Sunitinib is superior to interferon alpha with respect to quality of life for patients with renal cell carcinoma.

Abstract

Randomized trials have shown that both anti-vascular endothelial growth factor (VEGF) therapy and inhibition of the mammalian target of rapamycin have superior clinical efficacy when compared with interferon alpha in the first-line treatment of advanced renal cell carcinoma. In 2007, a pivotal phase III trial randomly allocated 750 patients with advanced renal cell carcinoma to receive either the VEGF-receptor tyrosine kinase inhibitor sunitinib or interferon alpha, and showed that sunitinib led to improved response rates, progression-free and overall survival. In this Practice Point, we discuss the data reported by Cella et al., which showed that the quality of life of patients in this trial was better with sunitinib than interferon alpha; these differences were predominantly due to better control of disease-related symptoms by sunitinib. This landmark study is the first to report comparative quality-of-life data for an anti-VEGF therapy and a cytokine therapy.

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? nature clinical practice oncology january 2009 vol 6 no 1
www.nature.com/clinicalpractice/onc
cOMMentarY
Renal cell carcinoma (RCC) accounts for 13,000
deaths per year in the US, and advanced disease is
associated with a 5-year survival of less than 10%.
The goal of systemic therapy in the management
of advanced solid malignancies is largely pallia-
tive, with a focus on maximizing duration of life,
progression-free interval and the duration of
good symptom control. In randomized trials, the
anti-vascular endothelial growth factor (VEGF)
therapies bevacizumab, sorafenib and sunitinib,
and the inhibitors of the mammalian target of
rapamycin (mTOR) everolimus and temsiro-
limus, have been shown to prolong progression-
free survival and, in some cases, overall sur-
vival, compared with previous therapies.1–4
Sunitinib was the first agent to demonstrate
superiority compared with interferon α (IFN-α)
as first-line therapy for patients with advanced
RCC. This randomized, phase III study of 750
patients reported improvements in response
rate (31% versus 6%) and progression-free sur-
vival (11 months versus 5.5 months) for patients
who received sunitinib compared to those who
received IFN-α.1 An update has now reported
an overall survival benefit with sunitinib in a
censored population that excluded the 60% of
patients who received second-line treatment,
usually anti-VEGF therapy.2
SUMMARY
Randomized trials have shown that both anti-vascular endothelial growth factor (VEGF) therapy
and inhibition of the mammalian target of rapamycin have superior clinical efficacy when
compared with interferon α in the first-line treatment of advanced renal cell carcinoma. In 2007, a
pivotal phase III trial randomly allocated 750 patients with advanced renal cell carcinoma to
receive either the VEGF-receptor tyrosine kinase inhibitor sunitinib or interferon α, and showed
that sunitinib led to improved response rates, progression-free and overall survival. In this Practice
Point, we discuss the data reported by Cella et al., which showed that the quality of life of patients
in this trial was better with sunitinib than interferon α; these differences were predominantly due to
better control of disease-related symptoms by sunitinib. This landmark study is the first to report
comparative quality-of-life data for an anti-VEGF therapy and a cytokine therapy.
Keywords interferon α, quality of life, renal cell carcinoma, sunitinib, tyrosine kinase inhibitor
Cella et al. used several validated, patient-
reported questionnaires to evaluate quality
of life (QoL), which included the general
Functional Assessment of Cancer Therapy
(FACT-G) questionnaire, the 15-item Kidney
Symptom Index (FKSI-15) and Disease Related
Symptoms (FKSI-DRS), the EuroQol Group’s
EQ-5D and a visual analog scale (VAS).5 The
questionnaires assess symptoms including
fatigue, pain, weight loss, cough, fever and
hematuria, as well as physical, social, emotional
and functional well-being, self-care, usual
activities, pain or discomfort and anxiety or
depression. The assessments were completed
at screening, on days 1 and 28 of each 42-day
treatment cycle, and at the end of treatment
or study withdrawal. The study reported that
patients who received sunitinib had better QoL
than those who received IFN-α by all methods
evaluated. Sunitinib-treated patients had higher
FKSI-15 and FKSI-DRS scores at each cycle
than IFN-α-treated patients (P <0.0001), which
indicates a better QoL.5 Scores associated with
either agent actually dropped after cycle 1, but
those associated with sunitinib returned to, or
rose above, base-line, whereas those with IFN-α
remained below base-line throughout the study.
FACT-G and EuroQol scores were maintained
with sunitinib throughout the study period but
dropped significantly with IFN-α (FACT-G,
LM Pickering is a
Consultant in Medical
Oncology, L Pyle is a
Senior Research Nurse
and JMG Larkin
is a Consultant in
Medical Oncology
at the Department
of Medicine, Royal
Marsden Hospital,
London, UK.
Correspondence
*Department of Medicine
Royal Marsden Hospital
Fulham Road
London SW3 6JJ
UK
james.larkin@rmh.nhs.uk
Received 20 October 2008
Accepted 7 November 2008
www.nature.com/clinicalpractice
doi:10.1038/ncponc1283
Sunitinib is superior to interferon α
with respect to quality of life
for patients with renal cell carcinoma
Lisa M Pickering, Linda Pyle and James MG Larkin*
practice pOintpractice pOint

