Medicine
®
OBSERVATIONAL STUDY
Retrospective Analysis of the Efficacy and Safety of Sorafenib in Chinese Patients With Metastatic Renal Cell Carcinoma and Prognostic Factors Related to Overall Survival Xiaoteng Yu, MD, Gang Guo, MD, Xuesong Li, MD, PhD, Cuijian Zhang, MD, Lihua Huang, MD, PhD, Dong Fang, MD, Yi Song, MD, Xu Zhang, MD, PhD, and Liqun Zhou, MD, PhD
Abstract: Sorafenib has been recommended as first- or second-line treatment for metastatic renal cell carcinoma (mRCC) by several guidelines. The objective of this study is to evaluate the efficacy of sorafenib monotherapy in Chinese patients with mRCC and determine the prognostic clinicopathologic factors associated with survival in these patients. This is a single-arm retrospective study conducted in 2 tertiary medical centers; 140 mRCC patients were enrolled between January 2007 and June 2014. Sorafenib was administered at a dose of 400 mg twice daily, and continued until disease progression, at which point the dose was increased to 600 or 800 mg twice daily, or the onset of an intolerable adverse drug event (ADE) that required dose reduction or temporary suspension of treatment. The primary endpoint was overall survival (OS), and the secondary endpoints included progression-free survival (PFS), objective response rate (ORR), disease control rate (DCR), and safety. The median follow-up time was 32 months. The median OS and PFS were 24 months (range, 3–88 months) and 16 months (range, 0–88 months), respectively. Patients with clear cell carcinoma had a greater OS (P ¼ 0.001) whereas sarcomatoid differentiation (P ¼ 0.045) and disease progression (P ¼ 0.010) negatively impacted OS; time from kidney surgery or biopsy to initiation of sorafenib treatment was associated with PFS (P ¼ 0.027). Efficacy analysis revealed that 3 (2.1%) patients achieved complete responses, 28 (20.0%) patients experienced partial responses, 88 (62.9%) patients had stable disease, and 21 (15.0%) patients developed progressive disease. Moreover, the ORR was 22.1%, and the DCR was 85.0%. Most ADEs were classified as grades 1 or 2 with only 14 (10.0%) patients experiencing a severe ADE (grade 3). Sorafenib monotherapy can achieve promising OS and PFS for Chinese patients with mRCC, especially in those with clear cell carcinoma, with manageable adverse events.
Editor: Ming-hui Wu. Received: March 16, 2015; revised: June 28, 2015; accepted: July 20, 2015. From the Department of Urology (XY, XL, CZ, LH, DF, YS, LZ), Peking University First Hospital, Institute of Urology, National Urological Cancer Center, Peking University; and Department of Urology (GG, XZ), State Key Laboratory of Kidney Diseases, Chinese People’s Liberation Army General Hospital, Beijing, China. Correspondence: Liqun Zhou, Department of Urology, Peking University First Hospital, Institute of Urology, National Urological Cancer Center, Peking University, Beijing 100034, China (e-mail: zhouliqunmail@ sina.com). Supplemental Digital Content is available for this article. YX, GG, and LX equally contributed to this study. The authors have no funding and conflicts of interest to disclose. Copyright # 2015 Wolters Kluwer Health, Inc. All rights reserved. This is an open access article distributed under the Creative Commons Attribution-NonCommercial-NoDerivatives License 4.0, where it is permissible to download, share and reproduce the work in any medium, provided it is properly cited. The work cannot be changed in any way or used commercially. ISSN: 0025-7974 DOI: 10.1097/MD.0000000000001361
Medicine
Volume 94, Number 34, August 2015
(Medicine 94(34):e1361) Abbreviations: ADE = adverse drug event, CI = confidence interval, CR = complete response, DCR = disease control rate, HR = hazard ratio, IL-2 = interleukin-2, mRCC = metastatic renal cell carcinoma, ORR = objective response rate, OS = overall survival, PD = progressive disease, PFS = progression-free survival, PR = partial response, RCC = renal cell carcinoma, RECIST = Response Evaluation Criteria in Solid Tumors, SD = stable disease.
