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Sorafenib tolerability in elderly patients with
advanced renal cell carcinoma: results from a
large pooled analysis
G Procopio
*
,1
, J Bellmunt
2
, J Dutcher
3
, S Bracarda
4
, J Knox
5
, A Brueckner
6
, I Molnar
7
, B Escudier
8
and
T E Hutson
9
1
Department of Medical Oncology 1, Fondazione IRCCS ‘Istituto Nazionale Tumori’, Milan, Italy;
2
Department of Solid Tumor
Oncology (Genitourinary and Gastrointestinal), University Hospital del Mar-IMIM, Barcelona, Spain;
3
St Luke’s Roosevelt Hospital
Center, Beth Israel Medical Center, Continuum Cancer Centers, New York, NY, USA;
4
Department of Medical Oncology,
Ospedale San Donato-USL8, Arezzo, Italy;
5
Department of Medical Oncology and Hematology, Princess Margaret Hospital,
Toronto, ON, Canada;
6
Bayer HealthCare, Leverkusen, Germany;
7
Bayer HealthCare Pharmaceuticals Inc, Montville, NJ, USA;
8
Department of Cancer Medicine, Institute of Gustave-Roussy, Villejuif, France and
9
Texas Oncology at Baylor Charles A.
Sammons Cancer Center, Dallas, TX, USA
Background: Elderly patients tend to be underrepresented in renal cell carcinoma (RCC) clinical trials. The Sorafenib RCC
Integrated Database includes data from six clinical trials and two expanded-access studies evaluating sorafenib monotherapy in
44600 patients with RCC. Using this database, sorafenib tolerability and treatment patterns were analysed according to age
group (o55, 55–o65, 65–o75, or X75 years).
Methods: Dosing patterns, and incidence, prevalence and cumulative incidence of drug-related adverse events (DRAEs) and fatal
DRAEs were assessed.
Results: Overall, 4684 patients were evaluable (o55 years, n ¼ 1126; 55–o65, n ¼ 1579; 65–o75, n ¼ 1382; X75, n ¼ 559).
Treatment patterns were generally similar across subgroups, although sorafenib treatment duration was B30% shorter in the
X75-years subgroup. There were no substantial differences in any-grade DRAEs with sorafenib between subgroups. Drug-related
adverse events and dose modifications due to DRAEs tended to occur in months 0–3 and declined thereafter; there was no
evidence of cumulative toxicity. Fatal DRAEs were rare (0.7% overall; 95% confidence interval, 0.5–1.0%).
Conclusion: Sorafenib was well tolerated regardless of age in a heterogeneous population of RCC patients.
The incidence of cancer and cancer-related mortality increases
with age (Altekruse et al, 2011). For renal cell carcinoma (RCC),
median age at diagnosis is B64 years, with 425% of patients
aged 475 years (based on data for the United States (Altekruse
et al, 2011)). Outcomes appear to be worse in older patients;
mortality related to RCC was seven-fold higher in nephrecto-
mized patients aged X75 years vs those aged 50–75 years
(Karakiewicz et al, 2008). Additionally, overall survival in RCC
patients correlates negatively with the severity and number of
comorbidities (Berger et al, 2008); comorbidity prevalence
increases with age (Coebergh et al, 1999). Despite these observa-
tions, older patients are generally underrepresented in clinical trials
(Lewis et al, 2003; Surbone, 2011). A major reason
for this seems to be strict exclusion criteria based on organ-system
abnormalities and functional status limitations (Lewis et al, 2003).
The advent of targeted therapies has revolutionized RCC
treatment, but pivotal registration trials have tended to enrol
small proportions of patients aged 465 years (Escudier et al,
*Correspondence: Dr G Procopio, E-mail: Giuseppe.Procopio@istitutotumori.mi.it.
Received 20 July 2012; revised 8 November 2012; accepted 10 November 2012;
published online 15 January 2013
& 2013 Cancer Research UK. All rights reserved 0007 – 0920/13
FULL PAPER
Keywords: elderly; renal cell carcinoma; sorafenib; targeted therapies; tyrosine kinase inhibitors
British Journal of Cancer (2013) 108, 311–318 | doi: 10.1038/bjc.2012.543
www.bjcancer.com | DOI:10.1038/bjc.2012.543 311
2007a,b; Hudes et al, 2007; Motzer et al, 2007, 2008; Rini et al,
2008, 2011; Sternberg et al, 2010). The consequence is a lack of
evidence-based recommendations for the treatment of elderly
patients with RCC.
