Introduction
Given that nearly 25% of all patients with kidney
cancer present with locally advanced or metastatic renal cell
carcinoma (RCC), kidney cancer is a malignancy with a poor
prognosis (1). Conventional
therapies, such as chemotherapy and radiation therapy are not
effective and only 10 to 20% of patients benefit from immunotherapy
(2–4). Recently enhanced understanding of the
etiology of advanced RCC has led to the development of angiogenesis
inhibitor agents.
In randomized clinical trials (RCTs), first
generation angiogenesis inhibitors sunitinib, sorafenib and
bevacizumab plus interferon α, have demonstrated efficacy in
prolonging progression-free survival and/or overall survival as
first-line treatment (4–6). The efficacy of sunitinib and
sorafenib has also been established in expanded access programs
(EAP) (7,8). Due to their strong efficacy profiles,
these agents have become the new standard of treatment for advanced
RCC. All these drugs were approved by corresponding regulatory
agencies for use in the US, Europe and Asia (9–13).
However, RCTs and EAPs have also demonstrated that
these angiogenesis inhibitors are associated with high rates of
toxicity and treatment modifications, including discontinuations
and dose changes. Since clinical trials may not be representative
of real-life clinical practice due to treatment selection criteria,
observational studies are necessary to understand the effects of
treatment in the wider population of patients who actually receive
these therapies. Small observational studies conducted in
real-world clinical practice settings in US, Korea, Japan and
Europe have provided further evidence of high toxicity profiles
associated with these agents (14–21).
Data from these varied care settings highlight that adverse events
(AEs) in advanced RCC patients receiving angiogenesis therapies are
common and often lead to treatment modifications, including
treatment discontinuation.
As the use of angiogenesis inhibitors rises over
time and treatment paradigms continue to evolve, there is a
critical need to gain a thorough understanding of toxicity profiles
and treatment patterns of these agents across various real-world
clinical settings. Therefore, the goal of this study was to examine
the toxicity profiles of sunitinib, sorafenib, and bevacizumab in
advanced RCC among patients treated in US, Europe and Asia, and
describe how clinicians in these settings modify treatment
according to patient experiences.
Materials and methods
Study design
A retrospective study was conducted using data from
medical records for eligible patients with advanced RCC who
received anti-angiogenic therapies. The observation period for each
patient started from the date of first angiogenesis inhibitor
prescription or administration to the earliest of date of death,
last follow-up date at the clinic or date of medical record
abstraction. Data on second-line angiogenesis inhibitor treatment
were also abstracted. The study drugs sunitinib, sorafenib and
bevacizumab are manufactured by Pfizer, Bayer Healthcare
Pharmaceuticals, and Hoffmann-LaRoche Inc., respectively.
Study population
To become eligible in the study patients were
required to meet the following inclusion criteria: i) have had a
confirmed histological and/or cytological diagnosis of locally
advanced or metastatic RCC; ii) 18 years old or older at the time
of confirmed diagnosis of advanced RCC; and iii) received at least
1 dose of oral sunitinib or sorafenib or intravenous (IV)
administration of bevacizumab with or without interferon, after
January 1, 2005. Previous immunotherapy or chemotherapy was not
allowed. Patients were excluded if their first angiogenesis
inhibitor treatment was initiated less than three months prior to
the start date of medical record data abstraction, which varied
across sites, to ensure adequate follow-up time.
Data source
Medical records for eligible patients were
retrospectively abstracted by the clinical staff at 18 community
oncology clinics in the US, and at 21 tertiary oncology centers
across US (n=2), Europe (n=11; France n=2, Ireland n=3, Italy n=1,
Spain n=2 and UK n=3), and Asia (n=8; Korea n=3 and Taiwan n=5).
Data collected included date of RCC diagnosis, sociodemographic
information, comorbidities, prior radiological treatments,
metastatic site(s), baseline Eastern Cooperative Oncology Group
(ECOG) performance status, dates and doses of anti-angiogenesis
therapies prescribed or administered, reasons for changes in
anti-angiogenesis therapies, and information on AEs. Other key data
elements abstracted included the first and last dates of sunitinib,
sorafenib and bevacizumab treatments, treatment modifications, and
baseline and follow-up tumor measurements. Data were collected
using a web-based case report form (CRF) created for this study.
Data collection for this study spanned from July, 2007 through May,
2011. This study was approved in all centers by the ethics
committees for tertiary oncology clinics and the New England
Institutional Review Board for oncology community clinics in the
US.
Outcome definitions
Assessment of toxicity
All toxicity was analyzed retrospectively according
to the experience recorded by investigators in daily clinical
practice. AEs were graded using the National Cancer Institute
Common Terminology Criteria for AEs (CTCAE) version 3.0. (22). If the severity of the AE was
unknown then grade 1 was assigned. Only AEs experienced by patients
during their first-line angiogenesis inhibitor treatment were
considered for the assessment of safety.
Assessment of treatment patterns
Treatment modifications that occurred during
first-line angiogenesis inhibitor treatment were examined. Reasons
for treatment modifications were also abstracted from patients'
medical records, if available. Treatment modifications considered
were treatment discontinuation, treatment interruption (temporary
stoppage of treatment with intent to resume treatment), dose
reduction and dose increase. Patterns of switching between
different angiogenesis inhibitors to second-line treatment were
also examined, including reasons for switching.
Treatment duration
The duration of first-line treatment extended from
the date of initiation of treatment to the date of treatment end,
death, or last follow-up, whichever occurred first. Patients who
did not discontinue their treatment were censored at the last
follow-up.
Statistical analysis
Descriptive statistics were used to characterize
baseline patient characteristics and report AE occurrences, and
treatment patterns. Means and medians were used to describe
continuous variables while frequencies and proportions were used to
describe categorical variables. The Kaplan-Meier survival analysis
method was used to calculate median treatment duration and account
for censoring. The corresponding 95% confidence intervals (CI) were
calculated using the log transformation method. All analyses were
performed using SAS software version 9.2 (SAS Institute Inc., Cary,
NC, USA).
Results
Patient characteristics
Table I presents
the baseline characteristics of the patients. A total of 883
patients satisfied the eligibility criteria, including 157 (US),
349 (Europe), and 125 (Asia) patients treated with sunitinib; 131
(US), 60 (Europe), and 16 (Asia) patients treated with sorafenib;
and 22 (US), 20 (Europe), and 3 (Asia) patients treated with
bevacizumab. Most patients across the three geographical regions
initiated treatment on recommended dosing: 50 mg QD 4/2 for
sunitinib [range: 44.8% (Asia) to 84.8% (Europe)], 400 mg BID for
sorafenib [range: 68.8% (Asia) to 80.0% (Europe)], and 10 mg/kg
Q2WK for bevacizumab [range: 66.7% (Asia) to 91.0% (US)].
 | Table I.Baseline clinical characteristics
among patients with advanced RCC receiving first-line angiogenesis
inhibitor treatment.a |
Table I.
