Efficacy and safety of sunitinib on metastatic renal cell carcinoma: a single-institution experience.

Abstract

We assessed the efficacy and safety of the tyrosine kinase inhibitor sunitinib in Korean patients with metastatic renal cell carcinoma (mRCC).
Between September 2007 and December 2009, all twenty-one patients who had mRCC with a clear-cell component were retrospectively reviewed. Sunitinib was administered orally at a dose of 50 mg daily until disease progression or intolerance to treatment occurred. The primary end point of this study was the objective tumor response assessed by Response Evaluation Criteria in Solid Tumors (RECIST), and the secondary end points were progression-free survival (PFS) and overall survival (OS) rates as well as assessment of adverse effects.
After a median of 17.4 months (range, 5.7-33.1 months) of treatment, 11 patients (52.4%) had an objective response with a complete response in 1 patient (4.8%), and a partial response in 10 patients (47.6%) as the best tumor response. The median PFS was 13.4 months (95% confidence interval [CI], range, 12.3-14.5 months), and the median OS was 28.1 months (95% CI, 21.8-34.4 months). All patients experienced adverse events of some sort, but the studied treatment protocol was well tolerated and most patients experienced reversible grade 1 or 2 toxicities.
Sunitinib was efficacious in the treatment of metastatic clear-cell RCC, and was well tolerated in Korean patients. Although sunitinib treatment-related adverse events such as hand-foot syndrome and facial/generalized edema were observed with a higher incidence than in Western trials, they were mainly mild to moderate, and readily managed.

Full text

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Korean Journal of Urology
Ⓒ The Korean Urological Association, 2010
450
Korean J Urol 2010;51:450-455
www.kjurology.org
DOI:10.4111/kju.2010.51.7.450
Urological Oncology
Efficacy and Safety of Sunitinib on Metastatic Renal Cell
Carcinoma: A Single-Institution Experience
Eugene Hwang, Hyo Jin Lee1, Chong Koo Sul, Jae Sung Lim
Departments of Urology, 1Internal Medicine, Chungnam National University School of Medicine, Daejeon, Korea
Purpose: We assessed the efficacy and safety of the tyrosine kinase inhibitor sunitinib
in Korean patients with metastatic renal cell carcinoma (mRCC).
Materials and Methods: Between September 2007 and December 2009, all twenty-one
patients who had mRCC with a clear-cell component were retrospectively reviewed.
Sunitinib was administered orally at a dose of 50 mg daily until disease progression
or intolerance to treatment occurred. The primary end point of this study was the ob-
jective tumor response assessed by Response Evaluation Criteria in Solid Tumors
(RECIST), and the secondary end points were progression-free survival (PFS) and over-
all survival (OS) rates as well as assessment of adverse effects.
Results: After a median of 17.4 months (range, 5.7-33.1 months) of treatment, 11 pa-
tients (52.4%) had an objective response with a complete response in 1 patient (4.8%),
and a partial response in 10 patients (47.6%) as the best tumor response. The median
PFS was 13.4 months (95% confidence interval [CI], range, 12.3-14.5 months), and the
median OS was 28.1 months (95% CI, 21.8-34.4 months). All patients experienced ad-
verse events of some sort, but the studied treatment protocol was well tolerated and
most patients experienced reversible grade 1 or 2 toxicities.
Conclusions: Sunitinib was efficacious in the treatment of metastatic clear-cell RCC,
and was well tolerated in Korean patients. Although sunitinib treatment-related ad-
verse events such as hand-foot syndrome and facial/generalized edema were observed
with a higher incidence than in Western trials, they were mainly mild to moderate, and
readily managed.
Key Words: Neoplasm metastasis; Renal cell carcinoma; Sunitinib
This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial
License (http://creativecommons.org/licenses/by-nc/3.0) which permits unrestricted non-commercial use,
distribution, and reproduction in any medium, provided the original work is properly cited.