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january 2009 vol 6 no 1
nature clinical practice oncology ?
www.nature.com/clinicalpractice/onc
Competing interests
The authors have declared
associations with the
following companies: Bayer,
Novartis, Pfizer, Roche and
Schering-Plough. See the
article online for full details
of the relationships.
P <0.0001; EuroQol EG-5D, P = 0.0052; EuroQol
VAS, P <0.0001).5
Most QoL assessments in RCC have been per-
formed in trials of surgery or in trials comparing
immunotherapies. Few studies have addressed
QoL in the post-cytokine era of management
of advanced RCC. The only other randomized
trial to report QoL associated with an anti-
VEGF therapy was a placebo-controlled trial
in which 80% of the patients were treated in
the second-line setting6 and, therefore, is not
directly comparable. QoL evaluation by FKSI
and FACT-G showed no differences in mean
overall score between the two groups, although
sorafenib-treated patients reported significantly
fewer symptoms than placebo-treated patients.6
In 2008, two open-label case series assessed QoL
by the European Organisation for Research
and Treatment of Cancer Core Questionnaire
(EORTC QLQ-C30) tool in 51 and 52 patients
treated with sunitinib or sorafenib (study 1) or
axitinib (study 2), respectively.7,8 Both studies
described modest deterioration in QoL in the
first 4 weeks after initiation of therapy, with
a return to base-line by 16 weeks in the first
study.7,8 The only other reported phase III rando-
mized trials of first-line anti-VEGF therapy are
the AVOREN3 and CALGB 902069 trials in
which patients received IFN-α with or without
bevacizumab. Both trials reported toxicity but
neither has reported QoL data. Neither of these
randomized, placebo-controlled trials of mTOR
inhibitors has reported QoL data; however, in
a phase III study of everolimus versus placebo
in patients who had progressed following prior
anti-VEGF therapy, QoL was similar in both
treatment groups.4
The study reported by Cella et al., demon-
strates the superior QoL associated with sunitinib
compared with that of IFN-α in the first-line
setting.5 The authors are to be commended; this
study is the most comprehensive report of QoL
in any randomized trial of targeted therapies in
advanced RCC to date, with an impressive ques-
tionnaire completion rate in excess of 95%.5
The authors are clear about the limitations of the
study. For example, the outcome might have been
confounded by factors such as preference for oral
over subcutaneous administration. Adjustments
were not made for country of enrollment, sex,
age, ethnicity or base-line performance status;
however, these factors are unlikely to have
influenced the outcome significantly because
of the randomized nature of the study. The
authors assessed whether the superior QoL
associated with sunitinib related to superior
antitumor efficacy and symptom control or to
reduced drug-specific toxicity.5 Although they
were unable to reach a firm conclusion, the longi-
tudinal use of different QoL tools, particularly
their own FKSI, suggest that superior antitumor
efficacy is probably the most influential factor.
The study by Cella et al. provides robust evi-
dence that sunitinib maintains QoL more effec-
tively than IFN-α. Thus, the most important
outcome of this study for patients and practic-
ing renal oncologists is the added confidence it
brings to the already widely held view that suni-
tinib is not only more efficacious and better tol-
erated than IFN-α, but also leads to a better QoL.
Further robust QoL analyses are to be encour-
aged as clinical trials aim to determine the
optimal targets and regimens for the plethora of
agents becoming available for the treatment
of advanced RCC.
References
1 Motzer RJ et al. (2007) Sunitinib versus interferon alfa
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2 Figlin RA et al. (2008) Overall survival with sunitinib
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metastatic renal cell carcinoma (mRCC) [abstract
#5024]. J Clin Oncol 26 (suppl): 256S
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alfa-2a for treatment of metastatic renal cell carcinoma:
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2103–2111
4 Motzer RJ et al. (2008) Efficacy of everolimus in
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PrACTICe PoINT
In addition to its previously established response,
progression-free and overall survival benefits,
sunitinib maintains quality of life more effectively
than interferon α in the first-line systemic treatment
of advanced renal cell carcinoma.
practice pOintpractice pOint