Abstract

Objective

Effects of sorafenib in general clinical practice, especially those with patients of Asian ethnicity, have been rarely investigated. We assessed efficacy, safety and prognostic factors for progression-free survival in Japanese patients receiving sorafenib for advanced renal cell carcinoma.

Methods

We performed a retrospective analysis of 159 Japanese patients with renal cell carcinoma. Progression-free survival was estimated by the Kaplan–Meier method. Objective response (per Response Evaluation Criteria in Solid Tumors) and safety were assessed. Cox proportional hazards model was used to identify independent prognostic factors for progression-free survival.

Results

The median progression-free survival was 9.0 months (95% confidence interval, 7.5–10.6 months). In 142 patients with measurable lesions, the objective response rate was 21.8%, and disease control was achieved in 85 (59.9%) patients. Adverse events of any grade occurred in 152 patients (95.6%). Most common adverse events causing discontinuation or interruption of sorafenib were hand-foot skin reaction (22%), rash (10.7%) and liver dysfunction (10.7%). Dose reduction or therapy interruption due to adverse events was required in 128 patients (80.5%). Univariate and multivariate analysis revealed that favorable prognosis according to Memorial Sloan-Kettering Cancer Center prognostic factors and relative dose intensity during the first month of treatment of ≥50% were significant factors for predicting superior progression-free survival with sorafenib treatment.

Conclusions

Sorafenib was effective in Japanese patients with advanced renal cell carcinoma in general clinical practice and was tolerated although most patients required dose reduction or interruption of therapy. Future studies should establish new strategies for treatment without sacrificing both efficacy and patient quality of life.

INTRODUCTION

Renal cell carcinoma (RCC) is the most common cancer of the kidney (1), and 75% of RCCs have a clear cell histology (2). RCC presents with metastatic disease in up to 30% of patients at the time of diagnosis, and recurrence develops in ∼40% of patients treated for a localized tumor (3). Advanced RCC is a highly chemoresistant disease. Until recently, immunotherapy was recommended as a first-line systemic therapy, but multi-targeted tyrosine kinase inhibitors (TKIs) including sorafenib and sunitinib have added new treatment options for patients with advanced RCC. In a phase 2 randomized discontinuation trial and the pivotal phase 3 Treatment Approaches in Renal Cancer Global Evaluation Trial (TARGET), sorafenib significantly prolonged progression-free survival (PFS) in patients with advanced RCC (4,5). Most of the previously reported clinical trials of sorafenib for advanced RCC included few patients of Asian ethnicity. In addition, patients in these clinical trials had to meet strict eligibility criteria including good performance status, no serious co-morbidities and adequate organ function. As a matter of course, few studies have reported on the experience of daily clinical practice in patients of Asian ethnicity treated with sorafenib and particularly that with Japanese patients. The aim of this study was to document the efficacy, prognostic factors and safety of treatment with sorafenib in Japanese patients with advanced RCC. Additionally, we examined the number of doses of sorafenib necessary to prolong PFS time.

PATIENTS AND METHODS

Patients who had been treated with sorafenib were identified by retrospective review of patients clinically diagnosed with RCC between April 2005 and July 2010 in 15 Japanese hospitals described in the Acknowledgements. Pretreatment evaluation consisted of a physical examination, laboratory tests, computed tomography scan and/or total body bone scan. Tumor response was evaluated by the treating urologist every 1–3 months according to the Response Evaluation Criteria in Solid Tumors (RECIST1.0) guidelines (6). Patients were evaluated for this study at the time of sorafenib administration according to modified Momorial Sloan-Kettering Cancer Center (MSKCC) risk groups. For patients as second-line therapy, risk factors are Eastern Cooperative Oncology Group Performance Status (ECOG PS) ≥ 2, low hemoglobin and high calcium. For patients as first-line therapy, additional risk factors were raised lactate dehydrogenase and time to use of sorafenib of <1 year (7,8). Adverse events as a result of treatment were evaluated at each visit during and after treatment. The average daily dose of sorafenib was calculated on the 30th, 60th and 90th days. The actual dose intensity (ADI) was defined as the cumulative dose received actually divided by the duration of the study therapy in weeks. Relative dose intensity (RDI) was defined as ADI divided by the dose prescribed for the duration of the study therapy (800 mg × the number of days the patient received treatment) (9).