INTRODUCTION
R
enal cell carcinoma (RCC) accounts for nearly 3% of all adult malignancies, and its incidence is increasing in China.1,2 The poor prognosis of these patients is due in part to its late detection; approximately one-third of patients are diagnosed with metastatic RCC (mRCC) at first presentation.3 In addition, although surgery is the most effective treatment, approximately 20% to 40% of patients experience distant metastasis or local recurrence after primary nephrectomy4 with a 5-year survival rate of 2 organs Single organ Metastasis Only lung involved Others Metastatic sites Lung Bone Liver Brain Adrenal gland Lymph node Others Progressive disease Yes No Survival status Alive Dead
(N ¼ 140) 57.34 (17–79) 101 (72.1%) 39 (27.9%) 12 (1–144)
112 (80.0%) 28 (20.0%) 117 13 3 6 1
(83.6%) (9.3%) (2.1%) (4.3%) (0.7%)
106 (75.7%) 23 (16.4%) 11 (7.9%) 125 12 1 2
(89.3%) (8.6%) (0.7%) (1.4%)
9 (6.4%) 131 (93.6%) 95 40 3 2
(67.9%) (28.6%) (2.1%) (1.4%)
101 (72.1%) 39 (27.9%) 58 (41.4%) 82 (58.6%) 86 44 12 1 14 26 4
(61.4%) (31.4%) (8.6%) (0.7%) (10.0%) (18.6%) (2.9%)
79 (56.4%) 61 (43.6%) 59 (42.1%) 81 (57.9%)
5-FU ¼ 5-fluorouracil, IFN ¼ interferon, IL-2 ¼ interleukin-2. Data were represented as mean with range (minimum to maximum) for continuous variables and n (%) for categorical ones.
Copyright
#
2015 Wolters Kluwer Health, Inc. All rights reserved.
Medicine
Volume 94, Number 34, August 2015
Sorafenib for Metastatic Renal Cell Carcinoma
intervals (95% CIs). Variables with significance level of P < 0.1 in the univariate Cox-regression model were selected for multivariate analysis. Kaplan–Meier survival curves with a log-rank test were performed to identify the OS and PFS among the clinical and pathological characteristics.18 All statistical assessments were 2-tailed, and P values 2 organs 52 (51.5%) Single organs 29 (74.4%) Metastasis Only lung involved 31 (53.4%) Others 50 (61.0%) Progressive disease Yes 56 (70.9%) No 25 (41.0%) Having at least once ADEs with grade 3 or 4 Yes 11 (78.6%) No 70 (55.6%)
Univariate
Multivariate
HR (95% CI)
P Value
HR (95% CI)
43 (42.6%) 16 (41.0%) 10 (1–144)
1.213 (0.745, 1.976) Reference
0.438
—
0.994 (0.984, 1.003)
0.205
—
49 (43.8%) 10 (35.7%)
0.818 (0.484, 1.382) Reference
0.452
—
47 (44.3%) 8 (34.8%) 4 (36.4%)
1.064 (0.603, 1.878) 1.133 (0.517, 2.486)
0.830 0.755
— —
58 (46.4%) 1 (6.7%)
0.386 (0.216, 0.692) Reference
0.001
2 (22.2%) 57 (43.5%)
2.123 (0.973, 4.629) Reference
49 (48.5%) 10 (25.6%)
Alive
P Value
59
Reference
0.329 (0.182, 0.596) Reference
2 cycles, and 21 (15.0%) patients developed PD. The ORR included patients with CR and PR. Moreover, the DCR, including patients with CR, PR, or SD, was 85.0%.
Analysis of Sorafenib Safety in mRCC Patients As shown in Table 4, the 6 most common ADEs after sorafenib initiation were diarrhea (48.6% of patients), hand–
4
| www.md-journal.com
FIGURE 2. Kaplan–Meier curves of overall survival (OS) times for 140 Chinese metastatic renal cell carcinoma patients receiving sorafenib by pathological result. The log-rank test was performed to identify the significance of OS by specific characteristics, including (A) clear cell carcinoma, (B) sarcomatoid differentiation, and (C) progressive disease. 95% CI, 95% confidence intervals of median OS times. ‘‘þ’’ indicates censored cases. Copyright