Sorafenib is an antiangiogenic, antiproliferative vascular
endothelial growth factor receptor tyrosine kinase inhibitor
(VEGFR-TKI) first approved for treatment of advanced RCC
(Escudier et al, 2007a, 2009a; Stadler et al, 2010; Beck et al, 2011).
Age subgroup analyses suggest that sorafenib is well tolerated and
effective across age groups, but the proportions of elderly patients
have tended to be small, and not reflective of real-world patient
populations (Eisen et al, 2008b; Bukowski et al, 2010; Stadler et al,
2010; Beck et al, 2011; Procopio, 2011). The Sorafenib-RCC (Sor-
RCC) Integrated Database includes safety data from 44600
patients enrolled in eight company-sponsored sorafenib mono-
therapy clinical studies. The large number of patients in the
database, 440% of whom are X65 years old, allowed a
retrospective examination of baseline demographics, treatment
patterns, and sorafenib tolerability within age subsets, with a
particular focus on the oldest patients (X75 years).
PATIENTS AND METHODS
Patients and database. Clinical data from patients with RCC
treated with sorafenib monotherapy in company-sponsored trials
were pooled into the Sor-RCC Integrated Database. Trial data were
included if patients received only sorafenib monotherapy, and
adverse events (AEs) were measured using National Cancer
Institute Common Terminology Criteria for Adverse Events
version 3.0. Eight Phase I, II, and III trials met these criteria
(n ¼ 4684; Supplementary Table 1): six were clinical development
trials ( n ¼ 1008); two were part of the expanded-access programme
(n ¼ 3676) (Akaza et al, 2007; Escudier et al, 2007a, 2009b; Stadler
et al, 2010; Beck et al, 2011; Tolcher et al, 2011). All studies have
completed; some patients remain in follow-up. The present
analysis includes data collected from November 2003 to January
2009.
The starting dose of sorafenib in all trials was 400 mg twice
daily. In the first-line study of sorafenib vs interferon, the protocol
allowed dose escalation to 600 mg twice daily in patients with
disease progression. The 44 patients who received at least one dose
at this level were included in the integrated database at both 400
and 600 mg twice daily. In all studies, the per protocol dose
modification schedule, if required, was reduction to 400 mg once
daily, followed by additional dose reduction to a single 400 mg dose
every other day, if necessary.
Subgroup analyses. Analyses were conducted in patient sub-
groups defined by age at study entry: o55 years, 55–o65 years,
65–o75 years, and X75 years. Incidence of a drug-related AE
(DRAE) was defined as the number of patients with a DRAE
starting or worsening during treatment, or within 7 days after
treatment end, divided by the number of patients at risk. Drug-
related adverse event prevalence was defined as the total number of
DRAEs in the population occurring (new or continuing) in a given
time interval, divided by the number of patients at risk during that
interval. Drug-related serious AEs (DRSAEs) were DRAEs that
were life-threatening or that led to hospitalisation, death, persistent
or significant disability, or birth defects.
Statistical analysis. Descriptive safety analyses (means, medians,
ranges) and frequency tables were used to analyse baseline
characteristics, incidence and prevalence of DRAEs and DRSAEs,
and concurrent medications for the patients in each subpopulation.
RESULTS
Patients. The Sor-RCC Integrated Database includes individual
data from 4684 patients enrolled in eight company-sponsored
clinical trials and expanded-access programmes (Supplementary
Table 1). Most patients (78%) were from the expanded-access
programmes and received open-label sorafenib in community-
based practice settings. Four age subgroups were defined: o55
years (n ¼ 1126; 24%), 55–o65 years (n ¼ 1579; 34%), 65–o75
years (n ¼ 1382; 30%), and X75 years (n ¼ 559; 12%). Although
the X75-year-old subgroup was proportionally the smallest, it is
the largest RCC population of advanced age to be studied to date.
Patients were predominantly male, with clear-cell histology and a
pattern of metastases typical for advanced RCC (i.e., lung, liver,
lymph nodes, and bone) (Table 1). The proportion of patients with
brain metastases (2.1%) was low, consistent with such patients
generally being excluded from clinical trials; in the expanded-
access programmes, patients with stable brain metastases were
allowed. The percentage of nephrectomized patients was slightly
lower in patients aged X75 years (81%) than in the younger age
subgroups (range 87–90%). The proportion of the oldest patients
who had received cytokines was somewhat lower than in the other
groups (36% vs 51–59%).