Baseline clinical characteristics
among patients with advanced RCC receiving first-line angiogenesis
inhibitor treatment.a
| United States
| Europe
| Asia
|
|---|
| SU (n=157) | SOR (n=131) | BEV (n=22) | SU (n=349) | SOR (n=60) | BEV (n=20) | SU (n=125) | SOR (n=16) | BEV (n=3) |
|---|
| Initial dose, n
(%) | 50 mg
QD 4/2 127 (80.9)
37.5 mg
QD (4/2) 4 (2.5)
25 mg
QD (4/2) 7 (4.5)
Other 16 (10.2)
Unknown 3 (1.9) | 800 mg
BID 1 (0.8)
400 mg
BID 97 (74.0)
200 mg
BID 25 (19.1)
Other 8 (6.1) | 10 mg/kg
Q2WK 20 (91.0)5 mg/kg
Q2WK 1 (4.5)
Unknown 1 (4.5) | 50 mg
QD 4/2 296 (84.8)
37.5 mg
QD 4/2 29 (8.3)
Other 14 (4.0)
Unknown 10 (2.9) | 800 mg
BID 4 (6.7)
400 mg
BID 48 (80.0)
Other 5 (8.3)
Unknown 3 (5.0) | 11 mg/kg
Q2WK 1 (5.0)
10 mg/kg
Q2WK 16 (80.0)
Unknown 3 (15.0) | 50 mg
QD 4/2 56 (44.8)
37.5 mg
QD 4/2 11 (8.8)
25 mg
QD 4/2 1 (0.8)
Other 57 (45.6) | 800 mg
BID 3 (18.8)
400 mg
BID 11 (68.8)
Other 2 (12.5) | 10 mg/kg
Q2WK 2 (66.7)
Unknown 1 (33.3) |
| Age at TI
(years) | | | | | | | | | |
| Median
(range) | 62.3
(29.7–93.3) | 65.6
(26.0–88.0) | 61.1
(41.9–86.8) | 62.0
(23.3–88.6) | 63.0
(27.2–86.3) | 61.1
(45.5–76.2) | 57.3
(24.3–86.1) | 54.3
(46.2–80.4) | 55.5
(35.4–78.1) |
| Mean (SD) | 63.7 (11.6) | 65.7 (11.3) | 60.7 (12.3) | 61 (11.7) | 62 (12.1) | 60 (8.5) | 58 (13.5) | 57 (10.2) | 56 (21.3) |
| Male, n (%) | 102 (65.0) | 82 (62.6) | 16 (72.7) | 240 (68.8) | 47 (78.3) | 15 (75.0) | 102 (81.6) | 11 (68.8) | 2 (66.7) |
| ECOG PS, n (%) | | | | | | | | | |
| 0 | 27 (17.2) | 26 (19.8) | 4 (18.2) | 108 (30.9) | 20 (33.3) | 7 (35.0) | 19 (15.2) | 2 (12.5) | 0 (0.0) |
| 1 | 41 (26.1) | 41 (31.3) | 7 (31.8) | 74 (21.2) | 7 (11.7) | 5 (25.0) | 48 (38.4) | 6 (37.5) | 2 (66.7) |
| 2 | 5 (3.2) | 12 (9.2) | 3 (13.6) | 19 (5.4) | 2 (3.3) | 1 (5.0) | 10 (8.0) | 1 (6.3) | 0 (0.0) |
| 3 | 1 (0.6) | 1 (0.8) | 0 (0.0) | 3 (0.9) | 0 (0.0) | 0 (0.0) | 2 (1.6) | 0 (0.0) | 0 (0.0) |
| 4 | 0 (0.0) | 0 (0.0) | 0 (0.0) | 2 (0.6) | 0 (0.0) | 0 (0.0) | 0 (0.0) | 0 (0.0) | 0 (0.0) |
| Unknown | 83 (52.9) | 51 (38.9) | 0 (0.0) | 143 (41.0) | 31 (51.7) | 7 (35.0) | 46 (36.8) | 7 (43.8) | 1 (33.3) |
| No. of MS, n
(%) | | | | | | | | | |
| 0 | 9 (5.7) | 2 (1.3) | 0 (0.0) | 16 (4.6) | 3 (5.0) | 0 (0.0) | 1 (0.8) | 1 (6.3) | 1 (33.3) |
| 1 | 63 (40.1) | 68 (43.3) | 7 (31.8) | 156 (44.7) | 28 (46.7) | 5 (25.0) | 76 (60.8) | 11 (68.8) | 1 (33.3) |
| 2 | 50 (31.8) | 39 (24.8) | 7 (31.8) | 100 (28.7) | 17 (28.3) | 8 (40.0) | 35 (28.0) | 2 (12.5) | 0 (0.0) |
| >2 | 33 (21.0) | 18 (11.5) | 7 (31.8) | 76 (21.8) | 12 (20.0) | 7 (35.0) | 13 (10.4) | 2 (12.5) | 1 (33.3) |
| Unknown | 2 (1.3) | 4 (2.5) | 1 (4.5) | 1 (0.3) | 0 (0.0) | 0 (0.0) | 0 (0.0) | 0 (0.0) | 0 (0.0) |
| Metastatic sites, n
(%) | | | | | | | | | |
| Lung | 88 (56.1) | 77 (58.8) | 12 (54.5) | 225 (64.5) | 36 (60.0) | 15 (75.0) | 83 (66.4) | 10 (62.5) | 1 (33.3) |
| Lymph nodes | 40 (25.5) | 18 (13.7) | 6 (27.3) | 111 (31.8) | 21 (35.0) | 8 (40.0) | 21 (16.8) | 2 (12.5) | 1 (33.3) |
| Liver | 16 (10.2) | 19 (14.5) | 5 (22.7) | 70 (20.1) | 8 (13.3) | 3 (15.0) | 17 (13.6) | 3 (18.8) | 0 (0.0) |
| Bone | 57 (36.3) | 40 (30.5) | 9 (40.9) | 74 (21.2) | 12 (20.0) | 5 (25.0) | 34 (27.2) | 4 (25.0) | 1 (33.3) |
| Brain | 16 (10.2) | 10 (7.6) | 3 (13.6) | 23 (6.6) | 3 (5.0) | 2 (10.0) | 5 (4.0) | 2 (12.5) | 0 (0.0) |
| Time from initial
RCC diagnosis to treatment (months) | | | | | | | | | |
| Median
(range) | 4.4
(0.1–339.3) | 6.4
(0.1–480.8) | 21.6
(1.2–86.1) | 9.8
(0.0–222.4) | 21.3
(0.5–158.4) | 13.8
(1.1–101.7) | 9.4
(0.0–222.6) | 3.8 (0.3–83.8) | 9.0 (6.6–39.1) |
| <1 year, n
(%) | 99 (63.1) | 76 (58.0) | 10 (45.5) | 186 (53.3) | 25 (41.7) | 10 (50.0) | 68 (54.4) | 11 (68.8) | 2 (66.7) |
| Prior therapy, n
(%) | | | | | | | | | |
| Nephrectomy | 114 (72.6) | 89 (67.9) | 18 (81.8) | 242 (69.3) | 50 (83.3) | 18 (90.0) | 97 (77.6) | 12 (75.0) | 2 (66.7) |
| Radiation
therapy | 36 (22.9) | 33 (25.2) | 11 (50.0) | 23 (6.6) | 10 (16.7) | 2 (10.0) | 7 (5.6) | 1 (6.3) | 0 (0.0) |
| Comorbidities, n
(%) | | | | | | | | | |
| Hypertension | 43 (27.4) | 41 (31.3) | 10 (45.5) | 66 (18.9) | 31 (51.7) | 4 (20.0) | 42 (33.6) | 4 (25.0) | 0 (0.0) |
| Diabetes | 3 (1.9) | 4 (3.1) | 2 (9.1) | 17 (5.8) | 10 (18.5) | 0 (0.0) | 16 (12.8) | 3 (18.8) | 0 (0.0) |
Toxicity profile
Table II presents
the rates of all grade and grade 3/4 AEs. The proportion of
sunitinib patients experiencing at least one AE was about 87%
across all regions. Among patients receiving sorafenib, 78.3%
(Europe) to 87.8% (US) experienced at least one AE, and among
patients receiving bevacizumab, 33.3% (Asia) to 77.3% (US)
experienced at least one AE. Specific AEs experienced by at least
5% of patients in at least one treatment group are reported. The
three most common all grade AEs in patients treated with sunitinib
were fatigue/asthenia [range: 18.4% (Asia) to 58.5% (Europe)],
mucositis/stomatitis [range: 22.9% (US) to 42.1% (Europe)] and
diarrhea [range: 17.6% (Asia) to 34.4% (US)]. Patients treated with
sorafenib commonly experienced the following all grade AEs:
fatigue/asthenia [range: 6.3% (Asia) to 39.7% (US)], diarrhea
[range: 6.7% (Asia) to 35.1% (US)], and nausea [range: 5.0%
(Europe) to 23.7% (US)]. Among patients who received bevacizumab,
the most common all grade AEs reported on the medical charts were
fatigue/asthenia [up to 45.4% (US)] and proteinuria [up to 22.7%
(US)].