#
2015 Wolters Kluwer Health, Inc. All rights reserved.
Medicine
Volume 94, Number 34, August 2015
Sorafenib for Metastatic Renal Cell Carcinoma
TABLE 3. Association of Progression-Free Survival With Patients’ Clinical and Pathological Characteristics (N ¼ 140) Progressive Situation Characteristics Total patients Sex Male Female Time from kidney surgery or biopsy to initiation of sorafenib Prior nephrectomy Yes No Prior systemic therapy Treatment naı¨ve Second line after immunotherapy Second line after sunitinib Pathology Clear cell Othersa Sarcomatoid differentiation Yes No Multiorgans >2 organs Single organs Metastasis Only lung involved Others Having at least once ADEs with grade 3 or 4 Yes No
Univariate HR (95% CI)
P Value
Non-PS
PS
36
104
28 (27.7%) 8 (20.5%) 17.41 (1–144)
73 (72.3%) 31 (79.5%) 17.31 (1–89)
1.043 (0.680, 1.601) Reference 0.990 (0.981, 0.999)
30 (26.8%) 6 (21.4%)
82 (73.2%) 22 (78.6%)
0.969 (0.604, 1.555) Reference
27 (25.5%) 7 (30.4%) 2 (18.2%)
79 (74.5%) 16 (69.6%) 9 (81.8%)
Reference 0.788 (0.459, 1.353) 1.421 (0.708, 2.851)
35 (28.0%) 1 (6.7%)
90 (72.0%) 14 (93.3%)
0.656 (0.371, 1.158) Reference
0.146
2 (22.2%) 34 (26.0%)
7 (77.8%) 97 (74.0%)
1.451 (0.671, 3.138) Reference
0.344
7 (17.9%) 29 (28.7%)
32 (82.1%) 72 (71.3%)
1.075 (0.707, 1.635) Reference
0.735
17 (29.3%) 19 (23.2%)
41 (70.7%) 63 (76.8%)
0.969 (0.653, 1.437) Reference
0.876
1 (7.1%) 35 (27.8%)
13 (92.9%) 91 (72.2%)
1.031 (0.573, 1.854) Reference
0.919
0.846 0.028
0.896
0.387 0.323
ADEs ¼ adverse drug-related events, PS ¼ progressive status, which included patients either with progressive disease or those that were dead at last follow-up. Clinical and pathological characteristic data were presented as n (%) for a given PS situation. Univariate Cox-regression model analysis was applied, and results were shown as hazard ratio (HR) with corresponding 95% confidence intervals (95% CIs). Multivarariate analysis was not performed because of only one variable with significance level
®
OBSERVATIONAL STUDY
Retrospective Analysis of the Efficacy and Safety of Sorafenib in Chinese Patients With Metastatic Renal Cell Carcinoma and Prognostic Factors Related to Overall Survival Xiaoteng Yu, MD, Gang Guo, MD, Xuesong Li, MD, PhD, Cuijian Zhang, MD, Lihua Huang, MD, PhD, Dong Fang, MD, Yi Song, MD, Xu Zhang, MD, PhD, and Liqun Zhou, MD, PhD
Abstract: Sorafenib has been recommended as first- or second-line treatment for metastatic renal cell carcinoma (mRCC) by several guidelines. The objective of this study is to evaluate the efficacy of sorafenib monotherapy in Chinese patients with mRCC and determine the prognostic clinicopathologic factors associated with survival in these patients. This is a single-arm retrospective study conducted in 2 tertiary medical centers; 140 mRCC patients were enrolled between January 2007 and June 2014. Sorafenib was administered at a dose of 400 mg twice daily, and continued until disease progression, at which point the dose was increased to 600 or 800 mg twice daily, or the onset of an intolerable adverse drug event (ADE) that required dose reduction or temporary suspension of treatment. The primary endpoint was overall survival (OS), and the secondary endpoints included progression-free survival (PFS), objective response rate (ORR), disease control rate (DCR), and safety. The median follow-up time was 32 months. The median OS and PFS were 24 months (range, 3–88 months) and 16 months (range, 0–88 months), respectively. Patients with clear cell carcinoma had a greater OS (P ¼ 0.001) whereas sarcomatoid differentiation (P ¼ 0.045) and disease progression (P ¼ 0.010) negatively impacted OS; time from kidney surgery or biopsy to initiation of sorafenib treatment was associated with PFS (P ¼ 0.027). Efficacy analysis revealed that 3 (2.1%) patients achieved complete responses, 28 (20.0%) patients experienced partial responses, 88 (62.9%) patients had stable disease, and 21 (15.0%) patients developed progressive disease. Moreover, the ORR was 22.1%, and the DCR was 85.0%. Most ADEs were classified as grades 1 or 2 with only 14 (10.0%) patients experiencing a severe ADE (grade 3). Sorafenib monotherapy can achieve promising OS and PFS for Chinese patients with mRCC, especially in those with clear cell carcinoma, with manageable adverse events.