Statistical Analysis

PFS time was measured from the date of the initiation of sorafenib treatment until radiologically documented confirmation of disease progression or death of the patient. Distributions of PFS and time on sorafenib were estimated with the Kaplan–Meier method. Associations between PFS and potential prognostic factors were assessed with the log-rank test in univariate analysis. The Cox proportional hazards model was subsequently used in multivariate analysis in a step-wise manner. All statistical analyses were performed with SPSS version 11 (SPSS, Inc., Chicago, IL, USA), and a value of P < 0.05 was considered statistically significant.

RESULTS

Patient Characteristics

Of the advanced RCC patients, 159 were identified as having been treated with sorafenib. Patient characteristics are shown in Table 1. A total of 134 patients underwent nephrectomy during the course of their disease. The remaining 25 patients with/without metastatic RCC did not undergo nephrectomy primarily due to unresectable RCC. Ninety-nine patients received cytokine therapy (i.e. with interferon and/or interleukin-2), and 149 patients received sorafenib as first-line TKI therapy. A daily dose of 800 mg of sorafenib was initiated in 129 patients, but 27 patients required dose reduction from the start of therapy. Dose modification was carried out based on the clinician's discretion on the basis of tumor response and adverse events.

Table 1.

Patient characteristics (n= 159)

Variable No. of patients (%) Total no. of patients evaluated 
Framework of the treatment  159 
 Registration studies 1 (0.6)  
 Daily practice 158 (99.4)  
 Both 1 (0.6)  
Age at targeted therapy initiation, years  159 
 Median 69  
 Range 41–92  
Sex  159 
 Male 123 (77.4)  
 Female 36 (22.6)  
T-classification at initial diagnosis  157 
 T1 23 (14.6)  
 T2 9 (5.7)  
 T3 23 (14.6)  
 T4 102 (65)  
Prior therapy  159 
 First-line therapy 60 (37.7)  
 Second-line therapy 57 (35.8)  
 Third-line therapy 41 (25.8)  
 Fourth-line therapy 1 (0.7)  
Kind of prior therapy 
 IFN-α 98 (61.6%)  
 IL-2 39 (24.5%)  
 Other TKIs 10 (6.3%)  
Histology  132 
 Clear cell carcinoma 102 (77.3)  
 Non-clear cell carcinoma 30 (22.7)  
Sites of metastatic disease  159 
 Lung 102 (64.2)  
 Bone 48 (30.2)  
 Lymph node 39 (24.5)  
 Liver 32 (20.1)  
 Kidney 17 (10.7)  
 Pancreas 10 (6.3)  
 Adrenal gland 9 (5.7)  
 Brain 8 (5)  
Number of metastatic foci  155 
 1 78 (50.3)  
 2 44 (28.4)  
 3 or more 33 (21.3)  
Prior Nephrectomy  159 
 Yes 134 (84.3)  
 No 25 (15.7)  
MSKCC prognostic factors  139 
 Favorable 28 (20.1)  
 Intermediate 87 (62.6)  
 Poor 24 (17.3)  
Variable No. of patients (%) Total no. of patients evaluated 
Framework of the treatment  159 
 Registration studies 1 (0.6)  
 Daily practice 158 (99.4)  
 Both 1 (0.6)  
Age at targeted therapy initiation, years  159 
 Median 69  
 Range 41–92  
Sex  159 
 Male 123 (77.4)  
 Female 36 (22.6)  
T-classification at initial diagnosis  157 
 T1 23 (14.6)  
 T2 9 (5.7)  
 T3 23 (14.6)  
 T4 102 (65)  
Prior therapy  159 
 First-line therapy 60 (37.7)  
 Second-line therapy 57 (35.8)  
 Third-line therapy 41 (25.8)  
 Fourth-line therapy 1 (0.7)  
Kind of prior therapy 
 IFN-α 98 (61.6%)  
 IL-2 39 (24.5%)  
 Other TKIs 10 (6.3%)  
Histology  132 
 Clear cell carcinoma 102 (77.3)  
 Non-clear cell carcinoma 30 (22.7)  
Sites of metastatic disease  159 
 Lung 102 (64.2)  
 Bone 48 (30.2)  
 Lymph node 39 (24.5)  
 Liver 32 (20.1)  
 Kidney 17 (10.7)  
 Pancreas 10 (6.3)  
 Adrenal gland 9 (5.7)  
 Brain 8 (5)  
Number of metastatic foci  155 
 1 78 (50.3)  
 2 44 (28.4)  
 3 or more 33 (21.3)  
Prior Nephrectomy  159 
 Yes 134 (84.3)  
 No 25 (15.7)  
MSKCC prognostic factors  139 
 Favorable 28 (20.1)  
 Intermediate 87 (62.6)  
 Poor 24 (17.3)  