| Table II.Adverse events by severity among
patients with advanced RCC receiving first-line angiogenesis
inhibitor treatment.a |
Table II.
Adverse events by severity among
patients with advanced RCC receiving first-line angiogenesis
inhibitor treatment.a
| United States
| Europe
| Asia
|
|---|
| SU (n=157) | SOR (n=131) | BEV (n=22) | SU (n=349) | SOR (n=60) | BEV (n=20) | SU (n=125) | SOR (n=16) | BEV (n=3) |
|---|
| Patients with at
least one adverse event, n (%) | | | | | | | | | |
| All grades | 137 (87.3) | 115 (87.8) | 17 (77.3) | 302 (86.5) | 47 (78.3) | 13 (65.0) | 111 (88.8) | 13 (81.3) | 1 (33.3) |
| Grades 3 and
4 | 46 (29.3) | 41 (31.3) | 3 (13.6) | 84 (24.1) | 11 (18.3) | 4 (20.0) | 34 (27.2) | 6 (37.5) | 0 (0.0) |
| Specific adverse
events, n (%)b | | | | | | | | | |
| Abdominal
pain | | | | | | | | | |
| All grades | 11 (7.0) | 10 (7.6) | 0 (0.0) | 4 (1.1) | 0 (0.0) | 0 (0.0) | 3 (2.4) | 1 (6.3) | 0 (0.0) |
| Grades 3 and
4 | 1 (0.6) | 0 (0.0) | 0 (0.0) | 0 (0.0) | 0 (0.0) | 0 (0.0) | 1 (0.7) | 1 (6.3) | 0 (0.0) |
| Alopecia | | | | | | | | | |
| All grades | 1 (0.6) | 10 (7.6) | 0 (0.0) | 8 (2.3) | 0 (0.0) | 1 (5.0) | 2 (1.6) | 1 (6.3) | 0 (0.0) |
| Grades 3 and
4 | 0 (0.0) | 0 (0.0) | 0 (0.0) | 0 (0.0) | 0 (0.0) | 0 (0.0) | 0 (0.0) | 0 (0.0) | 0 (0.0) |
| Anemia | | | | | | | | | |
| All grades | 18 (11.5) | 5 (3.8) | 0 (0.0) | 10 (2.9) | 1 (1.7) | 0 (0.0) | 10 (8.0) | 1 (6.3) | 0 (0.0) |
| Grades 3 and
4 | 0 (0.0) | 0 (0.0) | 0 (0.0) | 1 (0.3) | 0 (0.0) | 0 (0.0) | 2 (1.6) | 0 (0.0) | 0 (0.0) |
| Anorexia | | | | | | | | | |
| All grades | 26 (16.6) | 17 (13.0) | 5 (22.7) | 47 (13.5) | 5 (8.3) | 1 (5.0) | 24 (19.2) | 1 (6.3) | 0 (0.0) |
| Grades 3 and
4 | 0 (0.0) | 2 (1.5) | 0 (0.0) | 1 (0.3) | 0 (0.0) | 0 (0.0) | 0 (0.0) | 0 (0.0) | 0 (0.0) |
| Constipation | | | | | | | | | |
| All grades | 13 (8.3) | 10 (7.6) | 2 (9.1) | 25 (7.2) | 2 (3.3) | 0 (0.0) | 8 (6.4) | 0 (0.0) | 0 (0.0) |
| Grades 3 and
4 | 1 (0.6) | 0 (0.0) | 0 (0.0) | 0 (0.0) | 0 (0.0) | 0 (0.0) | 0 (0.0) | 0 (0.0) | 0 (0.0) |
| Cough | | | | | | | | | |
| All grades | 4 (2.5) | 4 (3.1) | 1 (4.5) | 10 (2.9) | 0 (0.0) | 0 (0.0) | 10 (8.0) | 1 (6.3) | 0 (0.0) |
| Grades 3 and
4 | 0 (0.0) | 0 (0.0) | 0 (0.0) | 0 (0.0) | 0 (0.0) | 0 (0.0) | 0 (0.0) | 0 (0.0) | 0 (0.0) |
| Decreased taste
sensation | | | | | | | | | |
| All grades | 15 (9.6) | 4 (3.1) | 0 (0.0) | 24 (6.9) | 0 (0.0) | 0 (0.0) | 2 (1.6) | 0 (0.0) | 0 (0.0) |
| Grades 3 and
4 | 1 (0.6) | 0 (0.0) | 0 (0.0) | 0 (0.0) | 0 (0.0) | 0 (0.0) | 0 (0.0) | 0 (0.0) | 0 (0.0) |
| Dehydration | | | | | | | | | |
| All grades | 11 (7.0) | 6 (4.6) | 0 (0.0) | 3 (0.9) | 0 (0.0) | 0 (0.0) | 0 (0.0) | 0 (0.0) | 0 (0.0) |
| Grades 3 and
4 | 1 (0.6) | 0 (0.0) | 0 (0.0) | 1 (0.3) | 0 (0.0) | 0 (0.0) | 0 (0.0) | 0 (0.0) | 0 (0.0) |
| Diarrhea | | | | | | | | | |
| All grades | 54 (34.4) | 46 (35.1) | 4 (18.2) | 119 (34.1) | 4 (6.7) | 2 (10.0) | 22 (17.6) | 3 (18.8) | 0 (0.0) |
| Grades 3 and
4 | 4 (2.5) | 5 (3.8) | 0 (0.0) | 8 (2.3) | 0 (0.0) | 0 (0.0) | 1 (0.8) | 1 (6.3) | 0 (0.0) |
| Dyspnea | | | | | | | | | |
| All grades | 18 (11.5) | 8 (6.1) | 1 (4.5) | 26 (7.4) | 1 (1.7) | 1 (5.0) | 6 (4.8) | 3 (18.8) | 0 (0.0) |
| Grades 3 and
4 | 4 (2.5) | 1 (0.8) | 0 (0.0) | 3 (0.9) | 0 (0.0) | 0 (0.0) | 0 (0.0) | 0 (0.0) | 0 (0.0) |
| Edema (any
location) | | | | | | | | | |
| All grades | 11 (7.0) | 1 (0.8) | 0 (0.0) | 17 (4.9) | 0 (0.0) | 1 (5.0) | 14 (11.2) | 0 (0.0) | 0 (0.0) |
| Grades 3 and
4 | 0 (0.0) | 0 (0.0) | 0 (0.0) | 2 (0.6) | 0 (0.0) | 0 (0.0) | 1 (0.8) | 0 (0.0) | 0 (0.0) |
| Epistaxis | | | | | | | | | |
| All grades | 0 (0.0) | 0 (0.0) | 0 (0.0) | 11 (3.2) | 0 (0.0) | 0 (0.0) | 3 (2.4) | 0 (0.0) | 0 (0.0) |
| Grades 3 and
4 | 0 (0.0) | 0 (0.0) | 0 (0.0) | 1 (0.3) | 0 (0.0) | 0 (0.0) | 0 (0.0) | 0 (0.0) | 0 (0.0) |
| Fatigue or
asthenia | | | | | | | | | |
| All grades | 72 (45.9) | 52 (39.7) | 10 (45.4) | 204 (58.5) | 21 (35.0) | 4 (20.0) | 23 (18.4) | 1 (6.3) | 0 (0.0) |
| Grades 3 and