Editor: Ming-hui Wu. Received: March 16, 2015; revised: June 28, 2015; accepted: July 20, 2015. From the Department of Urology (XY, XL, CZ, LH, DF, YS, LZ), Peking University First Hospital, Institute of Urology, National Urological Cancer Center, Peking University; and Department of Urology (GG, XZ), State Key Laboratory of Kidney Diseases, Chinese People’s Liberation Army General Hospital, Beijing, China. Correspondence: Liqun Zhou, Department of Urology, Peking University First Hospital, Institute of Urology, National Urological Cancer Center, Peking University, Beijing 100034, China (e-mail: zhouliqunmail@ sina.com). Supplemental Digital Content is available for this article. YX, GG, and LX equally contributed to this study. The authors have no funding and conflicts of interest to disclose. Copyright # 2015 Wolters Kluwer Health, Inc. All rights reserved. This is an open access article distributed under the Creative Commons Attribution-NonCommercial-NoDerivatives License 4.0, where it is permissible to download, share and reproduce the work in any medium, provided it is properly cited. The work cannot be changed in any way or used commercially. ISSN: 0025-7974 DOI: 10.1097/MD.0000000000001361
Medicine
Volume 94, Number 34, August 2015
(Medicine 94(34):e1361) Abbreviations: ADE = adverse drug event, CI = confidence interval, CR = complete response, DCR = disease control rate, HR = hazard ratio, IL-2 = interleukin-2, mRCC = metastatic renal cell carcinoma, ORR = objective response rate, OS = overall survival, PD = progressive disease, PFS = progression-free survival, PR = partial response, RCC = renal cell carcinoma, RECIST = Response Evaluation Criteria in Solid Tumors, SD = stable disease.
INTRODUCTION
R
enal cell carcinoma (RCC) accounts for nearly 3% of all adult malignancies, and its incidence is increasing in China.1,2 The poor prognosis of these patients is due in part to its late detection; approximately one-third of patients are diagnosed with metastatic RCC (mRCC) at first presentation.3 In addition, although surgery is the most effective treatment, approximately 20% to 40% of patients experience distant metastasis or local recurrence after primary nephrectomy4 with a 5-year survival rate of 2 organs Single organ Metastasis Only lung involved Others Metastatic sites Lung Bone Liver Brain Adrenal gland Lymph node Others Progressive disease Yes No Survival status Alive Dead
(N ¼ 140) 57.34 (17–79) 101 (72.1%) 39 (27.9%) 12 (1–144)
112 (80.0%) 28 (20.0%) 117 13 3 6 1
(83.6%) (9.3%) (2.1%) (4.3%) (0.7%)
106 (75.7%) 23 (16.4%) 11 (7.9%) 125 12 1 2
(89.3%) (8.6%) (0.7%) (1.4%)
9 (6.4%) 131 (93.6%) 95 40 3 2
(67.9%) (28.6%) (2.1%) (1.4%)
101 (72.1%) 39 (27.9%) 58 (41.4%) 82 (58.6%) 86 44 12 1 14 26 4
(61.4%) (31.4%) (8.6%) (0.7%) (10.0%) (18.6%) (2.9%)
79 (56.4%) 61 (43.6%) 59 (42.1%) 81 (57.9%)
5-FU ¼ 5-fluorouracil, IFN ¼ interferon, IL-2 ¼ interleukin-2. Data were represented as mean with range (minimum to maximum) for continuous variables and n (%) for categorical ones.
