Single dose regorafenib-induced hypertensive crisis
Gastrointestinal stromal tumors (GISTs) are uncommon tumors of the gastrointestinal (GI) tract. Regorafenib is a new multikinase inhibitor and is approved for the treatment of GISTs in patients who develop resistance to imatinib and sunitinib. The most common drug-related adverse events with regoraf...
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Інститут експериментальної патології, онкології і радіобіології ім. Р.Є. Кавецького НАН України
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| Цитувати: | Single dose regorafenib-induced hypertensive crisis / B. Yilmaz, Y. Kemal, F. Teker, E. Kut, G. Demirag, I. Yucel // Experimental Oncology. — 2014. — Т. 36, № 2. — С. 134-135. — Бібліогр.: 15 назв. — англ. |
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irk-123456789-1453562019-01-21T01:23:15Z Single dose regorafenib-induced hypertensive crisis Yilmaz, B. Kemal, Y. Teker, F. Kut, E. Demirag, G. Yucel, I. Case report Gastrointestinal stromal tumors (GISTs) are uncommon tumors of the gastrointestinal (GI) tract. Regorafenib is a new multikinase inhibitor and is approved for the treatment of GISTs in patients who develop resistance to imatinib and sunitinib. The most common drug-related adverse events with regorafenib are hypertension, hand-foot skin reactions, and diarrhea. Grade IV hypertensive side effect has never been reported after a single dose. In this report, we present a case of Grade IV hypertensive side effect (hypertensive crisis and seizure) after a single dose of regorafenib. A 54-year-old male normotensive GIST patient was admitted to the emergency department with seizure and encephalopathy after the first dosage of regorafenib. His blood pressure was 240/140 mmHg upon admission. After intensive treatment with nitrate and nitroprusside, his blood pressure returned to normal levels in five days. Regorafenib was discontinued, and he did not experience hypertension again. This paper reports the first case of Grade IV hypertension after the first dosage of regorafenib. We can suggest that hypertension is an idiosyncratic side effect unrelated to the dosage. Key Words: hypertension, regorafenib, gastrointestinal stromal tumor. 2014 Article Single dose regorafenib-induced hypertensive crisis / B. Yilmaz, Y. Kemal, F. Teker, E. Kut, G. Demirag, I. Yucel // Experimental Oncology. — 2014. — Т. 36, № 2. — С. 134-135. — Бібліогр.: 15 назв. — англ. 1812-9269 http://dspace.nbuv.gov.ua/handle/123456789/145356 en Experimental Oncology Інститут експериментальної патології, онкології і радіобіології ім. Р.Є. Кавецького НАН України |
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Case report Case report Yilmaz, B. Kemal, Y. Teker, F. Kut, E. Demirag, G. Yucel, I. Single dose regorafenib-induced hypertensive crisis Experimental Oncology |
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Gastrointestinal stromal tumors (GISTs) are uncommon tumors of the gastrointestinal (GI) tract. Regorafenib is a new multikinase inhibitor and is approved for the treatment of GISTs in patients who develop resistance to imatinib and sunitinib. The most common drug-related adverse events with regorafenib are hypertension, hand-foot skin reactions, and diarrhea. Grade IV hypertensive side effect has never been reported after a single dose. In this report, we present a case of Grade IV hypertensive side effect (hypertensive crisis and seizure) after a single dose of regorafenib. A 54-year-old male normotensive GIST patient was admitted to the emergency department with seizure and encephalopathy after the first dosage of regorafenib. His blood pressure was 240/140 mmHg upon admission. After intensive treatment with nitrate and nitroprusside, his blood pressure returned to normal levels in five days. Regorafenib was discontinued, and he did not experience hypertension again. This paper reports the first case of Grade IV hypertension after the first dosage of regorafenib. We can suggest that hypertension is an idiosyncratic side effect unrelated to the dosage. Key Words: hypertension, regorafenib, gastrointestinal stromal tumor. |
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Article |
| author |
Yilmaz, B. Kemal, Y. Teker, F. Kut, E. Demirag, G. Yucel, I. |
| author_facet |
Yilmaz, B. Kemal, Y. Teker, F. Kut, E. Demirag, G. Yucel, I. |
| author_sort |
Yilmaz, B. |
| title |
Single dose regorafenib-induced hypertensive crisis |