Clinical comorbidities tended to increase with age. For example,
the proportion of patients aged o55 years with cardiovascular risk
factors or diabetes mellitus was approximately half that in the other
groups (Table 1). Similarly, the concomitant medications received
suggested more cardiovascular comorbidities in the older age
groups: use of anti-angiotensin agents, calcium-channel blockers,
b-blockers, diuretics, and lipid-reducing agents in the youngest
subgroup was approximately half that in the oldest patients
(Supplementary Table 2).
Treatment duration. Treatment duration was similar among
patients aged o55, 55–o65, and 65–o75 years (mean, 6.5–6.7
months; median, 4.0–4.2 months; Table 2). In the oldest patients,
treatment duration (mean: 4.5 months; median: 3.1 months) was
about 30% shorter than in the three younger subgroups. Sorafenib
therapy continued for X12 months in a notable proportion of
patients in each subgroup, including older patients: 15% of patients
aged o55 years, 16% of patients 55–o65 years, 17% of patients
65–o75 years, and 8% of patients X75 years.
Safety
DRAE incidence. The incidence of DRAEs of any grade appeared
to be constant or decreased slightly with age (Table 3). Grade 3/4
DRAE incidence increased modestly with age: 33% of the youngest
patients experienced X1 grade 3/4 DRAE while on treatment
compared with 41% of the oldest patients. The most common any-
grade DRAEs were hand–foot skin reaction (HFSR), diarrhoea,
rash/desquamation, alopecia, and fatigue; incidence did not differ
markedly between age groups, with the possible exception of grade
3/4 fatigue in the X75-year-old subgroup (Table 3). The incidence
of treatment-emergent hypertension was low and predominantly
grade 1/2.
DRAE prevalence. Changes in the safety profile of sorafenib over
time (prevalence) were examined by assessing the occurrence of
any DRAE (grades 1–4) in 3-month intervals (Figure 1). The
percentage of patients experiencing any DRAE was fairly constant
over time, and generally showed a similar distribution across the
age groups (Figure 1A). The prevalence of any grade 4 DRAE was
low and never exceeded 5% in any interval. Grade 3 DRAEs
occurred most frequently in months 0–3; prevalence decreased
thereafter with a concurrent trend for an increase in the prevalence
of grade 1/2 DRAEs.
BRITISH JOURNAL OF CANCER Sorafenib in elderly patients with RCC: a pooled analysis
312 www.bjcancer.com | DOI:10.1038/bjc.2012.543
The prevalence of the grade 3/4 DRAEs that had the highest
incidence was examined in more detail (Figures 1B–F). Prevalence
patterns for these DRAEs were broadly consistent with those for
any DRAE. Grade 3 HFSR, and grade 3/4 rash/desquamation and
fatigue tended to occur most frequently in the first 3 months and
decreased in later intervals; this pattern was observed across the
age subgroups. Compared with younger patients, a slightly higher
proportion of patients aged X75 years exhibited grade 3/4 fatigue
and a lower proportion exhibited grade 3 HFSR. Hypertension
prevalence at each grade was fairly equal across age groups,
although there was a slight trend towards increased grade 1/2
hypertension in patients aged o55 years. Diarrhoea prevalence
followed a slightly different pattern to the other DRAEs. Grade 1/2
diarrhoea was least frequent in the first 3 months in all age groups,
and tended to increase over time. Importantly, the prevalence of
grade 3 diarrhoe a was low throughout, and there were no instances
of grade 4 diarrhoea.
DRSAE incidence and prevalence. The incidence and prevalence
of DRSAEs followed a similar pattern to those for DRAEs
(Supplementary Table 3). The overall incidence of DRSAEs
increased somewhat with age, from 11.3% in the youngest group
to 19.9% in the oldest. The incidence of any grade 3/4 DRSAE was
slightly higher in the oldest group (14%) than in the younger
groups (8–11%). The most common specific DRSAEs (incidence
X0.5%) were hypertension, fatigue, HFSR, rash, and diarrhoea.
The incidence of all grade DRSAEs exceeded 2% only for fatigue
and rash, and only in the X75-year-old subgroup.
The prevalence of grade 3/4 DRSAEs was highest in the first
3 months of treatment, and then dropped by 50% or more later in
treatment. Patients aged X75 years experienced somewhat higher
levels of DRSAEs in the first 6 months than patients in the other
groups.