Article History:
received 14 May, 2010
accepted 21 June, 2010
Corresponding Author:
Jae Sung Lim
Department of Urology, Chungnam
National University School of Medicine,
33, Munhwa-ro, Jung-gu, Daejeon
301-721, Korea
TEL: +82-42-280-7779
FAX: +82-42-257-0966
E-mail: uro17@cnu.ac.kr
INTRODUCTION
Renal cell carcinoma (RCC) is the most common malig-
nancy of the kidney [1]. Although surgery is curative for lo-
calized disease, up to 30% of patients with RCC present
with metastatic disease at the time of diagnosis [2,3], and
more than 25% of patients with locally advanced RCC de-
velop distant metastasis despite curative resection [4].
Since RCC is highly resistant to chemotherapy, high dose
interleukin-2 or interferon-alfa therapy is widely used as
a first-line treatment of metastatic disease, but they pro-
vide only a modest response rate of less than 20% [5]. Thus,
the outcome of metastatic RCC is quietly depressing: The
5-year overall survival rate is less than 10% [3]. Effective
systemic therapy for RCC is mandatory.
　In conventional RCC, the loss of von Hippel-Lindau pro-
tein function leads to overexpression of vascular endothe-
lial growth factor (VEGF) and platelet-derived growth fac-
tor that promote tumor angiogenesis [6,7]. Sunitinib is an
orally active multi-targeted tyrosine kinase inhibitor that
specifically inhibits VEGF receptor (VEGFR), platelet- de-
rived growth factor receptor (PDGFR), FMS-like tyrosine
kinase-3 (flt-3), and stem c-Kit protein (c-Kit) [8]. The effi-
cacy on metastatic RCC has been confirmed in both phase
II and III trials, where it was shown to improve the median
progression-free survival (PFS), yield a higher response

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Korean J Urol 2010;51:450-455
Efficacy and Safety of Sunitinib on Metastatic RCC
451
TABLE 1. Patient demographics and disease characteristics
Patient
No.
Age
MSKCC risk
factors
Sites of metastases Previous treatment
Follow up
(months)
Cycles
Best
response
1
2
3
68
60
63
Favorable
Favorable
Favorable
Lung, liver
Lung
L/N
Nephrectomy
Radiotherapy
Cytokine, nephrectomy,
radiotherapy
Nephrectomy
Cytokine, nephrectomy
Cytokine, nephrectomy
Cytokine, nephrectomy
Nephrectomy
Radiotherapy
29.5
20
33.1
17
12
19
PR
PR
PR
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
61
75
67
57
67
64
55
62
69
75
70
67
54
68
46
53
69
73
Favorable
Intermediate
Intermediate
Intermediate
Intermediate
Intermediate
Intermediate
Intermediate
Intermediate
Intermediate
Intermediate
Poor
Poor
Poor
Poor
Poor
Poor
Poor
Liver
L/N
Lung
Lung, L/N
Bone, liver
Lung
Lung
Lung, L/N
Bone, adrenal gland
Lung, pancreas
Lung, L/N
Lung
Lung, L/N
Bone, lung, L/N
Bone, L/N
Adrenal gland, bone, lung, L/N
Bone, lung
Bone, lung
18
26.7
13
28.1
8.3
24.1
15.6
9.9
23.2
17
14.3
19.3
25.6
9.7
10.5
6.2
9.3
5.7
10
13
7
17
5
15
9
5
11
11
8
12
15
6
6
3
4
3
SD
CR
PR
PR
PR
PR
PR
SD
SD
SD
PD
PR
PR
SD
SD
SD
PD
PD
Nephrectomy
Cytokine, nephrectomy
Cytokine, nephrectomy
Cytokine, nephrectomy
Nephrectomy
Nephrectomy
　
MSKCC: Memorial Sloan-Kettering Cancer Center, PR: partial response, L/N: lymph nodes, SD: stable disease, CR: complete response,
PD: progressive disease
rate (RR), and afford a better quality of life over interfer-
on-alfa [9-11]. Based on current data, sunitinib is now the
preferred drug for first-line treatment of metastatic RCC
[10,11].
　However, these studies were performed mainly in
Western populations. The difference in behaviors of RCC
in different ethnic groups has been demonstrated [12].