| title_short |
Single dose regorafenib-induced hypertensive crisis |
| title_full |
Single dose regorafenib-induced hypertensive crisis |
| title_fullStr |
Single dose regorafenib-induced hypertensive crisis |
| title_full_unstemmed |
Single dose regorafenib-induced hypertensive crisis |
| title_sort |
single dose regorafenib-induced hypertensive crisis |
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Інститут експериментальної патології, онкології і радіобіології ім. Р.Є. Кавецького НАН України |
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2014 |
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Case report |
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http://dspace.nbuv.gov.ua/handle/123456789/145356 |
| citation_txt |
Single dose regorafenib-induced hypertensive crisis / B. Yilmaz, Y. Kemal, F. Teker, E. Kut, G. Demirag, I. Yucel // Experimental Oncology. — 2014. — Т. 36, № 2. — С. 134-135. — Бібліогр.: 15 назв. — англ. |
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Experimental Oncology |
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134 Experimental Oncology 36, 134–135, 2014 (June)
SINGLE DOSE REGORAFENIB-INDUCED HYPERTENSIVE CRISIS
B. Yilmaz*, Y. Kemal, F. Teker, E. Kut, G. Demirag, I. Yucel
Department of Medical Oncology, Faculty of Medicine, Ondokuz Mayis University, Samsun 55139, Turkey
Gastrointestinal stromal tumors (GISTs) are uncommon tumors of the gastrointestinal (GI) tract. Regorafenib is a new multikinase
inhibitor and is approved for the treatment of GISTs in patients who develop resistance to imatinib and sunitinib. The most common
drug-related adverse events with regorafenib are hypertension, hand-foot skin reactions, and diarrhea. Grade IV hypertensive side
effect has never been reported after a single dose. In this report, we present a case of Grade IV hypertensive side effect (hyperten-
sive crisis and seizure) after a single dose of regorafenib. A 54-year-old male normotensive GIST patient was admitted to the emer-
gency department with seizure and encephalopathy after the first dosage of regorafenib. His blood pressure was 240/140 mmHg
upon admission. After intensive treatment with nitrate and nitroprusside, his blood pressure returned to normal levels in five days.
Regorafenib was discontinued, and he did not experience hypertension again. This paper reports the first case of Grade IV hyper-
tension after the first dosage of regorafenib. We can suggest that hypertension is an idiosyncratic side effect unrelated to the dosage.
Key Words: hypertension, regorafenib, gastrointestinal stromal tumor.
Gastrointestinal stromal tumors (GISTs) are un-
common tumors of the gastrointestinal (GI) tract.
These tumors originate in very early forms of cells
found in the wall of the GI tract called interstitial cells
of Cajal [1]. GISTs usually have mutations in proto-on-
cogenic genes encoding the receptor tyrosine kinase
(RTK) stem cell factor receptor (KIT) or platelet-de-
rived growth factor receptor alpha (PDGFR-α) [2–4].
The development of tyrosine kinase inhibitors that
target the changes in these genes has improved
the prognosis of GISTs. Imatinib and sunitinib inhibit
multiple RTKs, including KIT and PDGFR-α, and are
indicated for first- and second-line targeted therapy,
respectively, in patients with GISTs [2].
Almost all patients develop resistance to these
multikinase inhibitors [2]. Regorafenib is a new mul-
tikinase inhibitor and is approved for the treatment
of GISTs in patients who develop resistance to imatinib
and sunitinib and for metastatic colorectal cancer.
This is a novel broad-spectrum kinase inhibitor, with
activity against multiple targets, including vascular
endothelial growth factor receptor (VEGF) 1, 2, 3,
fibroblast growth factor receptor (FGFR) 1, PDGFR β,
tyrosine kinase with immunoglobulin and epidermal
growth factor homology domain 2 (TIE2) and the mu-
tant oncogenic kinases KIT, RET, B-RAF [5]. The most
common drug-related adverse events with regorafenib
are hypertension, hand-foot skin reactions, and diar-
rhea [6]. Grade IV hypertensive side effect has never
been reported after a single dose.
In this report, we present a case of Grade IV hyper-
tensive side effect (hypertensive crisis and seizure)
after a single dose of regorafenib.
Case report. A 54-year-old male was diagnosed with
a 17×8 cm gastric mass by a CT scan. The patient under-
went partial gastric resection and removal of the mass.