There were 34 (0.7%; 95% CI, 0.5–1.0%) grade 5 DRAEs during
the study; the overall incidence was broadly similar across age
Table 1. Baseline characteristics by age
Characteristics
Total patient
population
(N ¼ 4684)
Patients o55 years
of age (n ¼ 1126)
Patients 55–o65 years
of age (n ¼ 1579)
Patients 65–o75 years
of age (n ¼ 1382)
Patients X75 years
of age (n ¼ 559)
Male, % 70.8 72.0 74.0 68.7 65.8
Median age, years
(range)
62 (13–100) 49 (13–54) 59 (55–64) 69 (65–74) 78 (75–100)
ECOG PS, %
0 21.8 26.1 23.1 21.4 12.3
1 20.1 21.6 20.5 20.9 15.6
2 3.8 5.3 3.5 3.4 2.5
Missing
a
54.3 47.0 53.0 54.3 69.6
Metastatic sites, %
Bone 27.9 30.6 30.1 26.2 21.1
Brain 2.1 2.8 2.0 1.8 1.6
Liver 24.4 25.8 25.5 23.6 21.1
Lung 72.4 74.0 72.2 72.6 71.6
Lymph nodes 27.9 32.8 29.3 25.1 22.2
Histology subtypes, %
Clear cell 82.2 79.7 83.7 84.4 79.6
Predominantly
clear cell
15.6 18.5 14.3 13.2 19.5
Other 0.7 0.9 0.6 0.8 0.4
Prior treatment, %
Nephrectomy 86.8 89.8 86.6 87.6 81.2
Cytokine 52.4 59.4 55.5 50.7 35.6
Antineoplastic
agent
28.4 30.0 32.1 27.6 17.2
Medical history, %
Hypertension
b
48.0 28.2 46.5 59.5 63.5
Ischaemic coronary
artery disorders
4.4 1.9 3.8 5.9 7.5
Anaemia
c
10.5 10.6 10.7 10.3 11.1
Diabetes mellitus 15.1 8.7 15.9 19.0 16.5
High cholesterol
d
14.5 7.5 14.3 18.7 18.6
Abbreviations: ECOG PS ¼ Eastern Cooperative Oncology Group performance status; MedDRA ¼ Medical Dictionary for Regulatory Activities; NEC ¼ not elsewhere classified. MedDRA
s
is a
registered trademark of the International Federation of Pharmaceutical Manufacturers and Associations (IFPMA).
a
Performance status values were missing in a large number of patients because they were not captured in the expanded-access studies.
b
Per MedDRA terminology, vascular hypertensive disorders NEC.
c
Per MedDRA terminology, anaemia NEC.
d
Per MedDRA terminology, elevated cholesterol, elevated triglycerides, and hyperlipidaemias NEC.
Sorafenib in elderly patients with RCC: a pooled analysis BRITISH JOURNAL OF CANCER
www.bjcancer.com | DOI:10.1038/bjc.2012.543 313
subgroups (0.4–1.0%; Table 4). Most events occurred within
months 0–3 (Table 4). Grade 5 DRAEs occurring in X2 patients
were haemorrhage/bleeding events (n ¼ 6, bleeding sites differed
between patients), renal failure (n ¼ 5), cardiac ischaemia/infarc-
tion (n ¼ 3), perforation of the colon (n ¼ 2), and perforation of
the small bowel (n ¼ 2).
Dosing patterns. The median/mean daily dose of sorafenib was
consistent across age groups. The proportion of patients receiving
at least 90% of planned doses was slightly higher in patients aged
o55 years or 55–o65 years than in those aged 65–o75 years or
X75 years (Table 2).
The incidence of dose modifications (reductions or interrup-
tions) due to any AE was also generally similar between age groups.
In each age group, most patients (450%) did not require any dose
modification owing to AEs; the proportion of patients requiring
two or more dose modifications was low (20–23%; Figure 2A).
Most patients (498%) initiated treatment at the standard
dose (400 mg twice daily; Figure 2B). Compared with younger
patients, there was a trend for older patients to be dose interrupted
or dose reduced to 400 mg once daily due to AEs (Figure 2B). For
patients whose dose was reduced or interrupted, there was also a
trend for older patients not to be re-escalated to full dose,
compared with younger patients, with a concurrent trend for older
patients to remain at 400 mg once daily (Figure 2B). The
prevalence of dose modifications owing to DRAEs
(Supplementary Figure 1) was generally consistent with
the prevalence data for DRAEs (Figure 1). In the oldest patients,
the prevalence of dose modifications owing to DRAEs tended to be
higher than in younger patients; however, the relatively small
number of patients in the oldest group after month 12 precludes
meaningful conclusions.