TKI, tyrosine kinase inhibitor; MSKCC, Memorial Sloan-Kettering Cancer Center; IFN, interferon; IL-2, interleukin-2.

Treatment Outcome

The median follow-up time after treatment initiation was 9.1 months (range 0.3–63 months). In 142 patients with measurable lesions, radiologically confirmed complete response, partial response and stable disease of more than 3 months as best objective responses were observed in 1 (0.7%), 30 (21.1%) and 54 (38%) patients, respectively. The median PFS was 9.0 months [95% confidence interval (CI), 7.5–10.6 months; Fig. 1].

Figure 1.

Progression-free survival (PFS) of patients with advanced renal cell carcinoma (RCC) treated with sorafenib.

Figure 1.

Progression-free survival (PFS) of patients with advanced renal cell carcinoma (RCC) treated with sorafenib.

Adverse Events and Drug Exposure

Adverse events of any grade were experienced by 152 patients (95.6%). Dose reduction or therapy interruption due to adverse events was required in 128 patients (80.5%), and 27 (17.0%) started initial sorafenib therapy at reduced doses. The most common adverse events causing discontinuation or interruption of sorafenib included hand-foot skin reaction (22%), rash (10.7%), liver dysfunction (10.7%), general fatigue (8.8%) and hypertension (8.8%) (Table 2). In the 129 patients of sorafenib starting dose 800 mg per day, dose reduction was needed for 67 patients (51.9%) at the first one month. The average starting dose of sorafenib was 735 mg per day, whereas the average dose on the 30th, 60th and 90th day was 415, 388.2 and 426.8 mg, respectively. The average and median RDIs during the first month of treatment (1M-RDI) were 67.2 and 71.7%, respectively. The median duration of sorafenib treatment was 4.7 months (0.1–27.9).

Table 2.

Adverse events causing discontinuation or interruption of therapy

Category Adverse events n (%) 
Cardiac general Hypertension 14 (8.8) 
Myocardial infarction 1 (0.6) 
Congestive heart failure 1 (0.6) 
Arrhythmia 2 (1.3) 
Cardiac dysfunction 1 (0.6) 
Constitutional symptoms General fatigue 14 (8.8) 
Dermatology/skin Hand-foot skin reaction 35 (22) 
Urticaria/Rash 17 (10.7) 
Alopecia 3 (1.9) 
Gastrointestinal Anorexia 9 (5.7) 
Diarrhea 9 (5.7) 
Nausea/vomiting 7 (4.4) 
Hematochezia 5 (3.1) 
Metabolic/laboratory Lipase 1 (0.6) 
Hypercalcemia 1 (0.6) 
Alanine transaminase 1 (0.6) 
Amylase 3 (1.9) 
Hepatobiliary/pancreas Liver dysfunction 17 (10.7) 
Pancreatitis 1 (0.6) 
Blood/bone marrow Neutropenia 1 (0.6) 
Thrombocytopenia 1 (0.6) 
Hemorrhage/bleeding Hemorrhage (digestive tract) 2 (1.3) 
Hemorrhage (brain) 1 (0.6) 
Pulmonary/upper respiratory Hoarseness 2 (1.3) 
Dyspnea 1 (0.6) 
Pneumonia 1 (0.6) 
Category Adverse events n (%) 
Cardiac general Hypertension 14 (8.8) 
Myocardial infarction 1 (0.6) 
Congestive heart failure 1 (0.6) 
Arrhythmia 2 (1.3) 
Cardiac dysfunction 1 (0.6) 
Constitutional symptoms General fatigue 14 (8.8) 
Dermatology/skin Hand-foot skin reaction 35 (22) 
Urticaria/Rash 17 (10.7) 
Alopecia 3 (1.9) 
Gastrointestinal Anorexia 9 (5.7) 
Diarrhea 9 (5.7) 
Nausea/vomiting 7 (4.4) 
Hematochezia 5 (3.1) 
Metabolic/laboratory Lipase 1 (0.6) 
Hypercalcemia 1 (0.6) 
Alanine transaminase 1 (0.6) 
Amylase 3 (1.9) 
Hepatobiliary/pancreas Liver dysfunction 17 (10.7) 
Pancreatitis 1 (0.6) 
Blood/bone marrow Neutropenia 1 (0.6) 
Thrombocytopenia 1 (0.6) 
Hemorrhage/bleeding Hemorrhage (digestive tract) 2 (1.3) 
Hemorrhage (brain) 1 (0.6) 
Pulmonary/upper respiratory Hoarseness 2 (1.3) 
Dyspnea 1 (0.6) 
Pneumonia 1 (0.6) 