Immunohistochemical analysis revealed that the tumor
was positive for CD117 and CD34 but negative for S100,
and the patient was diagnosed with GIST. The CT scan
showed hepatic and splenic metastasis 10 months after
the surgery. The patient received imatinib treatment
at 400 mg/day and was examined every three months.
A CT scan at the 15th month of imatinib treatment showed
progression in the size of the metastasis and new lymph
nodes. We discontinued imatinib and prescribed sunitinib
50 mg/day (28 days on, 14 days off). A CT scan at the 28th
month of sunitinib treatment showed tumor progression.
Therefore, sunitinib treatment was changed to oral rego-
rafenib 160 mg/day.
The patient was normotensive and had no previous
history of high blood pressure. He was not receiving
any medication except imatinib and sunitinib. The pa-
tient had routinely taken his blood pressure since com-
mencing the tyrosine kinase inhibitor treatment. Eight
hours after the first dosage of regorafenib, the patient
was admitted to the emergency department with
seizure and encephalopathy. His blood pressure was
240/140 mmHg upon admission. A cranial CT scan
was performed and excluded metastasis. All blood
workup was normal, including liver, kidney, and thyroid
function. Echocardiography was normal.
After intensive treatment with nitrate and nitroprus-
side, his blood pressure returned to normal levels
in five days. Regorafenib was discontinued, and he did
not experience hypertension again. After all work-up,
the case suggests that hypertensive crisis was related
to the single dose of regorafenib treatment.
Regorafenib is a novel oral multikinase inhibitor that
regulates tumor angiogenesis. In common with other
antiangiogenic drugs targeting the VEGF/VEGFR path-
way, one of the dose-limiting side effects of regorafenib
is hypertension [6]. A number of mechanisms have
been suggested for VEGF signaling pathway inhibi-
tor associated hypertension. According to one study,
Submitted: March 7, 2014.
*Correspondence: Fax: 090 362 457 60 41
E-mail: bahiddin.yilmaz@omu.edu.tr
Abbreviations used: GI tract — gastrointestinal tract;
GISTs — gastrointestinal stromal tumors; KIT — stem cell factor
receptor; PDGFR-α — platelet-derived growth factor receptor
alpha; RTK — receptor tyrosine kinase.
Exp Oncol 2014
36, 2, 134–135
CASE REPORT
Experimental Oncology 36, 134–135, 2014 (June) 135
VEGFR pathway inhibitors decrease NO synthesis and
lead to a loss of parallel capillary circulation in normal,
nontumor tissue, a process called rarefaction. Other
studies suggested a role for endothelial dysfunction,
leading to an increase in endothelin-1 (ET-1) and aortic
stiffness [7–10]. De Jesus-Gonzalez et al. [11] showed
that regorafenib induces coordinated and reversible
suppression of NO and stimulation of ET-1.
Two phase III studies of regorafenib have been
performed. In the CORRECT study, which included
patients with metastatic colorectal cancer, 36.7%
of 500 patients in the regorafenib group had hyperten-
sion [12]. Treatment-related Grade III hypertension oc-
curred in only 7% of cases. Grade IV hypertension was
not reported in this study. In the second rando mized,
placebo-controlled, phase III trial of patients with ad-
vanced GISTs, regorafenib-induced hypertension was
seen in 49% of 132 patients [6]. Among these, 23%
had Grade III hypertension, and only one patient had
Grade IV hypertension. The study contained no data
on the patient’s dosage or the duration of regorafenib
treatment.
George et al. [13] and Bruix et al. [14] reported
regorafenib-induced hypertension in 36% of patients
in two phase II studies (n = 33 and n = 36, respec-
tively). All the patients in George et al. [13] study had
Grade III hypertension. Bruix [14] reported a patient
with Grade ≥III hypertension, but the actual grade
was not reported whether grade III or IV in the study.
Eisen et al. [15] showed that only 3 of 49 patients had
Grade ≤IV hypertension during regorafenib usage
in their phase II clinical trial.
In conclusion, this paper reports the first case
of Grade IV hypertension after a single dose of rego-
rafenib. Grade IV hypertension is an unexpected adverse
effect of regorafenib therapy according to the afore-
mentioned five clinical trials. These studies included
750 patients, and only one case of Grade IV hyperten-
sion was reported. Our patient experienced Grade IV hy-
pertension after a single dose of regorafenib treatment,
and the hypertension ceased after discontinuation
of the drug. Our findings suggest that hypertension
is an idiosyncratic side effect unrelated to the dosage.
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