Table 2. Sorafenib treatment by age
Total population
(N ¼ 4684)
Patients o55 years
(n ¼ 1126)
Patients 55–o65
years (n ¼ 1579)
Patients 65–o75
years (n ¼ 1382)
Patients X75
years (n ¼ 559)
Duration of therapy
Mean, months 6.3 6.7 6.5 6.6 4.5
Median (range)
a
, months 3.9 (0–51.2) 4.2 (0–51.2) 4.0 (0–47.4) 4.0 (0–44.1) 3.1 (0–37.5)
Per 3- or 6-month interval, n (%)
o3 months 1820 (38.9) 402 (35.7) 612 (38.8) 518 (37.5) 265 (47.7)
3–o6 months 1349 (28.8) 328 (29.1) 439 (27.8) 400 (28.9) 171 (30.6)
6–o12 months 808 (17.3) 224 (19.9) 275 (17.4) 226 (16.4) 80 (14.3)
12–o18 months 323 (6.9) 75 (6.7) 103 (6.5) 124 (9.0) 21 (3.8)
18–o24 months 224 (4.8) 53 (4.7) 97 (6.1) 56 (4.1) 17 (3.0)
X24 months 160 (3.4) 44 (3.9) 53 (3.4) 58 (4.2) 5 (0.9)
Dosing
Median, mg per day (range) 792 (55.2–1600) 797 (156–1121) 796 (55–1335) 768 (73–1600) 768 (167–1600)
Mean (s.d.) 676 (171.2) 694 (159.7) 688 (163.0) 660 (180.0) 650 (186.6)
Patients receiving X90%
planned dose, n/n (%)
2515/4199 (59.9) 627/978 (64.1) 900/1417 (63.5) 687/1250 (55.0) 281/517 (54.4)
a
The mean dose of sorafenib was calculated for each patient, and the median of these means was calculated for each subgroup.
Table 3. Incidence of DRAEs occurring in X10% of patients by age
Total population
(N ¼ 4684)
Patients o55 years
(n ¼ 1126)
Patients 55–o65
years (n ¼ 1579)
Patients 65–o75
years (n ¼ 1382)
PatientsZ75 years
(n ¼ 559)
Grade, % of patients Any 3–4 Any 3–4 Any 3–4 Any 3–4 Any 3–4
Any DRAE 82.3 37.6 79.5 33.3 83.3 37.5 84.7 39.6 81.0 41.4
Hand–foot skin reaction 36.2 9.7 39.3 10.0 37.5 9.6 36.0 10.1 28.3 8.4
Diarrhoea 35.4 4.0 32.2 3.3 39.7 4.6 36.8 4.4 27.0 2.9
Rash/desquamation 30.2 4.3 30.6 4.1 30.2 3.6 30.6 5.0 29.3 5.0
Alopecia 21.5 o0.1 24.2 0.1 22.0 0 21.6 0 15.0 0.2
Fatigue 24.7 4.8 21.1 3.8 23.9 3.6 26.5 5.5 30.4 9.0
Nausea 13.7 1.2 16.3 1.3 13.4 1.3 12.5 0.9 12.0 1.4
Hypertension 17.4 5.0 15.9 3.6 18.6 5.4 14.5 5.9 13.2 5.2
Anorexia 14.8 1.4 13.2 1.2 13.4 1.2 16.4 1.7 18.6 2.0
Pruritus 9.2 0.4 10.7 0.5 9.7 0.3 8.4 0.3 6.8 0.4
Oral mucositis, clinical examination 9.6 0.8 10.4 0.7 8.9 1.1 10.1 0.6 9.3 0.9
Abbreviation: DRAEs ¼ drug-related adverse events.
National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE) version 3 and worst CTCAE grade.