Copyright
#
2015 Wolters Kluwer Health, Inc. All rights reserved.
Medicine
Volume 94, Number 34, August 2015
Sorafenib for Metastatic Renal Cell Carcinoma
intervals (95% CIs). Variables with significance level of P < 0.1 in the univariate Cox-regression model were selected for multivariate analysis. Kaplan–Meier survival curves with a log-rank test were performed to identify the OS and PFS among the clinical and pathological characteristics.18 All statistical assessments were 2-tailed, and P values 2 organs 52 (51.5%) Single organs 29 (74.4%) Metastasis Only lung involved 31 (53.4%) Others 50 (61.0%) Progressive disease Yes 56 (70.9%) No 25 (41.0%) Having at least once ADEs with grade 3 or 4 Yes 11 (78.6%) No 70 (55.6%)
Univariate
Multivariate
HR (95% CI)
P Value
HR (95% CI)
43 (42.6%) 16 (41.0%) 10 (1–144)
1.213 (0.745, 1.976) Reference
0.438
—
0.994 (0.984, 1.003)
0.205
—
49 (43.8%) 10 (35.7%)
0.818 (0.484, 1.382) Reference
0.452
—
47 (44.3%) 8 (34.8%) 4 (36.4%)
1.064 (0.603, 1.878) 1.133 (0.517, 2.486)
0.830 0.755
— —
58 (46.4%) 1 (6.7%)
0.386 (0.216, 0.692) Reference
0.001
2 (22.2%) 57 (43.5%)
2.123 (0.973, 4.629) Reference
49 (48.5%) 10 (25.6%)
Alive
P Value
59
Reference
0.329 (0.182, 0.596) Reference
2 cycles, and 21 (15.0%) patients developed PD. The ORR included patients with CR and PR. Moreover, the DCR, including patients with CR, PR, or SD, was 85.0%.
Analysis of Sorafenib Safety in mRCC Patients As shown in Table 4, the 6 most common ADEs after sorafenib initiation were diarrhea (48.6% of patients), hand–
4
| www.md-journal.com
FIGURE 2. Kaplan–Meier curves of overall survival (OS) times for 140 Chinese metastatic renal cell carcinoma patients receiving sorafenib by pathological result. The log-rank test was performed to identify the significance of OS by specific characteristics, including (A) clear cell carcinoma, (B) sarcomatoid differentiation, and (C) progressive disease. 95% CI, 95% confidence intervals of median OS times. ‘‘þ’’ indicates censored cases. Copyright
#
2015 Wolters Kluwer Health, Inc. All rights reserved.
Medicine
Volume 94, Number 34, August 2015
Sorafenib for Metastatic Renal Cell Carcinoma
TABLE 3. Association of Progression-Free Survival With Patients’ Clinical and Pathological Characteristics (N ¼ 140) Progressive Situation Characteristics Total patients Sex Male Female Time from kidney surgery or biopsy to initiation of sorafenib Prior nephrectomy Yes No Prior systemic therapy Treatment naı¨ve Second line after immunotherapy Second line after sunitinib Pathology Clear cell Othersa Sarcomatoid differentiation Yes No Multiorgans >2 organs Single organs Metastasis Only lung involved Others Having at least once ADEs with grade 3 or 4 Yes No
Univariate HR (95% CI)
P Value
Non-PS
PS
36
104
28 (27.7%) 8 (20.5%) 17.41 (1–144)
73 (72.3%) 31 (79.5%) 17.31 (1–89)
1.043 (0.680, 1.601) Reference 0.990 (0.981, 0.999)
30 (26.8%) 6 (21.4%)
82 (73.2%) 22 (78.6%)
0.969 (0.604, 1.555) Reference
27 (25.5%) 7 (30.4%) 2 (18.2%)
79 (74.5%) 16 (69.6%) 9 (81.8%)
Reference 0.788 (0.459, 1.353) 1.421 (0.708, 2.851)
35 (28.0%) 1 (6.7%)
90 (72.0%) 14 (93.3%)
0.656 (0.371, 1.158) Reference
0.146
2 (22.2%) 34 (26.0%)
7 (77.8%) 97 (74.0%)
1.451 (0.671, 3.138) Reference
0.344
7 (17.9%) 29 (28.7%)
32 (82.1%) 72 (71.3%)
1.075 (0.707, 1.635) Reference
0.735
17 (29.3%) 19 (23.2%)
41 (70.7%) 63 (76.8%)
0.969 (0.653, 1.437) Reference
0.876
1 (7.1%) 35 (27.8%)
13 (92.9%) 91 (72.2%)
1.031 (0.573, 1.854) Reference
0.919
0.846 0.028
0.896
0.387 0.323
ADEs ¼ adverse drug-related events, PS ¼ progressive status, which included patients either with progressive disease or those that were dead at last follow-up. Clinical and pathological characteristic data were presented as n (%) for a given PS situation. Univariate Cox-regression model analysis was applied, and results were shown as hazard ratio (HR) with corresponding 95% confidence intervals (95% CIs). Multivarariate analysis was not performed because of only one variable with significance level