Univariate Analysis

All 10 potential predictive factors assessed by univariate analysis are presented in Table 3. Factors that were significantly associated with poor PFS included non-clear cell carcinoma, absence of nephrectomy, prior to other TKI therapy, intermediate plus poor risk according to modified MSKCC prognostic factors (7,8) and a 1M-RDI of <50%. There were no differences in PFS when numbers and sites of metastasis (P = 0.35, 0.251, respectively) were compared or when patients receiving sorafenib first or receiving previous therapy (P = 0.718) were compared.

Table 3.

Results of univariate analysis of prognostic factors for progression-free survival (PFS)

Parameter No. of patients Median PFS (months) Log-rank P value 
Age, years   0.401 
 ≤70 73 9.0  
 >70 69 9.0  
Sex   0.918 
 Male 111 9.0  
 Female 31 9.0  
T-classification at initial diagnosis   0.292 
 T1–3 48 9.0  
 T4 92 9.0  
Prior therapy   0.718 
 First-line therapy 46 7.3  
 Second or more line therapy 96 9.1  
Prior to TKI therapy 
 Yes 3.0 0.001 
 No 133 9.0  
Histology   0.025 
 Clear cell carcinoma 92 10.0  
 Non-clear cell carcinoma 27 6.0  
Prior Nephrectomy   0.018 
 Yes 21 9.0  
 No 121 4.4  
No. of metastases   0.251 
 >1 69 7.3  
 1 71 9.0  
MSKCC prognostic factors   0.001 
 Favorable 25 24.0  
 Intermediate + poor 110 6.0  
1M-RDI   0.042 
 <50% 30 4.1  
 ≥50% 100 9.0  
Parameter No. of patients Median PFS (months) Log-rank P value 
Age, years   0.401 
 ≤70 73 9.0  
 >70 69 9.0  
Sex   0.918 
 Male 111 9.0  
 Female 31 9.0  
T-classification at initial diagnosis   0.292 
 T1–3 48 9.0  
 T4 92 9.0  
Prior therapy   0.718 
 First-line therapy 46 7.3  
 Second or more line therapy 96 9.1  
Prior to TKI therapy 
 Yes 3.0 0.001 
 No 133 9.0  
Histology   0.025 
 Clear cell carcinoma 92 10.0  
 Non-clear cell carcinoma 27 6.0  
Prior Nephrectomy   0.018 
 Yes 21 9.0  
 No 121 4.4  
No. of metastases   0.251 
 >1 69 7.3  
 1 71 9.0  
MSKCC prognostic factors   0.001 
 Favorable 25 24.0  
 Intermediate + poor 110 6.0  
1M-RDI   0.042 
 <50% 30 4.1  
 ≥50% 100 9.0  

PFS, progression-free survival; 1M-RDI, relative dose intensity during the first month of treatment. Bold values indicate P < 0.05.

Multivariate Analysis

In the resulting Cox proportional hazards model (Table 4), two factors [favorable risk according to modified MSKCC prognostic factors (hazard ratio (HR), 4.527; 95% CI 1.764–11.619; P = 0.002) and 1M-RDI ≥ 50% (HR, 2.615; 95% CI, 1.378–4.963; P = 0.003)] were identified as independent predictors of superior PFS time.