BRITISH JOURNAL OF CANCER Sorafenib in elderly patients with RCC: a pooled analysis
314 www.bjcancer.com | DOI:10.1038/bjc.2012.543
100
Patient age group
80
60
40
20
0
100
80
60
40
20
0
100
80
60
40
20
0
100
80
60
40
20
0
100
80
60
40
20
0
100
80
60
40
20
0
0
3
6
9
12
15
18
21
24
0
3
6
9
12
15
18
21
24
0
3
6
9
12
15
18
21
24
0
3
6
9
12
15
18
21
24
Month
<55 years
55–<65 years
65–<75 years
≥75 years
0
3
6
9
12
15
18
21
24
0
3
6
9
12
15
18
21
24
0
3
6
9
12
15
18
21
24
0
3
6
9
12
15
18
21
24
Month
<55 years
55–<65 years
65–<75 years
≥75 years
0
3
6
9
12
15
18
21
24
0
3
6
9
12
15
18
21
24
0
3
6
9
12
15
18
21
24
0
3
6
9
12
15
18
21
24
Month
<55 years 55–<65 years 65–<75 years ≥75 years
0
3
6
9
12
15
18
21
24
0
3
6
9
12
15
18
21
24
0
3
6
9
12
15
18
21
24
0
3
6
9
12
15
18
21
24
Month
<55 years 55–<65 years 65–<75 years ≥75 years
0
3
6
9
12
15
18
21
24
0
3
6
9
12
15
18
21
24
0
3
6
9
12
15
18
21
24
0
3
6
9
12
15
18
21
24
Month
<55 years 55–<65 years 65–<75 years ≥75 years
0
3
6
9
12
15
18
21
24
0
3
6
9
12
15
18
21
24
0
3
6
9
12
15
18
21
24
0
3
6
9
12
15
18
21
24
Month
<55 years 55–<65 years 65–<75 years ≥75 years
DRAE prevalence (%)
DRAE prevalence (%)
DRAE prevalence (%)DRAE prevalence (%)
DRAE prevalence (%)DRAE prevalence (%)
Any DRAE
Rash/desquamation
Hand–foot skin reaction
Fatigue
Hypertension
Patient age group
Grade 1
Grade 4
Grade 3
Grade 2
Diarrhoea
Figure 1. Prevalence of selected DRAEs by grade and time (3-month intervals over 24 months). (A) Any DRAE; (B–F) DRAEs with the highest
grade 3/4 incidence: (B) HFSR, (C) rash/desquamation, (D) fatigue, (E) diarrhoea, and (F) hypertension. For the selected DRAEs, the prevalence of
grade 4 DRAEs was p0.4% at any time point and in any age subgroup. No patient had grade 4 HFSR or diarrhoea. No patient had grade 4 fatigue,
hypertension or rash/desquamation after months 0–3, except fatigue in one patient aged 55–o65 years and two patients aged 65–o75 years,
during months 3–6; and in one patient aged 65–o75 years, during months 6–9. DRAE ¼ drug-related adverse event; HFSR ¼ hand–foot skin
reaction.
Table 4. Incidence and prevalence of grade 5 (fatal) DRAEs
Interval,
months
Total population
(N ¼ 4684)
Patients o55 years
(n ¼ 1126)
Patients 55–o65 years
(n ¼ 1579)
Patients 65–o75 years
(n ¼ 1382)
Patients X75 years
(n ¼ 559)
Grade 5 DRAEs at any time, n/n (%; 95% CI)
a
34/4684 (0.7; 0.5–1.0) 7/1126 (0.6; 0.3–1.3) 11/1579 (0.7; 0.3–1.2) 14/1382 (1.0; 0.6–1.7) 2/559 (0.4; 0.04–1.3)
Grade 5 DRAEs per 3-month interval, n/n (%)
o3 20/4684 (0.4) 2/1126 (0.2) 7/1579 (0.4) 9/1382 (0.7) 2/559 (0.4)
3–6 5/2864 (0.2) 2/724 (0.3) 1/967 (0.1) 2/864 (0.2) 0/294 (0)
6–9 2/1515 (0.1) 1/396 (0.3) 1/528 (0.2) 0/464 (0) 0/123 (0)
9–12 3/993 (0.3) 1/254 (0.4) 1/349 (0.3) 1/321 (0.3) 0/67 (0)
12–15 2/707 (0.3) 1/172 (0.6) 0/253 (0) 1/238 (0.4) 0/43 (0)
15–18 0/507 (0) 0/124 (0) 0/191 (0) 0/161 (0) 0/30 (0)
18–21 0/384 (0) 0/97 (0) 0/150 (0) 0/114 (0) 0/22 (0)
21–24 0/260 (0) 0/66 (0) 0/98 (0) 0/83 (0) 0/13 (0)
Abbreviations: CI ¼ confidence interval; DRAEs ¼ drug-related adverse events.
a
Number of fatal DRAEs occurring during the entire observation period.
National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE) version 3 and worst CTCAE grade.
Sorafenib in elderly patients with RCC: a pooled analysis BRITISH JOURNAL OF CANCER
www.bjcancer.com | DOI:10.1038/bjc.2012.543 315
DISCUSSION
The Sor-RCC Integrated Database is a valuable resource for
assessing tolerability and treatment patterns in 44600 patients
with RCC who received sorafenib in clinical trials or expanded-
access programmes. Both incidence and prevalence of AEs can be
ascertained from the database. The prevalence of AEs at specific
points in time gives an indication of whether the pattern of AEs
changes with time – for example, do new AEs appear in patients
receiving long-term therapy? Additionally, the database includes a
large number of elderly patients, with 1382 (30% of the database)
aged 65–o75 years at baseline and 559 patients aged X75 years.