4 | 8 (5.1) | 5 (3.8) | 1 (4.5) | 26 (7.4) | 4 (6.7) | 1 (5.0) | 1 (0.8) | 0 (0.0) | 0 (0.0) |
| Fever and/or
chills | | | | | | | | | |
| All grades | 15 (9.6) | 6 (4.6) | 0 (0.0) | 3 (0.9) | 0 (0.0) | 0 (0.0) | 9 (7.2) | 1 (6.3) | 0 (0.0) |
| Grades 3 and
4 | 1 (0.6) | 0 (0.0) | 0 (0.0) | 2 (0.6) | 0 (0.0) | 0 (0.0) | 3 (2.0) | 0 (0.0) | 0 (0.0) |
| Hand-foot
syndrome | | | | | | | | | |
| All grades | 20 (12.7) | 33 (25.2) | 0 (0.0) | 91 (26.1) | 6 (10.0) | 0 (0.0) | 49 (39.2) | 6 (37.5) | 0 (0.0) |
| Grades 3 and
4 | 1 (0.6) | 8 (6.1) | 0 (0.0) | 10 (2.9) | 1 (1.7) | 0 (0.0) | 6 (4.8) | 2 (12.5) | 0 (0.0) |
| Hemorrhage | | | | | | | | | |
| All grades | 9 (5.7) | 7 (5.3) | 1 (4.5) | 7 (2.0) | 0 (0.0) | 0 (0.0) | 2 (1.6) | 0 (0.0) | 0 (0.0) |
| Grades 3 and
4 | 0 (0.0) | 2 (1.5) | 0 (0.0) | 1 (0.3) | 0 (0.0) | 0 (0.0) | 1 (0.8) | 0 (0.0) | 0 (0.0) |
| Hypertension | | | | | | | | | |
| All grades | 20 (12.7) | 12 (9.2) | 4 (18.2) | 50 (14.3) | 3 (5.0) | 1 (5.0) | 21 (16.8) | 1 (6.3) | 1 (33.3) |
| Grades 3 and
4 | 0 (0.0) | 2 (1.5) | 0 (0.0) | 0 (0.0) | 1 (1.7) | 0 (0.0) | 1 (0.8) | 0 (0.0) | 0 (0.0) |
|
Hypothyroidism | | | | | | | | | |
| All grades | 1 (0.6) | 0 (0.0) | 0 (0.0) | 17 (4.9) | 0 (0.0) | 0 (0.0) | 7 (5.6) | 0 (0.0) | 0 (0.0) |
| Grades 3 and
4 | 0 (0.0) | 0 (0.0) | 0 (0.0) | 0 (0.0) | 0 (0.0) | 0 (0.0) | 0 (0.0) | 0 (0.0) | 0 (0.0) |
| Mucositis or
stomatitis | | | | | | | | | |
| All grades | 36 (22.9) | 18 (13.7) | 2 (9.1) | 147 (42.1) | 4 (6.7) | 1 (5.0) | 46 (36.8) | 3 (18.8) | 0 (0.0) |
| Grades 3 and
4 | 4 (2.5) | 6 (4.6) | 0 (0.0) | 13 (3.7) | 0 (0.0) | 0 (0.0) | 4 (3.2) | 0 (0.0) | 0 (0.0) |
| Nausea | | | | | | | | | |
| All grades | 43 (27.4) | 31 (23.7) | 4 (18.2) | 74 (21.2) | 3 (5.0) | 1 (5.0) | 14 (11.2) | 2 (12.5) | 0 (0.0) |
| Grades 3 and
4 | 3 (1.9) | 2 (1.5) | 0 (0.0) | 3 (0.9) | 0 (0.0) | 0 (0.0) | 0 (0.0) | 0 (0.0) | 0 (0.0) |
| Oral pain | | | | | | | | | |
| All grades | 2 (1.3) | 2 (1.5) | 0 (0.0) | 16 (4.6) | 0 (0.0) | 0 (0.0) | 5 (4.0) | 0 (0.0) | 0 (0.0) |
| Grades 3 and
4 | 0 (0.0) | 0 (0.0) | 0 (0.0) | 0 (0.0) | 0 (0.0) | 0 (0.0) | 0 (0.0) | 0 (0.0) | 0 (0.0) |
| Other skin
problemsc | | | | | | | | | |
| All grades | 16 (10.2) | 16 (12.2) | 0 (0.0) | 38 (10.9) | 2 (3.3) | 0 (0.0) | 1 (0.8) | 1 (6.3) | 0 (0.0) |
| Grades 3 and
4 | 0 (0.0) | 0 (0.0) | 0 (0.0) | 0 (0.0) | 1 (1.7) | 0 (0.0) | 0 (0.0) | 0 (0.0) | 0 (0.0) |
| Pain | | | | | | | | | |
| All grades | 29 (18.5) | 27 (20.6) | 2 (9.1) | 56 (16.0) | 0 (0.0) | 3 (15.0) | 23 (18.4) | 3 (18.8) | 0 (0.0) |
| Grades 3 and
4 | 4 (2.5) | 5 (3.8) | 0 (0.0) | 4 (1.1) | 0 (0.0) | 0 (0.0) | 4 (3.2) | 0 (0.0) | 0 (0.0) |
| Proteinuria | | | | | | | | | |
| All grades | 0 (0.0) | 0 (0.0) | 5 (22.7) | 3 (0.9) | 0 (0.0) | 2 (10.0) | 2 (1.6) | 0 (0.0) | 0 (0.0) |
| Grades 3 and
4 | 0 (0.0) | 0 (0.0) | 3 (13.6) | 0 (0.0) | 0 (0.0) | 1 (5.0) | 1 (0.8) | 0 (0.0) | 0 (0.0) |
| Skin rash | | | | | | | | | |
| All grades | 19 (12.1) | 50 (38.2) | 2 (9.1) | 37 (10.6) | 5 (8.3) | 2 (10.0) | 26 (20.8) | 4 (25.0) | 0 (0.0) |
| Grades 3 and
4 | 1 (0.6) | 9 (6.9) | 0 (0.0) | 4 (1.1) | 1 (1.7) | 0 (0.0) | 0 (0.0) | 1 (6.3) | 0 (0.0) |
|
Thrombocytopenia | | | | | | | | | |
| All grades | 13 (8.3) | 3 (2.3) | 0 (0.0) | 15 (4.3) | 1 (1.7) | 0 (0.0) | 14 (11.2) | 0 (0.0) | 0 (0.0) |
| Grades 3 and
4 | 5 (3.2) | 0 (0.0) | 0 (0.0) | 3 (0.9) | 0 (0.0) | 0 (0.0) | 2 (1.6) | 0 (0.0) | 0 (0.0) |
| Urinary
problemsd | | | | | | | | | |
| All grades | 6 (3.8) | 9 (6.9) | 0 (0.0) | 1 (0.3) | 0 (0.0) | 0 (0.0) | 0 (0.0) | 1 (6.3) | 0 (0.0) |
| Grades 3 and
4 | 0 (0.0) | 1 (0.8) | 0 (0.0) | 0 (0.0) | 0 (0.0) | 0 (0.0) | 0 (0.0) | 0 (0.0) | 0 (0.0) |
| Vomiting | | | | | | | | | |
| All grades | 24 (15.3) | 16 (12.2) | 1 (4.5) | 27 (7.7) | 1 (1.7) | 1 (5.0) | 6 (4.8) | 2 (12.5) | 0 (0.0) |
| Grades 3 and
4 | 1 (0.6) | 2 (1.5) | 0 (0.0) | 1 (0.3) | 0 (0.0) | 0 (0.0) | 0 (0.0) | 0 (0.0) | 0 (0.0) |
| Weight loss | | | | | | | | | |
