Vol.3, No.2, 86-92 (2011) Health
doi:10.4236/health.2011.32016
Copyright © 2011 SciRes. Openly accessible at http://www.scirp.org/journal/HEALTH/
Sorafenib for advanced renal cell carcinoma in real-life
practice: a literature review*
Steven Simoens
Research Centre for Pharmaceutical Care and Pharmaco-economics, Katholieke Universiteit Leuven, Leuven, Belgium;
Received 3 November 2010; revised 12 January 2011; accepted 17 January 2011
ABSTRACT
Sorafenib is a new treatment indicated for pa-
tients with advanced renal cell carcinoma who
have failed prior cytokine-based therapy or are
considered unsuitable for such therapy. Al-
though treatment with sorafenib under ‘ideal
trial conditions’ has been extensively studied,
registration and reimbursement authorities are
also interested in the behavior of sorafenib in
real-life practice. This study aims to conduct a
literature review of the dosage and treatment
duration; safety, tolerability and effectiveness;
costs and cost-effectiveness of sorafenib in
routine clinical care. Studies were identified by
searching PubMed, Embase, Centre for Reviews
and Dissemination databases, Cochrane Data-
base of Systematic Reviews, and EconLit up to
November 2010. The literature search included
articles published in peer-reviewed journals,
congress abstracts, and internal studies of
Bayer Schering Pharma. Eight studies were in-
cluded. An open-label study observed stable
disease for at least eight weeks in 80% of pa-
tients. The most common drug-related adverse
events were hand-foot skin reaction, rash, hy-
pertension, and fatigue. Although treatment
with sorafenib led to fewer dose reductions, it
was also associated with a shorter treatment
duration, less time to progression and a shorter
survival time as compared to sunitinib. Monthly
health care costs were lower with sorafenib as
compared to sunitinib. A post-marketing sur-
veillance study showed that patients rated the
tolerability and effectiveness of sorafenib as
very good, good or sufficient. In conclusion, the
current evidence is too limited to derive con-
clusions and existing studies suffer from me-
thodological shortcomings.
Keywords: Sorafenib; Advanced Renal Cell
Carcinoma; Real-Life Practice; Literature Revie w
1. INTRODUCTION
Renal cell carcinoma (RCC) accounts for approxi-
mately 2% of all cancer cases [1]. It is the most common
form of kidney cancer and 25%–30% of patients present
with advanced (metastatic) disease at time of diagnosis.
An epidemiological literature review reported an annual
incidence of advanced RCC in major European countries,
the United States and Japan ranging from 1,500 to 8,600
cases [2]. The economic burden of advanced RCC has
been estimated at $107–$556 million in the United
States in 2006 [2].
Advanced RCC is a treatment-resistant malignancy:
patients who present with advanced disease have a poor
prognosis and median survival after diagnosis is less
than one year. Few effective therapeutic options are
available [3]. Surgery has limited or no effect. Cytokines,
which have been the mainstay of therapy for RCC, are
associated with significant toxicities. High dose inter-
leukin-2 provides clinical benefit to a relatively small
percentage of patients and has a significant toxicity pro-
file. Interferon alpha is associated with a modest re-
sponse rate and limited tolerability for many patients.
For patients who fail cytokine therapy or for whom these
therapies are not suitable, therapeutic options are limited.
Therefore, the need for new and more effective therapies
is high.
Treatment of advanced RCC may benefit from novel
agents, such as molecularly targeted therapies. One such
therapy, sorafenib (Nexavar®), is indicated for patients
with advanced RCC who have failed prior cyto-
kine-based therapy or are considered unsuitable for such
therapy [4]. In preclinical models, sorafenib decreased
angiogenesis through upstream inhibition of receptor
tyrosine kinases Vascular Endothelial Growth Factor
Receptor (VEGFR) and Platelet Derived Growth Factor
Receptor (PDGFR) as well as serine/threonine kinases in
*Financial support was received from Bayer Schering Pharma.

S. Simoens / Health 3 (2011) 86-92
Copyright © 2011 SciRes. Openly accessible at http://www.scirp.org/journal/HEALTH/
8787
the RAF/MEK/Extracellular signal Regulated Kinase
(RAF/MEK/ERK) pathway. Sorafenib also decreased
tumor cell proliferation through upstream inhibition of
receptor tyrosine kinases KIT and Fms like Tyrosine
Kinase 3 (FLT-3) [5-7].