Although the latter group is only 12% of the database, and this
relatively small proportion is undoubtedly a limitation, it never-
theless represents (to our knowledge) the largest group of RCC
patients aged X75 years whose treatment patterns have been
systematically studied. This is important because patients aged
465 years (and, even more so, those aged X75) are generally
underrepresented in clinical trials (Lewis et al, 2003; Surbone,
2011). We therefore used the Sor-RCC Integrated Database to
evaluate dosing patterns, and the incidence and prevalence of
DRAEs in patients with RCC receiving sorafenib treatment,
including subanalyses according to age.
The Sor-RCC Integrated Database included patients from
randomized clinical trials, which have strict inclusion criteria,
but 78% were from expanded-access programmes. Inclusion
criteria for such programmes are less strict than those for RCTs;
however, patients are prospectively accrued according to
set protocols. This raises the possibility that patients with poorer
performance status and major comorbidities will still be under-
represented relative to unselected patients. However, the demo-
graphics and baseline characteristics of our population were
broadly consistent with those in the general population with RCC.
The ratio of men:women was B2:1 and median age was 62 years,
consistent with cancer statistics for the United States (2004–2007;
Altekruse et al, 2011). In addition, a medical history of
cardiovascular comorbidities was more frequent in older patients
than younger patient in our database, consistent with previous
observations (Coebergh et al, 1999). Together, these results suggest
that the patient population in our database is generally
representative of patients in clinical practice, including those with
comorbidities.
Our analyses were not controlled for prognostic risk group, and
the possible confounding effects of this variable cannot be
excluded. However, while acknowledging this possible limitation,
we conclude that sorafenib was generally well tolerated regardless
of age. There were no substantial differences in the incidence of
specific any-grade or grade 3/4 DRAEs between age groups. The
higher frequency of comorbidities in older patients than in younger
patients did not appear to result in more DRAEs with sorafenib.
For example, the incidence and severity of hypertension as a DRAE
was not substantially different between age subgroups despite the
numerically higher incidence of comorbid hypertension in older
patients than in younger patients. Notably, sorafenib was generally
well tolerated regardless of presence or absence of baseline
cardiovascular comorbidities in a subgroup analysis of the EU-
ARCCS expanded-access study (Eisen et al, 2008a).
Analysis of DRAE prevalence did not indicate cumulative
toxicity with long-term sorafenib therapy. Across age subgroups,
the prevalence of grade 3/4 DRAEs tended to decrease over the
course of therapy, with a concurrent trend for increasing
prevalence of grade 1/2 DRAEs, suggesting a shift to less-severe
toxicity with continued sorafenib treatment. This could reflect
successful management of DRAEs during long-term therapy; it has
been suggested that effective monitoring and management of AEs
is key to optimising sorafenib duration of therapy (Hutson et al,
2010; Edmonds et al, 2012).
Fatal DRAEs were rare across age subgroups in this analysis.
This is important, as two meta-analyses previously concluded that
VEGFR-TKIs were associated with an increased risk of fatal AEs
compared with placebo/control (Schutz et al, 2012; Sivendran et al,
2012). Schutz and coworkers reported an overall incidence of fatal
DRAEs of 1.5% with sunitinib, sorafenib or pazopanib, and
suggested that their meta-analysis may have actually under-
estimated the incidence of fatal AEs associated with these agents,
as patients in clinical trials tend to have better performance status
than those in clinical practice. Sivendran and coworkers reported a
fatal AE rate of 3.68% for patients receiving sunitinib, sorafenib or
pazopanib for RCC compared with 2.27% for patients receiving
control. A subgroup analysis of the three sorafenib studies
evaluated (two in RCC and one in HCC) suggested a higher rate
of fatal events for sorafenib (3.21%) compared with control
(2.15%). However, for each meta-analysis, some important caveats
should be considered. The meta-analysis from Schutz and
coworkers included patients with various malignancies, and
included both monotherapy and combination therapy trials; the
incidence of fatal DRAEs in patients with a particular malignancy
receiving a specific therapy therefore cannot be ascertained from
the meta-analysis. The report from Sivendran and coworkers
considered fatal AEs regardless of causality (not specifically
DRAEs). In addition, the authors acknowledge that their findings
with regard to sorafenib should be considered only as hypothesis
generating, as the total number of events involved was relatively
few. Importantly, the Sor-RCC Integrated Database includes data
for a large number of patients (N ¼ 4684) from monotherapy
70
50
60
40
30
20
10
0
0
1
100
60
80
40
20
0
Proportion of patients (%)
<55 years
(n =1126)
≥75 years
(n =559)
65–<75 years
(n =1382)
55–<65 years
(n =1579)
Patient age group
≥2
Proportion of patients (%)
≥75 years
(n =559)
65–<75 years
(n =1382)
55–<65 years
(n =1579)
<55 years
(n =1126)
Patient a
g
e
g
roup
400 mg bid starting dose
Dose reduction/dose interruption due to AE*
Patients
†
re-escalated to 400 mg bid
Patients
†
remaining at 400 mg qd
Figure 2. Dosing patterns for patients experiencing AEs.