| All grades | 8 (5.1) | 12 (9.2) | 0 (0.0) | 1 (0.3) | 0 (0.0) | 0 (0.0) | 3 (2.4) | 0 (0.0) | 0 (0.0) |
| Grades 3 and
4 | 1 (0.6) | 0 (0.0) | 0 (0.0) | 0 (0.0) | 0 (0.0) | 0 (0.0) | 0 (0.0) | 0 (0.0) | 0 (0.0) |
Treatment patterns
Table III
summarizes treatment patterns for first-line treatment with
angiogenesis inhibitor. Median treatment duration, in months, was
6.1 (US), 10.7 (Europe) and 10.7 (Asia) for sunitinib; 5.1 (US),
8.5 (Europe) and 7.1 (Asia) for sorafenib; and 9.2 (US), 9.8
(Europe) and 7.5 (Asia) for bevacizumab. Treatment discontinuation
occurred in 62.4% (Asia) to 63.1% (US) of patients treated with
sunitinib, 68.8% (Asia) to 90.0% (Europe) of patients treated with
sorafenib, and 66.7% (Asia) to 81.8% (US) of patients treated with
bevacizumab. Reasons for treatment modifications were available at
all but one site. Among sites with these data, progressive disease
was the most commonly recorded reason for treatment discontinuation
[sunitinib, 33.1% (US) to 40.0% (Asia); sorafenib, 42.0% (US) to
55.6% (Europe); bevacizumab, 33.3% (Asia) to 46.7% (Europe)]
followed by AEs [sunitinib, 18.4% (Asia) to 23.6% (US); sorafenib,
6.3% (Asia) to 28.2% (US); bevacizumab, 0% (Asia) to 27.3% (US)].
Drug dosage was reduced in 34.4% (US) to 48.0% (Asia) of patients
treated with sunitinib, and 21.7% (Europe) to 45.8% (US) of
patients treated with sorafenib. AEs were the most commonly
reported reason for reduced dosage for sunitinib [29.2% (US), 37.1%
(Europe), and 36.8% (Asia)], and sorafenib [43.5% (US), 20.4%
(Europe), and 31.3% (Asia)]. After the discontinuation of
first-line treatment, 20.4% (US) to 24.0% (Asia) of patients
treated with sunitinib, 31.3% (Asia) to 50.0% (Europe) of patients
treated with sorafenib, and 59.1% (US) to 70.0% (Europe) of
patients treated with bevacizumab received second-line therapy.
| Table III.Treatment patterns among patients
with advanced RCC receiving first-line angiogenesis inhibitor
treatment |
Table III.
Treatment patterns among patients
with advanced RCC receiving first-line angiogenesis inhibitor
treatment
| Variable | United States
| Europe
| Asia
|
|---|
| SU (n=157) | SOR (n=131) | BEV (n=22) | SU (n=349) | SOR (n=60) | BEV (n=20) | SU (n=125) | SOR (n=16) | BEV (n=3) |
|---|
| First-line
treatment | | | | | | | | | |
| Patients who
discontinued first-line treatment, n (%) | 99 (63.1) | 103 (78.6) | 18 (81.8) | 220 (63.0) | 54 (90.0) | 16 (80.0) | 78 (62.4) | 11 (68.8) | 2 (66.7) |
| Duration of
treatmenta | | | | | | | | | |
| Median (95%
CI)b,c | 6.1 (5.1–7.1) | 5.1 (3.9–6.0) | 9.2 (6.0–18.9) | 10.7
(9.1–12.7) | 8.5 (7.2–14.0) | 9.8 (7.3–11.0) | 10.7
(7.0–14.2) | 7.1 (2.4–12.1) | 7.5 (6.6–7.2) |
| Mean (SD) | 7.8 (0.5) | 8.1 (0.8) | 13.7 (2.4) | 17.4 (1.1) | 15.0 (1.8) | 24.0 (13.8) | 8.4 (7.5) | 4.7 (3.4) | 6.9 (0.4) |
| Reason for
discontinuation, n (%)d,e | | | | | | | | | |
| Progressive
disease | 52 (33.1) | 55 (42.0) | 10 (45.5) | 107 (36.8) | 30 (55.6) | 7 (46.7) | 50 (40.0) | 7 (43.8) | 1 (33.3) |
| Adverse
events | 37 (23.6) | 37 (28.2) | 6 (27.3) | 55 (18.9) | 8 (14.8) | 3 (20.0) | 23 (18.4) | 1 (6.3) | 0 (0.0) |
| Complete
response | 0 (0.0) | 0 (0.0) | 0 (0.0) | 1 (0.3) | 0 (0.0) | 0 (0.0) | 0 (0.0) | 0 (0.0) | 0 (0.0) |
| Stable
disease | 0 (0.0) | 0 (0.0) | 0 (0.0) | 1 (0.3) | 1 (1.9) | 0 (0.0) | 0 (0.0) | 0 (0.0) | 0 (0.0) |
| Other | 16 (10.2) | 17 (13.0) | 2 (9.1) | 10 (3.4) | 2 (3.7) | 0 (0.0) | 6 (4.8) | 0 (0.0) | 1 (33.3) |
| Unknown | 0 (0.0) | 0 (0.0) | 0 (0.0) | 17 (5.8) | 10 (18.5) | 2 (13.3) | 3 (2.4) | 3 (18.8) | 0 (0.0) |
| Patients with
first-line treatment interruption, n (%)e | 49 (31.2) | 57 (43.5) | 5 (22.7) | 88 (30.2) | 8 (14.8) | 3 (20.0) | 40 (32.0) | 6 (37.5) | 1 (33.3) |
| Reason for
treatment interruption, n (%)d,e | | | | | | | | | |
| Adverse
event | 44 (28.0) | 51 (38.9) | 5 (22.7) | 68 (23.4) | 8 (14.8) | 3 (20.0) | 35 (28.0) | 4 (25.0) | 1 (33.3) |
| Surgery | 0 (0.0) | 0 (0.0) | 0 (0.0) | 6 (2.1) | 1 (1.9) | 0 (0.0) | 2 (1.6) | 1 (6.3) | 0 (0.0) |