In a randomized discontinuation Phase II study, pa-
tients with metastatic malignancies, including RCC pa-
tients with stable disease on sorafenib therapy, were
randomized to placebo or continued sorafenib therapy
[8]. Progression-free survival in patients with RCC was
significantly longer in the sorafenib group (163 days)
than in the placebo group (41 days) (p = 0.0001, hazard
ratio = 0.30).
In the largest, international, Phase III study in ad-
vanced RCC, the Treatment Approaches in Renal Cancer
Global Evaluation Trial [TARGET] [9], sorafenib dou-
bled median progression-free survival, 24 weeks versus
12 weeks, as compared with placebo (p < 0.000001; haz-
ard ratio = 0.40; 95% confidence interval: 0.40-0.55).
Age, Memorial Sloan-Kettering Cancer Center (MSKCC)
prognostic group, Eastern Cooperative Cancer Group
Performance Status (ECOG PS) and prior therapy did
not significantly affect the treatment effect size. In the
second interim analysis for overall survival, the median
survival was 19.3 months for patients randomized to
sorafenib as compared to 15.9 months for placebo pa-
tients (hazard ratio = 0.77; 95% confidence interval:
0.63-0.95; p = 0.015). This second interim analysis was
conducted following cross-over from placebo patients to
active treatment at the recommendation of the data
monitoring committee. The most common drug-related
adverse events associated with sorafenib therapy are
diarrhea, rash, alopecia and hand-foot skin reaction [4].
Treatment of advanced RCC with sorafenib under
“ideal trial conditions” has been extensively studied.
Literature studies have reviewed the pharmacodynamic
and pharmacokinetic profile, therapeutic efficacy, toler-
ability, dosage and administration of sorafenib [10-12].
The cost-efficacy has been assessed in a number of eco-
nomic evaluations [13]. In addition to such evidence,
registration and reimbursement authorities are interested
in the behavior of a drug in real-life practice, its effec-
tiveness and cost-effectiveness. Such data provide evi-
dence of the impact of a drug when for example patients
do not fulfill the inclusion criteria for randomized con-
trolled trials or do not fully comply with pharmacother-
apy.
The aim of this study is to conduct a review of the in-
ternational literature examining the treatment of ad-
vanced RCC with sorafenib in routine clinical care. The
literature study focuses specifically on the dosage and
treatment duration; safety, tolerability and effectiveness;
costs and cost-effectiveness of sorafenib. The findings
may serve to aid local decision-makers in allocating
scarce health care resources and to inform the prescrib-
ing behavior of physicians.
2. METHODS
2.1. Search Strategy
Studies were identified by searching PubMed, Embase,
Centre for Reviews and Dissemination databases (Data-
base of Abstracts of Reviews of Effects, National Health
Service Economic Evaluation Database, and Health
Technology Assessments Database), Cochrane Database
of Systematic Reviews, and EconLit up to November
2010. Additionally, the bibliography of included studies
was checked for other relevant studies. Search terms
included ‘renal cell carcinoma’, ‘kidney cancer’, ‘ad-
vanced’, ‘metastatic’, ‘nexavar’, ‘sorafenib’, ‘dosage’,
‘treatment duration’, ‘safety’, ‘tolerability’, ‘effective-
ness’, ‘costs’, ‘cost-effectiveness’, ‘economic evalua-
tion’, ‘real life’, ‘routine clinical care’ alone and in com-
bination with each other.
The literature search included articles published in
peer-reviewed journals. Relevant congress abstracts
were identified by searching the congress database of the
American Society of Clinical Oncology and the Out-
comes Research Digest, an electronic database of ab-
stracts presented at conferences of the International So-
ciety of Pharmacoeconomics and Outcomes Research.
Finally, Bayer Schering Pharma was contacted for any
unpublished studies.
2.2. Inclusion and Exclusion Criteria
The review was limited to the use of sorafenib in ad-
vanced RCC. Other registered indications (i.e. hepato-
cellular carcinoma) fell outside the scope of this study.