(A) Proportion of patients requiring 0, 1, or X2 dose reductions or
interruptions due to an AE; (B) Proportion of patients initiated at
400 mg bid and dose reduced or dose interrupted, followed by
re-escalation, or continuation at the lower dose of 400 mg once daily.
*Of those patients who received sorafenib 400 mg bid as the starting
dose.
w
Of those patients with a dose reduction/dose interruption from
400 mg bid. AE ¼ adverse event; bid ¼ twice daily; qd ¼ once daily.
BRITISH JOURNAL OF CANCER Sorafenib in elderly patients with RCC: a pooled analysis
316 www.bjcancer.com | DOI:10.1038/bjc.2012.543
studies in RCC only, and is thus particularly well suited for
evaluating the incidence of fatal DRAEs associated with sorafenib
treatment in RCC patients; our analysis in this large patient
population suggests that the incidence of fatal DRAEs with
sorafenib is approximately half that reported for VEGFR-TKIs by
Schutz and coworkers.
There were indications in our study that patients aged
X75 years were managed more conservatively than younger
patients. The oldest patients were less likely to have previously
received nephrectomy and/or cytokines, were treated for slightly
shorter time periods, and were more likely to have received dose
modifications and/or discontinuations due to DRAEs, particularly
early in treatment. These patients were also more likely to remain
on a lower dose after dose reduction, rather than be re-escalated to
the full dose. A limitation of our data is that performance status is
missing for most patients, so it is unclear whether these treatment
differences reflect greater frailty in older patients or complications
arising from the higher prevalence of comorbidities. Importantly,
an appreciable proportion of the oldest patients (8%) were able to
receive sorafenib therapy for X12 months.
CONCLUSIONS
In this large, pooled analysis of a diverse population of patients
with RCC, sorafenib was well tolerated across all age subgroups,
including those X75 years. These observations suggest that
sorafenib is a well tolerated and effective option for the treatment
of advanced RCC, regardless of patient age.
ACKNOWLEDGEMENTS
We are grateful to 7.4 Limited for providing editorial support,
with unrestricted financial support from Bayer HealthCare
Pharmaceuticals.
CONFLICT OF INTEREST
Giuseppe Procopio has received consulting fees and had an
advisory role from Bayer HealthCare Pharmaceuticals, Pfizer and
GSK. Joaquim Bellmunt has received consulting and lecture fees
from Bayer HealthCare Pharmaceuticals, Novartis and Roche.
Janice Dutcher has had an advisory role with Pfizer, Prometheus
and Genentech; has served on speakers’ bureaux for Pfizer,
Prometheus, Bayer HealthCare Pharmaceuticals/Onyx, Novartis
and GSK; and has received research funds from Prometheus,
Exelixis, and BMS. Sergio Bracarda has served on advisory boards
for Pfizer, GSK, Novartis, Bayer HealthCare Pharmaceuticals,
Boehringer Ingelheim, Sanofi-Aventis and Janssen-Cilag, and has
received lecture fees from Pfizer, Novartis and Sanofi-Aventis.
Jennifer Knox has received research support from Bayer Health-
Care Pharmaceuticals. Andreas Brueckner and Istvan Molnarg are
employees of Bayer HealthCare Pharmaceuticals. Bernard Escudier
has served as a consultant for Bayer HealthCare Pharmaceuticals,
GSK, Pfizer, Novartis, Roche and AVEO. Thomas Hutson has
received research support from, and served as a consultant and on
speakers’ bureaux for, Bayer HealthCare Pharmaceuticals, GSK,
Pfizer, AVEO, Novartis, Genentech and OrthoBiotech.
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