge at same dose, but if PPE recurs or is grade
3, resume at a reduced dose
Grade 3 (severe): ulcerative dermatitis or skin
changes with pain that interferes with
• Continue recommendations for “throughout treatment”
as above
• 1-wk follow-up
• Topical therapy for symptomatic relief (cortisone cream)
• Systemic strategies to reduce symptoms (e.g., pyridoxine
50–150 mg/day)
• Reduce dose from 300 mg/day to 200 mg/day, and then to
100 mg/day
• Withhold for grade ≥ 3 events until improvement to grade
• Resume at a reduced dose
• For recurrent toxicities, reduce dose to 100 mg/day after
resolution or improvement to grade 1 if continued
treatment is warranted
• For severe skin reactions, refer patient for urgent medical
• Systemic therapies (e.g., corticosteroids) may be
• Permanent discontinuation of vandetanib is recommended
• Withhold treatment for grade ≥ 3 or intolerable grade 2
events until improvement to grade 1
• Resume at reduced daily dose:
– 100 mg if previously 140 mg
– 60 mg if previously 100 mg
– 60 mg if previously 60 mg (if tolerated); otherwise,
discontinue permanently
bid, twice daily; qid, 4 times daily; tid, 3 times daily. a See the text under the heading dermatologic adverse events for more information about dermatologic toxicities.
M.S. Brose et al. Cancer Treatment Reviews 66 (2018) 64–73
before disease progression and switching agents. Following develop￾ment of resistance to both approved agents, participation in a clinical
trial, if available, is strongly encouraged prior to treatment with an off-
label agent. Anecdotal reports suggest that patients who progress on
one MKI may derive subsequent response or disease stability with a
change to another agent, or sometimes multiple agents.
Other agents have shown activity in advanced MTC and have been
used off label, some in the authors’ practices. Options include the MKIs
sunitinib (Sutent®), sorafenib (Nexavar®), pazopanib (Votrient®), do￾vitinib, and lenvatinib (Lenvima®), dacarbazine-based cytotoxic che￾motherapy (e.g., cyclophosphamide, vincristine, dacarbazine [CVD]),
and the oral dacarbazine prodrug, temozolomide (Temodar®)
[1,25–31]. In selected cases of progressive but more indolent, octreo￾tide-avid MTC, octreotide (Sandostatin®) or lanreotide (Somatuline®)
may slow disease progression [1,32]. When the bulk of disease is well
controlled but selective disease progression is observed, consideration
should be given to enhancing MKI therapy alternatively with directed/
focal therapies or enhancing systemic therapies. Antiresorptive bone
therapy plays a role in patients with primarily bony disease progression,
and radiotherapy and/or thermal ablation may be effective for focally
progressive or symptomatic bone lesions [1].
Advanced MTC defines a large unmet need as clinical research
moves beyond vandetanib and cabozantinib alone. Novel, more potent
and selective inhibitors of the RET tyrosine kinase and inhibitors of
other targets and pathways critical to MTC progression are currently in
clinical development [33]. Genomics and personal genome sequencing
may also ultimately be utilized to identify specific non-RET mutations
in MTC that may be targetable, such as HRAS [34,35]. Although the
agents currently in use are active in patients with and without RET
mutations, new agents under study that are more specific for RET
mutations (and lacking VEGFR activity) may require that all patients
without germline RET mutations have their tumors evaluated by ge￾netic sequencing to identify somatic molecular changes that may be
candidates for treatment with othertargeted agents. Finally, approaches
distinct from traditional small-molecule drugs that aim to harness the
patient’s immune response to fight MTC are being investigated, in￾cluding tumor-specific vaccines and immune checkpoint inhibitors
In summary, the broad range and potential severity of class-effect
MKI-related toxicities underscore the importance of proactive mon￾itoring for, early recognition of, and expeditious response to emerging
toxicities. With timely and effective supportive care and dose adjust￾ment as needed, most patients with advanced MTC should be able to
remain on treatment and potentially obtain the maximal benefit pos￾sible from these agents even though MTC is presently an incurable
The authors acknowledge Cricket Darby, PhD, of Connexion
Healthcare (Newtown, PA) for providing medical writing assistance in
the development of this manuscript; she has no conflicts of interest to
report. Editorial and design support were also provided by Connexion
Sanofi Genzyme (Cambridge, MA) funded editorial assistance sup￾plied by Connexion Healthcare in the development of this manuscript.
Disclosure of potential conflicts of interest
Marcia Brose, Keith C. Bible, Laura QM Chow, Jill Gilbert, and
Carolyn Grande are consultants to Sanofi Genzyme.
Robert I. Haddad has received research support for his institution
from Merck, Bristol-Myers Squibb, Celgene, AstraZeneca, and Pfizer,
and is a consultant to Sanofi Genzyme, Merck, AstraZeneca, Eisai,
Bristol-Myers Squibb, Pfizer, and Celgene.
Francis Worden has received funding in the capacity as co-Principal
Investigator of a clinical trial and participation in advisory board
meetings from Merck, in the capacity as a co-Principal Investigator of a
clinical trial from Bristol-Myers Squibb, and for participation in ad￾visory board meetings from Genzyme.
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