The literature review included studies on the treatment
of advanced RCC with sorafenib in real-life practice.
Clinical studies exploring the safety, tolerability and
efficacy of sorafenib under “ideal trial conditions” were
excluded. Cost studies were included if they compared
health care and/or other costs of sorafenib and an alter-
native treatment for advanced RCC. Evidence about
cost-effectiveness was derived from economic evalua-
tions. An economic evaluation was defined as a study
comparing sorafenib with an alternative treatment in
terms of both costs and consequences [14]. Economic
evaluations were excluded if treatment of advanced RCC
did not involve sorafenib or if studies analyzed a single
intervention without a comparator.
The review was limited to studies published in Eng-
lish, French, Dutch, or German for practical reasons.

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88
3. RESULTS
3.1. Search Results
Few studies have focused on the treatment of ad-
vanced RCC with sorafenib in real-life practice. The
researcher identified 89 citations, but only eight studies
were included in the review: two studies exploring dos-
age and treatment duration [15,16], two pre-marketing
surveillance studies [17,18] and one post-marketing sur-
veillance study [19], two analyses of a claims database
[20,21], and one economic evaluation [22]. The charac-
teristics of included studies are presented in Table 1.
3.2. Dosage and Treatment Duration
A retrospective analysis of a US claims database in-
vestigated dose-reduction patterns in patients with pri-
mary or advanced RCC treated with sorafenib or sunit-
inib [16]. The initial daily dosage was sorafenib 800 mg
or sunitinib 50 mg. Demographic characteristics were
similar between the two groups, except for a higher in-
cidence of stroke (7.9% vs 3.6%, p = 0.037) and other
cancer site (93.7% vs. 87.8%, p = 0.036) in the sorafenib
group. Significantly more patients receiving sunitinib
required dose reductions as compared with sorafenib
(35.5% vs 16.9%; p < 0.001). Significantly more dose
reductions occurred within the first three months with
sunitinib than with sorafenib (65% vs. 25%, p < 0.001).
The mean time to dose reduction was significantly long-
er for sorafenib than sunitinib (162 days vs 104 days, p =
0.003). These findings show that more dose reductions
were required in patients who initially received sunitinib
than in those who received sorafenib.
An Israeli study explored treatment duration and sur-
vival in patients with advanced RCC receiving first-line
treatment with either sorafenib or sunitinib [15]. Demo-
graphic and claims data were extracted from a health
services database. Treatment duration and patient sur-
vival were calculated and compared using a Kap-
lan-Meier analysis. The sample included 134 patients
receiving sunitinib and 29 patients receiving sorafenib.
There were no differences in demographic characteris-
tics between patient groups. Mean treatment duration
was 8.0 months (95% CI 6.8-9.0) and 5.7 months (95%
CI 3.8-7.8) for sunitinib and sorafenib, respectively (p =
0.071). Mean survival time amounted to 11.3 months
(95% CI 10.4-12.2) and 8.1 months (95% CI 6.1-10.1)
for sunitinib and sorafenib, respectively (p = 0.023). It
should be noted that this analysis enrolled a small num-
ber of patients receiving sorafenib. Also, future analyses
must control for patient clinical characteristics, which
may have been a major factor in treatment preferences,
and might have influenced treatment duration and sur-
vival.
3.3. Safety, Tolerability and Effectiveness
A non-randomized, open-label expanded access pro-
gramme included 2,504 patients from the United States
and Canada who were treated with oral sorafenib 400
mg twice daily [18]. This programme provided access to
sorafenib prior to regulatory approval and did not im-
pose strict patient inclusion criteria. The most common
drug-related adverse events were hand-foot skin reaction
(18%), rash (14%), hypertension (12%), and fatigue
(11%). Stable disease for at least eight weeks was ob-
served in 80% of patients, partial response in 4% of pa-
tients, and complete response in one patient. Median
progression-free survival amounted to 36 weeks (95%
confidence interval: 33-45 weeks) and median overall
survival was 50 weeks (95% confidence interval: 46-52
weeks). An additional analysis did not observe any sub-
stantial differences in safety and effectiveness of soraf-
enib between patients aged ≥70 and <70 years [17].