| Other | 13 (8.3) | 8 (6.1) | 1 (4.5) | 6 (2.1) | 0 (0.0) | 0 (0.0) | 3 (2.4) | 0 (0.0) | 0 (0.0) |
| Unknown | 0 (0.0) | 0 (0.0) | 0 (0.0) | 10 (3.4) | 0 (0.0) | 0 (0.0) | 4 (3.2) | 1 (6.3) | 0 (0.0) |
| Patients with
first-line treatment dose increase, n (%)8 | 18 (11.5) | 26 (19.8) | 0 (0.0) | 44 (12.6) | 5 (8.3) | 1 (5.0) | 19 (15.2) | 2 (12.5) | 0 (0.0) |
| Reason for dose
increase, n (%)d,e | | | | | | | | | |
| Good
tolerance | 4 (2.5) | 6 (4.6) | 0 (0.0) | 18 (6.2) | 1 (1.9) | 0 (0.0) | 0 (0.0) | 0 (0.0) | 0 (0.0) |
| Symptom
improvement | 0 (0.0) | 0 (0.0) | 0 (0.0) | 0 (0.0) | 0 (0.0) | 0 (0.0) | 3 (2.4) | 0 (0.0) | 0 (0.0) |
| Adverse events
improved | 1 (0.5) | 3 (2.3) | 0 (0.0) | 0 (0.0) | 0 (0.0) | 0 (0.0) | 0 (0.0) | 0 (0.0) | 0 (0.0) |
| Adverse
events | 0 (0.0) | 0 (0.0) | 0 (0.0) | 7 (2.4) | 0 (0.0) | 0 (0.0) | 4 (3.2) | 0 (0.0) | 0 (0.0) |
| Progressive
disease | 0 (0.0) | 4 (3.1) | 0 (0.0) | 4 (1.4) | 1 (1.9) | 0 (0.0) | 1 (0.8) | 1 (6.3) | 0 (0.0) |
| Other | 14 (8.9) | 16 (12.2) | 0 (0.0) | 6 (2.1) | 1 (1.9) | 0 (0.0) | 0 (0.0) | 0 (0.0) | 0 (0.0) |
| Unknown | 0 (0.0) | 0 (0.0) | 0 (0.0) | 7 (2.4) | 3 (5.6) | 0 (0.0) | 0 (0.0) | 0 (0.0) | 0 (0.0) |
| Patients with
first-line treatment dose reduction, n (%)8 | 54 (34.4) | 60 (45.8) | 0 (0.0) | 150 (43.0) | 13 (21.7) | 3 (15.0) | 60 (48.0) | 6 (37.5) | 0 (0.0) |
| Reason for dose
reduction, n (%)d,e | | | | | | | | | |
| Adverse
events | 47 (29.9) | 57 (43.5) | 0 (0.0) | 108 (37.1) | 11 (20.4) | 3 (20.0) | 46 (36.8) | 5 (31.3) | 0 (0.0) |
| Other | 11 (7.0) | 5 (3.8) | 0 (0.0) | 7 (2.4) | 0 (0.0) | 0 (0.0) | 6 (4.8) | 1 (6.3) | 0 (0.0) |
| Unknown | 0 (0.0) | 0 (0.0) | 0 (0.0) | 9 (3.1) | 2 (3.7) | 0 (0.0) | 10 (8.0) | 0 (0.0) | 0 (0.0) |
| Patients who
experienced at least one treatment modification, n (%) f | 136 (86.6) | 118 (90.1) | 19 (86.4) | 250 (85.9) | 51 (94.4) | 15 (100.0) | 106 (84.8) | 14 (87.5) | 3 (100.0) |
| Patients who
experienced at least one treatment modification due to adverse
events, n (%)e,f | 88 (56.1) | 84 (64.1) | 11 (50.0) | 154 (52.9) | 18 (33.3) | 8 (53.3) | 74 (59.2) | 7 (43.8) | 1 (33.3) |
| Second- and
third-line treatment | | | | | | | | | |
| Patients who
received second-line treatment, n (%) | 32 (20.4) | 60 (45.8) | 13 (59.1) | 79 (22.6) | 30 (50.0) | 14 (70.0) | 30 (24.0) | 5 (31.3) | 2 (66.7) |
| Reason for
first-line treatment discontinuation, n (%)d,e | | | | | | | | | |
| Progressive
disease | 20 (12.7) | 40 (30.5) | 6 (27.3) | 46 (15.8) | 17 (31.5) | 0 (0.0) | 23 (18.4) | 2 (12.5) | 1 (33.3) |
| Adverse
events | 12 (7.6) | 21 (16.0) | 5 (22.7) | 18 (6.2) | 2 (3.7) | 0 (0.0) | 5 (4.0) | 1 (6.3) | 0 (0.0) |
| Surgery | 0 (0.0) | 0 (0.0) | 0 (0.0) | 1 (0.3) | 0 (0.0) | 0 (0.0) | 2 (1.6) | 0 (0.0) | 0 (0.0) |
| Other | 1 (0.6) | 3 (2.3) | 2 (9.1) | 1 (0.3) | 0 (0.0) | 0 (0.0) | 2 (1.6) | 0 (0.0) | 1 (33.3) |
| Unknown | 0 (0.0) | 0 (0.0) | 0 (0.0) | 3 (1.0) | 9 (16.7) | 0 (0.0) | 0 (0.0) | 2 (12.5) | 0 (0.0) |
Table IV describes
specific AEs reported as reasons for first-line treatment
modifications. Among the AEs of interest, vomiting was the most
common AE leading to discontinuation of first-line sunitinib in the
US (21.6%), fatigue/asthenia was most common in Europe (32.7%), and
mucositis or stomatitis was the most common reason in Asia (34.8%).
For sorafenib, skin rash most commonly led to treatment
discontinuation in the US (27.8%); diarrhea and hand-foot syndrome
most commonly led to discontinuation in Europe (37.5%). The most
common AEs reported as reason for dose reduction for sunitinib
varied across regions: diarrhea in US (25.5%), fatigue in Europe
(31.5%) and mucositis or stomatitis in Asia (26.1%). Skin rash was
the most common AE for dose reduction among sorafenib patients in
US (31.6%), and hand-foot syndrome was the most common reason in
Europe (44.4%).
| Table IV.Adverse events reported as reasons
for treatment modifications among patients with advanced RCC
receiving first-line angiogenesis inhibitor treatment. |
Table IV.