Although the nature of these variations and associated mo-
lecular basis is not demonstrated, it is reasonable to eval-
uate the efficacy of sunitinib on metastatic RCC in those
of different ethnic backgrounds. Therefore, we perfomed
this retrospective study to assess the efficacy and safety of
sunitinib in Korean patients with metastatic RCC using an
institutional treatment protocol.
MATERIALS AND METHODS
1. Patients
The medical records of patients treated with sunitinib for
metastatic RCC were retrospectively reviewed between
September 2007 and December 2009. The inclusion cri-
teria were as follows: histologically confirmed clear-cell
RCC; metastases measurable on computed tomography
(CT) or magnetic resonance imaging (MRI); a performance
status of 0-2 based on Eastern Cooperative Oncology Group
(ECOG) criteria. Patients were excluded if they had brain
metastases. A total of 21 patients were found to fit the study
criteria. Patient demographics, prior therapy, best re-
sponses, and relevant toxicities were obtained from medi-
cal records, and survival data were collected by telephone
interviews. Risk factors associated with shorter survival
were assessed according to the Memorial Sloan-Kettering
Cancer Center (MSKCC) risk classification: a low serum
hemoglobin level, an elevated corrected serum calcium lev-
el, an elevated serum lactate dehydrogenase level, a poor
performance status, and an interval of less than 1 year be-
tween diagnosis and treatment [12].
2. Treatment schedule
Sunitinib was administered orally at a dose of 50 mg daily,
consisting of 4 weeks of treatment followed by a 2-week rest
period in cycles of 6 weeks (schedule 4-2). Dose reduction
of sunitinib was allowed to 37.5 mg and then 25 mg daily
depending on the type and severity of adverse events.
Treatment with sunitinib was continued until the occur-
rence of disease progression, unacceptable adverse events,
or patient withdrawal.
3. Study end points
The primary end point of this study was the objective clin-
ical response (complete response, partial response, stable
disease, or progressive disease), assessed by Response
Evaluation Criteria in Solid Tumors (RECIST) using regu-
lar physical examinations, CT/MRI, and bone scans (if bone
metastases were present at baseline) after each cycle for
the first 4 cycles thereafter until the end of treatment [13].

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Hwang et al
TABLE 2. Patient characteristics
Characteristics No. of patients (%)
Total patients
Sex
Male
Female
Median age-year (range)
ECOG performance status
0
1
2
Previous treatment
Cytokine
Radiation therapy
Nephrectomy
Sites of metastasis
Lung
Liver
Bone
Lymph nodes
No. of disease sites
1
2
≥3
MSKCC risk factors
Favorable (0)
Intermediate (1,2)
Poor (≥3)
21 (100)
17 (81)
4 (19)
63.9 (46-75)
12 (57.1)
6 (28.6)
3 (14.3)
7 (33.3)
3 (14.3)
13 (61.9)
15 (71.4)
3 (14.3)
7 (33.3)
9 (42.9)
8 (38.1)
10 (47.6)
3 (14.3)
4 (19.0)
10 (47.6)
7 (33.3)
ECOG: Eastern Cooperative Oncology Group. MSKCC: Memo-
rial Sloan-Kettering Cancer Center
FIG. 1. Progression-free survival in Korean patients with
metastatic clear-cell renal-cell carcinoma.
TABLE 3. Best responsea to sunitinib treatment
Response
No. of
patients (%)
Objective response
Complete response
Partial response
Stable disease for ≥3 months
Progressive disease or stable disease ＜3 months
11 (52.4)
1 (4.8)
10 (47.6)
7 (33.3)
3 (14.3)
a: tumor response was assessed by Response Evaluation Criteria
In Solid Tumor
The secondary end points were progression free survival
(PFS) and overall survival (OS) rates. PFS was defined as
the time from the start of treatment to the date of pro-
gressive disease or death. OS was defined as the time from
start of treatment to death or the date at which patients
were last known to be alive.
　The adverse events secondary to treatment were eval-
uated at each visit according to the National Cancer
Institute Common Terminology Criteria for Adverse
Events (CTCAE, version 3.0).
4. Statistical analysis
Estimates of median PFS and OS were calculated using the
Kaplan-Meier method, and 95% CIs were considered stat-
istically significant. All statistical analysis was done using
SPSS, version 11.0.