A prospective, open-label, non-interventional, non-
controlled, multicenter, observational Phase IV trial
evaluated the effectiveness and safety of sorafenib
treatment under daily-life conditions in Belgium [19]. A
small sample of 41 patients was enrolled from 32 study
centers. Twenty-four patients discontinued the study
prematurely. The reason indicated most frequently was
disease progression (11 patients). Only 34 and 15 pa-
tients could be evaluated after one and three months of
observation, respectively. The effectiveness of sorafenib
was judged sufficient, good or very good (as opposed to
‘insufficient’) for most patients after one month and after
three months. The proportion of progression-free pa-
tients was 0.56 (95% confidence interval: 0.38-0.73)
after one month and 0.73 (95% confidence interval:
0.45-0.92) after three months. The proportion tended to
increase over time, though the fact that these proportions
were calculated over the patients still observed (i.e. the
“healthier” patients) could explain this trend. The toler-
ability was judged very good, good or sufficient for 71%
of patients after one month and 67% of patients after
three months. All patients experienced at least one ad-
verse event, ten patients experienced at least one serious
adverse event. Among the reported adverse events, there
were eight patients with diarrhea, six patients with ano-
rexia, five patients with hand foot skin reaction and five
patients with rash. These adverse events are known side
effects of sorafenib [4].
3.4. Costs
Based on an analysis of a US claims database, a retro-
spective study quantified the health care costs of patients

S. Simoens / Health 3 (2011) 86-92
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8989
Table 1. Characteristics of studies included in literature review.
Country Sample Design InterventionsMeasures Results Conclusions
Dosage and treatment duration
United States
[16]
Patients with
primary or
advanced renal
cell carcinoma
Retrospective
study of claims
database
Sorafenib 800
mg; sunitinib
50 mg
Number of dose
reductions; time to
dose reduction
Significantly more patients receiv-
ing sunitinib required dose reduc-
tions as compared with sorafenib
(35.5% vs 16.9%; p < 0.001). Sig-
nificantly more dose reductions
occurred within the first three
months with sunitinib than with
sorafenib (65% vs. 25%, p < 0.001).
The mean time to dose reduction
was significantly longer for soraf-
enib than sunitinib (162 days vs
104 days, p = 0.003).
Significantly more
dose reductions were
required in patients
who initially received
sunitinib than in those
who received
sorafenib.
Israel [15]
163 patients with
advanced renal
cell carcinoma
Retrospective
study of claims
database
Sorafenib;
sunitinib
Treatment
duration; survival
time
Mean treatment duration was 8.0
months (95% CI 6.8-9.0) and 5.7
months (95% CI 3.8-7.8) for sunit-
inib and sorafenib, respectively (p =
0.071). Mean survival time amounted
to 11.3 months (95% CI 10.4-12.2)
and 8.1 months (95% CI 6.1-10.1)
for sunitinib and sorafenib, respec-
tively (p = 0.023).
Treatment duration
and survival time were
longer for patients
treated with sunitinib
than for patients
treated with sorafenib.
Safety, tolerability and effectiveness
United States
and Canada
[17,18]
2,504 patients
with renal cell
carcinoma
A
non-randomized,
open-label study
Sorafenib 800
mg
Incidence of
drug-related
adverse events;
treatment
response;
progression-free
and overall
survival.
Drug-related adverse events were
hand-foot skin reaction (18%), rash
(14%), hypertension (12%), fatigue
(11%). Stable disease for at least
eight weeks was seen in 80% of
patients, partial response in 4% of
patients, complete response in 1
patient. Median progression-free
survival was 36 weeks (95% con-
fidence interval: 33-45 weeks) and
median overall survival was 50
weeks (46-52 weeks). There were
no difference in safety and effec-
tiveness between patients aged ≥70
and <70 years.
The safety and
effectiveness of
sorafenib treatment
was in line with data
reported in the
sorafenib drug
information leaflet.
Belgium [19]
41 patients with
advanced renal
cell carcinoma
A prospective,
open-label,
non-interventiona
l, non-controlled,
multicenter,
observational
Phase IV trial
Sorafenib 800
mg
Number of
progression-free
patients;
tolerability,
num
b
er of patients
experiencing
adverse events
The proportion of progression-free
patients was 0.56 (95% confidence
interval: 0.38-0.73) after one month
and 0.73 (95% confidence interval:
0.45-0.92) after three months. The
tolerability was judged very good,
good or sufficient for 71% of pa-
tients after one month and 67% of
patients after three months. All
patients experienced at least one
adverse event, ten patients experi-
enced at least one serious adverse
event.