Adverse events reported as reasons
for treatment modifications among patients with advanced RCC
receiving first-line angiogenesis inhibitor treatment.
| United States | Europec | Asia |
|---|
|
|
|
|---|
| SU (n=157) | SOR (n=131) | BEV (n=22) | SU (n=291) | SOR (n=54) | BEV (n=15) | SU (n=125) | SOR (n=16) | BEV (n=3) |
|---|
| Treatment
discontinuation | | | | | | | | | |
| Patients who
discontinued first-line treatment due to adverse events, n (%) | 37 (23.6) | 36 (27.5) | 8 (36.4) | 55 (18.9) | 8 (14.8) | 3 (20.0) | 23 (18.4) | 1 (6.3) | 0 (0.0) |
| Adverse events
per discontinuation, mean (SD) | 2.3 (1.3) | 1.9 (1.0) | 1.5 (0.7) | 2.5 (1.1) | 3.1 (1.4) | 3 (1.7) | 2.5 (0.7) | 2.0 (N/A) | N/A |
| Adverse events
resulting in a treatment discontinuation, n (%)a,b | | | | | | | | | |
| Diarrhea | 5 (13.5) | 2 (5.6) | 0 (0.0) | 5 (9.1) | 3 (37.5) | 1 (33.3) | 0 (0.0) | 0 (0.0) | 0 (0.0) |
| Fatigue or
asthenia | 6 (16.2) | 8 (22.2) | 0 (0.0) | 18 (32.7) | 2 (25.0) | 1 (33.3) | 2 (8.7) | 0 (0.0) | 0 (0.0) |
| Hand-foot
syndrome | 4 (10.8) | 4 (11.1) | 0 (0.0) | 5 (9.1) | 3 (37.5) | 0 (0.0) | 5 (21.7) | 0 (0.0) | 0 (0.0) |
|
Hypertension | 2 (5.4) | 2 (5.6) | 0 (0.0) | 3 (5.5) | 1 (12.5) | 0 (0.0) | 2 (8.7) | 0 (0.0) | 0 (0.0) |
| Mucositis or
stomatitis | 0 (0.0) | 0 (0.0) | 0 (0.0) | 5 (9.1) | 1 (12.5) | 0 (0.0) | 8 (34.8) | 0 (0.0) | 0 (0.0) |
| Nausea | 7 (18.9) | 6 (16.7) | 0 (0.0) | 2 (3.6) | 0 (0.0) | 0 (0.0) | 0 (0.0) | 0 (0.0) | 0 (0.0) |
| Skin rash | 4 (10.8) | 10 (27.8) | 1 (12.5) | 3 (5.5) | 1 (12.5) | 0 (0.0) | 1 (4.3) | 1(100.0) | 0 (0.0) |
| Vomiting | 8 (21.6) | 4 (11.1) | 0 (0.0) | 4 (7.3) | 0 (0.0) | 1 (33.3) | 0 (0.0) | 0 (0.0) | 0 (0.0) |
| Dose
interruption | | | | | | | | | |
| Patients with
first-line treatment dose interruption due to adverse events, n
(%) | 44 (28.0) | 51 (38.9) | 5 (22.7) | 68 (23.4) | 8 (14.8) | 3 (20.0) | 35 (28.0) | 4 (25.0) | 1(33.3) |
| Adverse events
per interruption, mean (SD) | 2.0 (1.4) | 1.7 (1.3) | 1.2 (0.5) | 2.9 (1.3) | 2.4 (0.7) | 2.7 (1.2) | 2.6 (1.0) | 2.5 (0.6) | 2.0 (0.0) |
| Adverse events
resulting in a treatment interruption, n (%)a,b | | | | | | | | | |
| Diarrhea | 5 (11.4) | 9 (17.6) | 0 (0.0) | 15 (22.1) | 1 (12.5) | 0 (0.0) | 2 (5.7) | 0 (0.0) | 0 (0.0) |
| Fatigue or
asthenia | 15 (34.1) | 2 (3.9) | 0 (0.0) | 18 (26.5) | 2 (25.0) | 0 (0.0) | 5 (14.3) | 0 (0.0) | 0 (0.0) |
| Hand-foot
syndrome | 6 (13.6) | 8 (15.7) | 0 (0.0) | 7 (10.3) | 2 (25.0) | 0 (0.0) | 8 (22.9) | 2 (50.0) | 0 (0.0) |
|
Hypertension | 4 (9.1) | 5 (9.8) | 1 (20.0) | 2 (2.9) | 0 (0.0) | 0 (0.0) | 3 (8.6) | 0 (0.0) | 0 (0.0) |
| Mucositis or
stomatitis | 4 (9.1) | 10 (19.6) | 0 (0.0) | 17 (25.0) | 1 (12.5) | 1 (33.3) | 1 (2.9) | 0 (0.0) | 0 (0.0) |
| Nausea | 7 (15.9) | 5 (9.8) | 0 (0.0) | 6 (8.8) | 0 (0.0) | 0 (0.0) | 1 (2.9) | 1 (25.0) | 0 (0.0) |
| Skin rash | 1 (2.3) | 17 (33.3) | 0 (0.0) | 6 (8.8) | 3 (37.5) | 0 (0.0) | 1 (2.9) | 0 (0.0) | 0 (0.0) |
| Vomiting | 5 (11.4) | 4 (7.8) | 0 (0.0) | 10 (14.7) | 0 (0.0) | 0 (0.0) | 1 (2.9) | 1 (25.0) | 0 (0.0) |
| Dose reduction | | | | | | | | | |
| Patients with
first-line treatment dose reduction due to adverse events, n
(%) | 47 (29.9) | 57 (43.5) | 0 (0.0) | 108 (37.1) | 9 (16.7) | 3 (20.0) | 46 (36.8) | 5 (18.8) | 0 (0.0) |
| Adverse events
per reduction, mean (SD) | 2.1 (1.2) | 1.7 (1.2) | N/A | 3.3 (1.4) | 3.1 (1.9) | 4.0 (2.0) | 2.6 (0.8) | 2.4 (0.9) | N/A |
| Adverse events of
interest resulting in a dose reduction, n (%)a,b | | | | | | | | | |
| Diarrhea | 12 (25.5) | 13 (22.8) | 0 (0.0) | 27 (25.0) | 2 (22.2) | 0 (0.0) | 7 (15.2) | 1 (20.0) | 0 (0.0) |
| Fatigue or
asthenia | 10 (21.3) | 7 (12.3) | 0 (0.0) | 34 (31.5) | 3 (33.3) | 1 (33.3) | 3 (6.5) | 0 (0.0) | 0 (0.0) |
| Hand-foot
syndrome | 3 (6.4) | 14 (24.6) | 0 (0.0) | 19 (17.6) | 4 (44.4) | 0 (0.0) | 10 (21.7) | 3 (60.0) | 0 (0.0) |
|
Hypertension | 7 (14.9) | 6 (10.5) | 0 (0.0) | 9 (8.3) | 0 (0.0) | 0 (0.0) | 4 (8.7) | 1 (20.0) | 0 (0.0) |
| Mucositis or
stomatitis | 9 (19.1) | 10 (17.5) | 0 (0.0) | 32 (29.6) | 3 (33.3) | 1 (33.3) | 12 (26.1) | 0 (0.0) | 0 (0.0) |
| Nausea | 8 (17.0) | 4 (7.0) | 0 (0.0) | 18 (16.7) | 1 (11.1) | 0 (0.0) | 0 (0.0) | 0 (0.0) | 0 (0.0) |
| Skin rash | 1 (2.1) | 18 (31.6) | 0 (0.0) | 14 (13.0) | 1 (11.1) | 0 (0.0) | 3 (6.5) | 2 (40.0) | 0 (0.0) |
| Vomiting | 3 (6.4) | 2 (3.5) | 0 (0.0) | 13 (12.0) | 1 (11.1) | 0 (0.0) | 2 (4.3) | 0 (0.0) | 0 (0.0) |
Discussion
Findings from the current study with data from 883
patients contribute to the growing body of knowledge on the use of
sunitinib, sorafenib and bevacizumab as first-line agents among
patients with advanced RCC treated in real-world clinical practice
across different geographical regions. Tolerability and management
of side-effects for patients receiving sunitinib, sorafenib and
bevacizumab as first-line anti-angiogenesis treatment for advanced
RCC are significant issues for patients and the physicians who care
for them.