RESULTS
1. Patient characteristics
Between July 2007 and March 2010, all twenty-one pa-
tients who had metastatic RCC with a clear-cell component
were included in the analysis (Table 1, 2). There were 17
males (81%) and 4 females (19%), and the median age was
63.9 (range, 46-75 years). Of those patients, 4 patients
(19.0%) had low-risk disease, 10 patients (47.6%) had inter-
mediate-risk disease, and 7 patients (33.3%) had high-risk
disease according to the MSKCC criteria. The previous
treatments were as follows: previous nephrectomy in 13 pa-
tients (61.9%), cytokine therapy in 7 patients (33.3%), and
radiation therapy in 3 patients (14.3%). The most preva-
lent sites of metastases were as follows: the lung in 15 pa-
tients (71.4%), lymph nodes in 9 patients (42.9%), bone in
7 patients (33.3%), and liver in 3 patients (14.3%).
2. Treatment outcomes
After a median of 17.4 months (range, 5.7-33.1 months) of
treatment, 14 patients (66.7%) remained alive with the dis-
ease, and treatment was ongoing in 11 patients (52.4%).
Reasons for discontinuing treatment were progressive dis-
ease in 2 patients and adverse events in 1 patient. Accor-
ding to assessment with the RECIST criteria, 11 patients
(52.4%) had an objective response rate, with a complete re-
sponse in 1 patient (4.8%), and a partial response in 10 pa-
tients (47.6%) as the best tumor response rate (Table 3). The
median PFS was 13.4 months (95% confidence interval
[CI], range, 12.3-14.5 months) (Fig. 1), and the median OS
was 28.1 months (95% CI, 21.8-34.4 months) (Fig. 2).
3. Adverse events
All patients experienced adverse events of some sort: fa-

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Efficacy and Safety of Sunitinib on Metastatic RCC
453
FIG. 2. Overall survival in Korean patients with metastatic
clear-cell renal-cell carcinoma.
TABLE 4. Treatment-related adverse events and laboratory
abnormalities
Adverse events
No. of all
gradesa (%)
No. of grade
3 or 4 (%)
Treatment-related adverse events
Fatigue
Diarrhea
Hand-foot syndrome
Nausea/vomitting
Facial edema
Generalized edema
Dyspepsia
Stomatitis/mucositis
Rash
Skin discoloration
Constipation
Hypertension
Alopecia
Laborayory abnormalities
Neutropenia
Hepatic dysfunction
Anemia
Increased amylase/lipase
Thrombocytopenia
Renal insufficiency
Hyponatremia
Hypernatremia
Hyperkalemia
Hypokalemia
Hypothyroidism
13 (61.9)
12 (57.1)
12 (57.1)
10 (47.6)
9 (42.9)
7 (33.3)
7 (33.3)
6 (28.6)
6 (28.6)
4 (19.0)
4 (19.0)
2 (9.5)
1 (4.8)
3 (14.3)
0 (0)
4 (19.0)
0 (0)
0 (0)
1 (4.8)
0 (0)
0 (0)
2 (9.5)
3 (14.3)
0 (0)
0 (0)
0 (0)
9 (42.9)
8 (38.1)
7 (33.3)
7 (33.3)
5 (23.8)
4 (19.0)
3 (14.3)
2 (9.5)
2 (9.5)
1 (4.8)
1 (4.6)
6 (28.6)
1 (4.8)
4 (19.0)
0 (0)
6 (28.6)
3 (14.3)
2 (9.5)
0 (0)
0 (0)
1 (4.8)
0 (0)
a: adverse effects were graded according to the National Cancer
Institute Common Terminology Criteria for Adverse Events
ver. 3.0
tigue, diarrhea, and hand-foot syndrome were the most
common adverse effects. However, the treatment protocol
under study was well tolerated and most patients experi-
enced reversible grade 1 or 2 toxicities (Table 4). The most
commonly observed severe adverse events were hand-foot
syndrome, fatigue, and generalized edema; hand-foot syn-
drome was observed in 4 patients (19.0%), fatigue was ob-
served in 3 patients (14.3%), and generalized edema was
observed in 3 patients (14.3%) as grade 3 or 4.