The effectiveness of
sorafenib was judged
to be sufficient or
better by the majority
of patients. The
reported adverse
events were known
side effects of
sorafenib.
Costs
United States
[21]
364 patients with
primary or
advanced renal
cell carcinoma
under 65 years
of age
Retrospective
study of claims
database
Sorafenib;
sunitinib
Health care costs
(e.g. inpatient,
outpatient,
pharmacy costs)
Total monthly health care costs for
the sunitinib group were signifi-
cantly greater than for the sorafenib
group ($9,476 vs. $7,426, p <
0.01), representing an annual extra
cost of $24,588 for sunitinib as
compared with sorafenib. Incre-
mental monthly inpatient, phar-
macy and outpatient costs were
$861 (p = 0.01), $889 (p < 0.01),
and $300 (p = 0.14) for sunitinib as
compared with sorafenib.
Initial therapy with
sunitinib was more
expensive than
sorafenib in patients
with primary or ad-
vanced RCC under 65
years of age.

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United States
[20]
321 patients with
advanced renal
cell carcinoma
Retrospective
study of claims
database
Intravenous
bevacizumab;
sorafenib;
sunitinib
Health care costs
(e.g. inpatient,
outpatient,
pharmacy costs)
Total mean health care costs
amounted to $13,351, $6,998, and
$8,213 per patient per month for
bevacizumab, sorafenib and sunit-
inib, respectively (p < 0.05).
Health care costs of
sorafenib treatment
were lower than those
of treatment with
bevacizumab or
sunitinib.
Cost-effectiveness
Czech Repub-
lic [22]
31 patients with
advanced renal
cell carcinoma
Economic
evaluation based
on cohort study
Sorafenib;
sunitinib
Adverse events;
time to
progression; costs
to progression;
mortality
The main adverse events were skin
toxicity, oedema, arthralgia and
other pain. The mean time to pro-
gression was 8.3 months with
sorafenib and 10.4 months with
sunitinib. The mean cost to pro-
gression was €1,069 with sorafenib
and €1,566 with sunitinib. Nine
patients died.
The analysis of direct
medical costs in
patients with advanced
renal cell carcinoma
proved high costs
concerned with
multikinase inhibitors´
therapy.
with primary or advanced RCC who are privately in-
sured and are aged under 65 years [21]. Health care costs
included inpatient, outpatient and pharmacy costs. The
sample consisted of 144 patients receiving sorafenib and
220 patients receiving sunitinib as initial therapy. At
baseline, demographic characteristics between the two
patient groups were similar. Total monthly health care
costs for the sunitinib group were significantly greater
than for the sorafenib group ($9,476 vs. $7,426, p <
0.01), representing an annual extra cost of $24,588 for
sunitinib as compared with sorafenib. Incremental
monthly inpatient, pharmacy and outpatient costs were
$861 (p = 0.01), $889 (p < 0.01), and $300 (p = 0.14) for
sunitinib as compared with sorafenib. This analysis
showed that initial therapy with sunitinib was more ex-
pensive than sorafenib in patients with primary or ad-
vanced RCC aged under 65 years.
A US retrospective claims database analysis quanti-
fied the incremental costs associated with intravenous
administration of bevacizumab as compared to sunitinib
or sorafenib for the treatment of advanced RCC [20].
Patients receiving bevacizumab (n = 109) were matched
1:1 to patients receiving sorafenib or sunitinib. Drug,
inpatient, outpatient and pharmacy costs were calculated
per patient per month. Total mean health care costs
amounted to $13,351, $6,998, and $8,213 per patient per
month for bevacizumab, sorafenib and sunitinib, respec-
tively (p < 0.05). Assuming a median progression-free
survival of 8.5 months as shown for bevacizumab, the
incremental costs would be estimated at $39,188-42,080
per patient as compared to those treated with sorafenib
or sunitinib.