Table 4.

Results of multivariate analysis of prognostic factors for PFS

Parameter Hazard ratio 95% CI P value 
Favourable risk by MSKCC prognostic factors 4.527 1.764–11.619 0.002 
1M-RDI ≥ 50% 2.615 1.378–4.963 0.003 
Parameter Hazard ratio 95% CI P value 
Favourable risk by MSKCC prognostic factors 4.527 1.764–11.619 0.002 
1M-RDI ≥ 50% 2.615 1.378–4.963 0.003 

CI, confidence interval.

DISCUSSION

TKIs have added new treatment options for patients with advanced RCC; moreover, contemporary prognostic factors are required to provide relevant clinical information to patients receiving therapy. In fact, a pivotal phase 3 trial (TARGET) confirmed that sorafenib was effective in the treatment of advanced RCC and could provide a significant improvement in PFS with an acceptable adverse effects profile (5). But the efficacy, prognostic factors and safety of sorafenib therapy in the general population with advanced RCC have remained unclear, especially in patients of Japanese ethnicity (10–12). The present retrospective study revealed the efficacy, prognostic factors and safety of sorafenib in Japanese patients with advanced RCC who may be encountered in general clinical practice.

The median PFS time was 9.0 months and disease control, defined as radiologically confirmed complete response, partial response or stable disease of more than 3 months was achieved in 59.9% of the patients in our study. Median PFS time in our study was longer than that of TARGET, although it was almost the same as that of other reports of Japanese patients (7,9) and those of Asian ethnicity (8). One of the possible reasons for the difference in treatment outcome is the difference in ethnicity. Regarding this difference in RCC patients, Naito et al. (13) reported that the median survival time of Japanese patients with metastatic RCC in the cytokine era was approximately twice as long as that of previous studies of patients from North America or Europe. Although it is difficult to conclude that Asians had a more favorable clinical effect in the TKI era as well as in the cytokine era, another possible reason is that Japanese patients may tend to be more carefully monitored than overseas patients, and therefore, this attention may lead to earlier detection and treatment. The association of differences in ethnicity and the efficacy of sorafenib will require further investigation.

There are few reports on the prognostic factors for sorafenib. We previously found that 1M-RDI of not <50% and favorable risk according to MSKCC factors were the prognostic factors for predicting favorable PFS but not overall survival in first-line therapy-refractory RCC patients (9). In overall metastatic RCC patients treated with sorafenib, our univariate and multivariate analysis results revealed that favorable prognosis according to MSKCC prognostic factors and a 1M-RDI of ≥50% were significant factors for predicting superior PFS with sorafenib treatment. Zhang et al. (11) showed that ECOG status, presence of lymph node metastasis and nephrectomy prior to the development of metastasis were significant predictive factors for disease control by sorafenib. Heng et al. showed that a hemoglobin value less than the lower limit of normal, serum corrected calcium value greater than the upper limit of normal (ULN), Karnofsky performance status (KPS) <80%, time from initial diagnosis to initiation of therapy of less than 1 year, neutrophil count greater than ULN, and platelet count greater than ULN were independent adverse prognostic factors, although by vascular endothelial growth factor-targeted therapy (14).

There are great differences in adverse events experienced with sorafenib therapy between Japanese and American or European patients. The median sorafenib dose was 790 mg/day in the TARGET study, which almost aligns with the recommended dosage. But in our study, the average dose and 1M-RDI after initiation of treatment were 415 mg/day and 71.7%. Moreover, dose reduction and interruption of therapy due to adverse events were required in 80.5% of the patients in our study, which was significantly higher than that of the TARGET study (28%). The estimation of sorafenib dosage is very difficult because TKI dosage and dosage intervals are difficult to maintain due to adverse events. Although Ueda et al. (9) suggested that a dose of 600 mg was thought to be more preferable for Japanese patients, there is no evidence for this. In the present study, we could not determine what the suitable initial dose of sorafenib should be. However, it was very important to maintain at least a half dose of sorafenib for the first one month of therapy because a 1M-RDI of <50% was one of the factors indicating poor prognosis. In this study, 91 patients (70.5%) attained a 1M-RDI of not <50%, and a 1M-RDI of ≥50% might be tolerable in Japanese patients. In our study, the most common adverse event causing discontinuation or interruption of therapy was hand-foot skin reaction, and the profile of adverse events was almost the same as that of previous reports of Japanese patients. Strumberg et al. (15) reported that severity of skin reaction and diarrhea were significantly associated with time to progression, and in other reports, the probability of hand-foot skin reaction was substantially higher in Asian patients when compared with the American or European studies (4,16). The tolerable dose of targeted therapies for Japanese patients might be lower than that for Caucasians, suggesting the need for careful adjustment to maintain a 1M-RDI ≥ 50%.