　The most common laboratory abnormalities of grade 3
or 4 were neutropenia, thrombocytopenia, and anemia,
with neutropenia in 6 patients (28.6%), thrombocytopenia
in 6 patients (28.6%), and anemia in 4 patients (19.0%).
Neutropenia was observed in 6 patients (28.6%), but there
was no occurrence of associated fever or sepsis. Thrombocy-
topenia was observed in 6 patients (28.6%), but there was
no clinical significance such as bleeding tendencies. 1 pa-
tient (4.8%) experienced hypothyroidism and needed thy-
roid hormone replacement. A total of 6 patients (29%) re-
quired dose reduction from 50 mg/day to 37.5 mg/day with
further reductions to 25 mg/day due to grade 3 or 4 adverse
events, and 1 patient (4.8%) discontinued treatment due
to severe adverse events. The remaining 14 patients
(66.7%) tolerated and continued treatment with a standard
dose of sunitinib.
DISCUSSION
RCC is one of the most challenging malignancies with a dis-
mal prognosis because of the modest response to conven-
tional cytotoxic chemotherapeutic agents and limited sen-
sitivity to radiation therapy [14]. Cytokine therapy with in-
terferon-alfa or IL-2 have been the main treatment options
for metastatic disease, but these agents have limited effi-
cacy and are associated with considerable toxic effects.
Recent advances in understanding the molecular biology
of RCC have led to the development of several systemic
therapeutic agents targeting the VEGF and mammalian
target of rapamycin (mTOR) pathways as first and second
line treatments for metastatic disease, with impressive im-
provements in oncologic outcome [11,15].
　Sunitinib is one of several agents, including sorafenib,
bevacizumab, and temsirolimus, which target the in-
hibition of pro-angiogenic growth factor activity and have
shown favorable results in clinical trials against meta-
static clear-cell RCC [15-17]. Recent studies have con-
firmed the efficacy of sunitinib as a first line treatment for
metastatic clear-cell RCC [10,11], but these series were
mainly performed in different ethnicities in Western
countries. Thus, the potential ethnic differences in the effi-
cacy and safety of sunitinib have not been established. This
study evaluated whether Korean patients with metastatic
RCC had comparable oncologic outcomes and safety as pa-
tients in previous randomized studies.
　In patients with a poor prognosis according to the
MSKCC criteria, temsirolimus is recommended as a
first-line treatment, with sunitinib as a viable alternative
[18], but temsirolimus is not available for Korean patients
because of problems related to the insurance system; more
patients with poor prognostic factors were included in this
study. In terms of he MSKCC criteria, 33.3% of patients
were in the poor prognosis group. Considering the selection

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Hwang et al
bias of randomized controlled trials which include rela-
tively more favorable or intermediate risk group, the re-
sults of this study seem to reflect more reliable results in
Korean clinical practice.
　For the treatment outcome, sunitinib treatment showed
an objective response rate of 39% (range, 34-44%) and a
PFS of 11.0 months (range, 10.7-13.4 months) as well as an
OS of 26.4 months (range, 23.0-32.9 months) in previous
phase III randomized trials [10,11]. In the current study,
the objective response rate was 52.4%, which included a
complete response of 4.8%, and a partial response of 47.6%
as the best response rates. The median PFS and OS were
13.4 months and 28.1 months, respectively. Even though
it is difficult to directly compare this retrospective study
with previous randomized trials, it is obvious that meta-
static RCC patients benefitted from sunitinib treatment.
　All patients experienced treatment-related adverse
events, the majority of which were grade 1 or 2 in severity.
Fatigue, diarrhea, and hand-foot syndrome were the most
frequent adverse events, but grade 3 or 4 adverse events
were not frequent and were manageable. Most of patients
were able to resume sunitinib treatment following dose re-
duction, and only 1 patient among all cases discontinued
because of serious adverse events. Previous trials have re-
ported that side effects of sunitinib treatment were rever-
sible and tolerable; patients with grade 3 or 4 side effects
did not exceed 10% [10,11].