There were variations in treatment and outcomes
across global regions. In the US and Europe, patients receiving
sunitinib were almost twice as likely as those in Asia to initiate
therapy at 50 mg QD 4/2. This observation raises the issue relative
to the use of fixed doses of suntinib (and also of all molecularly
targeted agents), irrespective of parameters like gender and body
weight/body surface area. Indeed, a population pharmacokinetic
analysis identified low body weight (and female gender) as
covariates that significantly increase exposure to sunitinib,
potentially leading to increased toxicity (23). Moreover, the most commonly
experienced AEs also varied across region. In the US and Europe,
fatigue was the most common AE among patients receiving sunitinib,
sorafenib and bevacizumab while hand-foot syndrome was the most
common AE in Asian patients receiving sunitinib or sorafenib.
Notably, the AEs most commonly leading to treatment discontinuation
also varied.
Despite these differences, there were some universal
findings across settings. Notably, the median treatment duration
was generally shorter in this observational study compared with
that reported in RCTs and EAPs. The median treatment duration for
sunitinib was 11 and 16.6 months in the RCT and EAP (4,7),
respectively, whereas the median ranged from 6.1 to 10.7 months
across regions in this study. Similarly, the median treatment
duration for sorafenib was 12 months in the EAP (8) whereas it ranged from 5.1 to 8.5
months across regions in the current analysis. For bevacizumab the
median treatment duration was 9.7 months in one RCT (24) and 8.2 months in another RCT
(25) whereas it ranged from 7.5
to 9.8 months across regions in this study.
Treatment discontinuation was high, reaching 63.1%
among sunitinib patients in the US, 90.0% among sorafenib patients
in Europe, and 81.8% of bevacizumab patients in US. For patients
who discontinued sunitinib treatment due to AEs the average number
of AEs per discontinuation was 2.3–2.5 across regions; for
sorafenib it was 1.9–3.1. This illustrates that in real-world
practice physicians manage multiple AEs per patient and may
discontinue or modify treatment based on the observed effects of
these AEs. The proportion of patients with any type of treatment
modification due to an AE was also consistently high across all
regions, reaching 59.2% among sunitinib patients in Asia, 64.1%
among sorafenib patients in US and 53.3% of bevacizumab patients in
Europe.
This study builds upon prior evidence from RCTs and
EAPs on the toxicity and treatment patterns of angiogenesis
inhibitors. Similar to results in this global chart review study,
treatment discontinuation was high in RCTs and EAPs. In the RCT
comparing sunitinib to interferon α, 86% of patients experienced a
treatment discontinuation (versus 62.4 to 63.1% in the current
study) (4). In the EAP for
sorafenib, 100% of patients experienced a treatment discontinuation
(versus 68.8 to 90.0% in the current study) (8). In the RCT comparing bevacizumab plus
interferon to placebo, 72% of patients experienced a treatment
discontinuation (versus 66.7 to 81.8% in the current study)
(24). In RCTs, diarrhea was the
most commonly reported AE for both sunitinib and sorafenib (versus
fatigue in the US and Europe, and hand-foot syndrome in Asia in the
current study) and anorexia was the most commonly reported AE for
bevacizumab (versus fatigue in the current study for US and Europe)
(4,8,24).
In EAPs for sunitinib and sorafenib, the most commonly reported AEs
were diarrhea and hand-foot syndrome.
Differences with RCT may arise due to differences in
the underlying study populations as well as how data are collected.
For example, the proportion of patients with brain metastasis in
the current study were 7.0, 7.2 and 11.1%, for sunitinib, sorafenib
and bevacizumab, respectively, while these patients were excluded
in RCTs. Besides, RCTs have well-defined operational definitions
for AE identification and gradation, as well as a rigorous protocol
to capture them whereas in a retrospective setting such as in the
current study, AEs are captured based on the treating physicians'
reports and judgments. Sometimes physicians may record only those
AEs that lead to a treatment modification or if the AEs are severe
enough to warrant specific treatment; therefore, under-reporting of
AEs in this study may have occurred.
Findings from this study were generally consistent
with those from other observational studies (14–20).
In the Korean study by Hong et al (14), 76% of sunitinib patients had a dose
interruption or dose reduction due to AEs, and 11% overall
discontinued due to toxicity. A high proportion of patients in that
study (>75%) experienced fatigue, anorexia and hand-foot
syndrome. In the Korean study by Hwang et al (15), 29% of sunitinib patients
experienced a dose reduction. In the UK study by Ansari et
al (16), 15% of sunitinib
patients experienced a dose discontinuation in their first cycle of
treatment, and 75% experienced at least one dose reduction.
Notably, the number of patients in the current study was several
fold higher than the aforementioned observational studies.
Some disparities in study results between this study
and other observational studies reported above may have occurred
due to differences in treatment durations, frequency of patient
visits where AEs are reported, incomplete or inadequate recording
of AEs, and differences in practice patterns relative to management
of AEs across countries. Differences in drug approval dates,
affecting drug availability, could have affected practice patterns
as well. Differences in healthcare should also be kept in mind
while making comparisons across studies.
There are some limitations associated with this
study. Since data collection for this study preceded marketing
authorization for pazopanib in Europe, this study does not include
information on patients receiving pazopanib as first-line
treatment. Further, due to the small sample sizes in certain groups
for some regions, especially bevacizumab in all regions and
sorafenib in Asia, the findings reported are descriptive in
nature.
This multi-country study provides evidence that AEs
are common in patients with advanced RCC treated with angiogenesis
inhibitors, and that these AEs often lead to treatment
modifications in the real-world clinical setting. This real-world
practice study suggests that management of toxicities associated
with anti-angiogenic agents for the treatment of advanced RCC
presents significant issues for treating physicians and patients.
The findings from this study further underscore the continued need
for novel tolerable treatment options for advanced RCC.
Additionally, the results of this study show the potential benefits
of use of observational studies to further understand real-world
treatment patterns and outcomes, beyond information that may be
available from other data sources.
Acknowledgements
This study was funded by
GlaxoSmithKline (GSK), Collegeville, PA. The funding from GSK was
not contingent upon the study results. GSK participated in the
study design, results interpretation and manuscript preparation as
reflected in the authorship by GSK employees, M.P.N., J.R.D. and
F.M.. A molecule with similar mechanism of action developed by GSK
(pazopanib) was recently approved by the United States Food and
Drug Administration and European Medical Agency for treatment of
patients with advanced renal cell carcinoma. The institutions where
W.K.O., D.M., C.P., A.L., R.E., F.S., R.H., D.C., J.B., S.Y.R.,
J.-M.S., P.N., B.A.F., J.S., R.M., J.-H.A., J.W., Y.-H.C., Y.-C.O.,
P.D., C.-Y.H., J.M., P.-H.C. and C.-K.C. are, have received
research funds from Analysis Group Inc. M.S.D. and C.K. are
employees of Analysis Group Inc., which has received research
grants from GSK.
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