The limitations of this study include the potential selection bias associated with retrospective analysis, incomplete data collection (e.g. grade of adverse events) and heterogeneity in the clinicians' experiences of using sorafenib because this was a multicenter study. Further investigation into ethnic differences in efficacy and toxicity profiles is needed. It is crucial to establish a new strategy for patients to receive continuous treatment without sacrificing both efficacy and patient quality of life.

CONCLUSION

Sorafenib was effective in Japanese patients with advanced RCC and was tolerated in the daily clinical practice setting although individualized dose reduction was required. The median PFS time was 9.0 months. Univariate and multivariate analysis revealed that favorable groups according to MSKCC prognostic factors and a 1M-RDI of ≥50% were significant factors for predicting superior PFS with sorafenib treatment.

Conflict of interest statement

None declared.

Acknowledgements

The authors wish to thank the investigators, their staff, and the affiliated institutions for the important contribution to this study in The Osaka Renal Cell Carcinoma Clinical Study Collaboration. Dr Mikio Nin, (Osaka Rosai Hospital); Dr Yasuyuki Arai, Dr Masashi Nakayama, (Osaka Medical Center for Cancer and Cardiovascular Diseases); Dr Yutaka Yasunaga, (National Hospital Organization Osaka National Hospital); Dr Tatsuya Kinoshita, (Sumitomo Hospital); Dr Tomomi Kishimoto, (Sakai Municipal Hospital); Dr Tetsuo Imazu, (Toyonaka Municipal Hospital); Dr Shingo Takada, Dr Kiyomi Matsumiya, (Osaka Police Hospital); Dr Hitoshi Inoue, (Ikeda Municipal Hospital); Dr Yasuji Ichikawa, (Hyogo Prefectural Nishinomiya Hospital); Dr Nobukazu Murosaki, Dr Masato Honda, (Kinki Central Hospital of the Mutual Aid Association of Public School Teachers); Dr Masao Kuroda, Dr Wataru Nakata, (Nissei Hospital); Dr Shigeru Saiki, (Otemae Hospital); Dr Nobumasa Fujimoto, Dr Takuo Koide, (Osaka Koseinenkin Hospital); Dr Hideki Sugao, (Minoh Municipal Hospital); Dr Shigeru Nakamori, (Higashiosaka City General Hospital); Dr Mototaka Sato, Dr Koji Hatano, Dr Masatoshi Mukai, Dr Akira Nagahara, Dr Motohide Uemura, Dr Daizo Oka and Dr Yasutomo Nakai, (Osaka University Graduate School Of Medicine).

References

1
Parkin
DM
Bray
F
Ferlay
J
Pisani
P
Global cancer statistics, 2002
CA Cancer J Clin
 , 
2005
, vol. 
55
 (pg. 
74
-
108
)
2
Reuter
VE
Presti
JC
Jr
Contemporary approach to the classification of renal epithelial tumors
Semin Oncol
 , 
2000
, vol. 
27
 (pg. 
124
-
37
)
3
Motzer
RJ
Bander
NH
Nanus
DM
Renal-cell carcinoma
N Engl J Med
 , 
1996
, vol. 
335
 (pg. 
865
-
75
)
4
Ratain
MJ
Eisen
T
Stadler
WM
Flaherty
KT
Kaye
SB
Rosner
GL
, et al.  . 
Phase II placebo-controlled randomized discontinuation trial of sorafenib in patients with metastatic renal cell carcinoma
J Clin Oncol
 , 
2006
, vol. 
24
 (pg. 
2505
-
12
)
5
Escudier
B
Eisen
T
Stadler
WM
Szczylik
C
Oudard
S
Siebels
M
, et al.  . 
Sorafenib in advanced clear-cell renal-cell carcinoma
N Engl J Med
 , 
2007
, vol. 
356
 (pg. 
125
-
34
)
6
Therasse
P
Arbuck
SG
Eisenhauer
EA
Wanders
J
Kaplan
RS
Rubinstein
L
, et al.  . 
New guidelines to evaluate the response to treatment in solid tumors
J Natl Cancer Inst
 , 
2000
, vol. 
92
 pg. 
205
 