　Nevertheless, routine monitoring such as evaluation of
blood pressure/ejection fraction and a thyroid function test
is recommended because there is possibility of serious ad-
verse events. Emerging safety data indicate that cardiotox-
icity may be associated with sunitinib; left ventricular dys-
function is the main cardiac side effect of sunitinib and
might be partly a result of cardiomyocyte toxicity ex-
acerbated by hypertension [19]. Therefore, blood pressure
and left ventricular ejection fraction should be monitored,
especially in patients with cardiac risk factors. It is re-
ported that in patients treated with sunitinib, 85% of pa-
tients had abnormal results on thyroid function tests, in-
cluding elevation of thyroid stimulating hormone levels,
decreased T3 levels, and less commonly, decreased T4 or
free-thyroxine index levels [20]. Because an abnormal thy-
roid function test may rapidly progress from mild to pro-
found, regular surveillance is warranted at baseline and
every 2-3 months [21].
　In terms of adverse events, neutropenia, thrombocytope-
nia, and anemia were the most frequent grade 3 or 4 labo-
ratory abnormalities reported previously [10,11], and most
of them were improved by dose reduction. Neutropenia was
observed in 6 patients (28.6%), but there was no event of
associated fever or sepsis; thrombocytopenia was observed
in 6 patients (28.6%), but there was no clinical significance
such as bleeding tendencies; anemia increased amylase/li-
pase was observed in 7 patients (33.3%), but there were no
associated clinical manifestations of pancreatitis.
　Compared to Western trials, sunitinib treatment in
Korean patients achieved favorable oncological outcomes
in terms of objective response rate, PFS, and OS. It is inter-
esting to note that the favorable outcomes of the current
study are consistent with previous Korean studies [22,23].
Although the underlying reason for such a discrepancy re-
mains unclear at this time, one possible explanation is the
inherent differences caused by ethnic backgrounds. Fur-
ther large prospective studies are required to clarify
whether the ethnic background and its associated molec-
ular mechanisms contribute to the difference in the efficacy
of sunitinib across ethnic groups. In terms of adverse ef-
fects, a higher incidence of hand-foot syndrome and fa-
cial/generalized edema were observed relative to Western
trials, but they were mainly mild to moderate, and man-
aged readily.
　There are some limitations to this analysis. This was a
retrospective analysis of a small number of patients treat-
ed at a single institution, which allows for potential se-
lection bias. Furthermore, survival benefit may not be
weighted properly because this was not a randomized con-
trolled trial. However, this study provides evidence of the
clinical benefits of sunitinib treatment. Sunitinib was effi-
cacious and was well tolerated in Korean patients; the ob-
jective response rate, PFS, and OS in Korean patients were
compatible with the oncologic outcomes in previous
randomized trials. Further large prospective inves-
tigations are required to clarify such favorable efficacy pro-
files in Korean patients.
CONCLUSIONS
Sunitinib was efficacious in the treatment of metastatic
clear-cell RCC, and was well tolerated in Korean patients.
The objective response rate, PFS, and OS in Korean pa-
tients were compatible with the benefits shown in previous
randomized trials. Although sunitinib treatment-related
adverse events such as hand-foot syndrome and facial/gen-
eralized edema were observed in higher incidence than in
Western trials, they were mainly mild to moderate, and
readily managed. This study encourages the target ther-
apy of sunitinib in Koreans for metastatic RCC.
Conflicts of Interest
The authors have nothing to disclose.
REFERENCES
1. Parkin DM, Bray F, Ferlay J, Pisani P. Global cancer statistics,
2002. CA Cancer J Clin 2005;55:74-108.
2. Lam JS, Leppert JT, Belldegrun AS, Figlin RA. Novel approaches
in the therapy of metastatic renal cell carcinoma. World J Urol
2005;23:202-12.
3. Motzer RJ, Russo P, Nanus DM, Berg WJ. Renal cell carcinoma.
Curr Probl Cancer 1997;21:185-232.
4. Janzen NK, Kim HL, Figlin RA, Belldegrun AS. Surveillance af-
ter radical or partial nephrectomy for localized renal cell carcino-
ma and management of recurrent disease. Urol Clin North Am
2003;30:843-52.
5. Law TM, Motzer RJ, Mazumdar M, Sell KW, Walther PJ,