3.5. Cost-effectiveness
An economic evaluation assessed the cost-effectiveness
of sorafenib and sunitinib in routine clinical care in the
Czech Republic from a health care payer perspective
[22]. Disease progression and costs (i.e. drugs, labora-
tory tests and hospitalization) were assessed every two
months. Seventeen patients started therapy with sunitinib,
eight of whom converted to sorafenib after progression.
Three patients discontinued sunitinib therapy due to ad-
verse events. Fourteen patients started sorafenib therapy,
two of whom converted to sunitinib due to adverse
events. Two other patients converted to sunitinib fol-
lowing progression. The main adverse events were skin
toxicity, oedema, arthralgia and other pain. The mean
time to progression was 8.3 months with sorafenib and
10.4 months with sunitinib. The mean cost to progres-
sion was €1,069 with sorafenib and €1,566 with sunit-
inib. Nine patients died. Cost and outcome measures
were not combined into an incremental cost-effectiveness
ratio.
4. DISCUSSION
This article has conducted a literature review of the
treatment of advanced RCC with sorafenib in routine
clinical care. The evidence is too limited to derive con-
clusions and studies suffer from methodological short-
comings. The current evidence base is restricted to a few
studies presented at international conferences, one
peer-reviewed article and one internal study of Bayer
Schering Pharma. Furthermore, as advanced RCC is an
orphan disease, the majority of studies suffered from
small sample sizes.
Existing studies have primarily compared treatment
with sorafenib or with sunitinib. Although treatment with
sorafenib led to fewer dose reductions, it was also asso-
ciated with a shorter treatment duration, less time to
progression and a shorter survival time as compared to
sunitinib. Monthly health care costs were lower with
sorafenib as compared to sunitinib. A post-marketing
surveillance study showed that patients rated the toler-
ability and effectiveness of sorafenib as very good, good
or sufficient, although this study suffered from a small
sample size and limited time horizon.

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9191
To date, little is known about the (cost-) effectiveness
of sorafenib as compared with other approaches to treat
advanced RCC in routine clinical care. Although analy-
ses based on cohort studies, case-control studies, or be-
fore-and-after studies may suffer from a number of bi-
ases and do not always establish a causal relationship,
such studies would provide information about the safety,
tolerability, and effectiveness of sorafenib in real-life
practice. Information derived from such studies could be
integrated with cost information to conduct an economic
evaluation of the cost-effectiveness of sorafenib as
compared with other approaches to treat advanced RCC.
It is important to examine the impact of a drug in
real-life practice. Registration authorities wish to gain
insight into the health gain of the drug in real-life pa-
tients, to identify rare adverse events, to explore the ef-
fectiveness in the long run, or to study the drug as a
treatment for other diseases. Also, reimbursement au-
thorities in some countries grant conditional reimburse-
ment to a drug based on its cost-efficacy, while final
reimbursement is granted based on its cost-effectiveness
after the drug has been on the market for a number of
years. For instance, on 1st April 2007, Belgian reim-
bursement authorities conditionally approved the reim-
bursement of sorafenib treatment for advanced RCC for
a period of three years. The sponsor was obliged to sub-
mit complementary observational data including clinical
and economic data within 1.5 to 3 years after conditional
approval. Final reimbursement approval was granted in
August 2010.
One instrument to sustain the ongoing evaluation of a
drug may be the implementation of patient registries
designed to collect the necessary data to follow up and
evaluate uncertainties surrounding the longer-term effec-
tiveness and cost-effectiveness of a drug [23]. The use of
patient registries would support the decision-making
process, inform clinical practice, and could provide in-
formation about long-term adverse events. However,
patient registries have their limitations. A patient registry
may be biased if the patient aetiology and disease sever-
ity change over time. Also, patient registries tend to col-
lect data on a specific drug, but not on alternative treat-
ments, thus providing partial information to calculate the
cost-effectiveness of the drug relative to an alternative
treatment. Furthermore, new treatment strategies may
become available during the period covered by the reg-
istry. Therefore, patient registries need to be set up in a
flexible way to collect sufficient data and to account for
the evolution in patient population and treatment strate-
gies over their lifetime.
5. ACKNOWLEDGEMENTS
The author has no conflicts of interest that are relevant to the content
of this manuscript
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