7
Motzer
RJ
Bacik
J
Murphy
BA
Russo
P
Mazumdar
M
Interferon-alfa as a comparative treatment for clinical trials of new therapies against advanced renal cell carcinoma
J Clin Oncol
 , 
2002
, vol. 
20
 (pg. 
289
-
96
)
8
Motzer
RJ
Bacik
J
Schwartz
LH
Reuter
V
Russo
P
Marion
S
, et al.  . 
Prognostic factors for survival in previously treated patients with metastatic renal cell carcinoma
J Clin Oncol
 , 
2004
, vol. 
22
 (pg. 
454
-
63
)
9
Kawashima
A
Takayama
H
Arai
Y
Tanigawa
G
Nin
M
Kajikawa
J
, et al.  . 
One-month relative dose intensity of not less than 50% predicts favourable progression-free survival in sorafenib therapy for advanced renal cell carcinoma in Japanese patients
Eur J Cancer
 , 
2011
, vol. 
47
 (pg. 
1521
-
6
)
10
Akaza
H
Tsukamoto
T
Murai
M
Nakajima
K
Naito
S
Phase II study to investigate the efficacy, safety, and pharmacokinetics of sorafenib in Japanese patients with advanced renal cell carcinoma
Jpn J Clin Oncol
 , 
2007
, vol. 
37
 (pg. 
755
-
62
)
11
Zhang
H
Dong
B
Lu
JJ
Yao
X
Zhang
S
Dai
B
, et al.  . 
Efficacy of sorafenib on metastatic renal cell carcinoma in Asian patients: results from a multicenter study
BMC Cancer
 , 
2009
, vol. 
9
 pg. 
249
 
12
Ueda
T
Imamura
Y
Komaru
A
Fukasawa
S
Sazuka
T
Suyama
T
, et al.  . 
Treatment outcomes of sorafenib for first line or cytokinerefractory advanced renal cell carcinoma in Japanese patients
Int J Urol
 , vol. 
17
 (pg. 
811
-
5
)
13
Naito
S
Yamamoto
N
Takayama
T
Muramoto
M
Shinohara
N
Nishiyama
K
, et al.  . 
Prognosis of Japanese metastatic renal cell carcinoma patients in the cytokine era: a cooperative group report of 1463 patients
Eur Urol
 , vol. 
57
 (pg. 
317
-
25
)
14
Heng
DY
Xie
W
Regan
MM
Warren
MA
Golshayan
AR
Sahi
C
, et al.  . 
Prognostic factors for overall survival in patients with metastatic renal cell carcinoma treated with vascular endothelial growth factor-targeted agents: results from a large, multicenter study
J Clin Oncol
 , 
2009
, vol. 
27
 (pg. 
5794
-
9
)
15
Strumberg
D
Awada
A
Hirte
H
Clark
JW
Seeber
S
Piccart
P
, et al.  . 
Pooled safety analysis of BAY 43–9006 (sorafenib) monotherapy in patients with advanced solid tumours: Is rash associated with treatment outcome?
Eur J Cancer
 , 
2006
, vol. 
42
 (pg. 
548
-
56
)
16
Cheng
AL
Kang
YK
Chen
Z
Tsao
CJ
Qin
S
Kim
JS
, et al.  . 
Efficacy and safety of sorafenib in patients in the Asia-Pacific region with advanced hepatocellular carcinoma: a phase III randomised, double-blind, placebo-controlled trial
Lancet Oncol
 , 
2009
, vol. 
10
 (pg. 
25
-
34
)