- Email: [email protected]
Absence of Significant Correlation of Adverse Events Between First- and Second-Line Tyrosine Kinase Inhibitors in Patients With Metastatic Renal Cell Carcinoma
Original Study
Absence of Significant Correlation of Adverse Events Between First- and Second-Line Tyrosine Kinase Inhibitors in Patients With Metastatic Renal Cell Carcinoma Hideaki Miyake, Satoshi Imai, Ken-ichi Harada, Masato Fujisawa Abstract Several adverse events (AEs) are known to be commonly observed during treatment with different tyrosine kinase inhibitors (TKIs) in patients with metastatic renal cell carcinoma (mRCC) patients. However, no significant correlation appears present in the profiles of such AEs between first- and second-line TKI therapies. Therefore, a second-line targeted agent for patients with mRCC could be selected irrespective of the AE profile during first-line TKI therapy. Background: Several adverse events (AEs) commonly observed during treatment with different tyrosine kinase inhibitors (TKIs). The objective of the present study was to investigate whether the appearance of such AEs during treatment with first-line TKIs significantly affects the occurrence of AEs during second-line TKI therapy for patients with metastatic renal cell carcinoma (mRCC). Patients and Methods: The present study included 154 consecutive patients with mRCC treated with second-line TKIs after the discontinuation of first-line TKIs. The association of AEs, including diarrhea, fatigue, hand-foot syndrome, hypertension, and hypothyroidism, between first- and second-line therapies was analyzed in these 154 patients. Results: For all 5 AEs assessed in the present study, the proportion of patients experiencing AEs or those grade 3 during second-line TKI therapy was not significantly different among the following 3 groups: patients without AEs, those with grade 2 AEs, and those with grade 3 AEs during first-line TKI therapy. Furthermore, no significant difference was seen in progression-free or overall survival after the introduction of second-line TKIs between patients with and without grade 3 AEs during treatment with first-line TKIs. Conclusion: The incidence of AEs or grade 3 AEs during second-line TKI therapy are not dependent on the profiles of AEs during first-line TKI therapy in patients with mRCC. Therefore, AEs that occur during first-line TKI therapy should not affect the selection of second-line targeted agents for patients with mRCC. Clinical Genitourinary Cancer, Vol. 14, No. 1, e19-24 ª 2016 Elsevier Inc. All rights reserved. Keywords: Adverse events, First-line, Metastatic renal cell carcinoma, Second-line, Tyrosine kinase inhibitors
Introduction Until recently, immunotherapy using cytokines had been the mainstay of systemic therapy for patients with metastatic renal cell carcinoma (mRCC). However, this treatment could provide only limited efficacy, with a median overall survival (OS) of approximately 1 year.1 To overcome the poor prognostic outcomes of Division of Urology, Kobe University Graduate School of Medicine, Kobe, Japan Submitted: May 22, 2015; Revised: Aug 2, 2015; Accepted: Aug 8, 2015; Epub: Aug 15, 2015 Address for correspondence: Hideaki Miyake, MD, PhD, Division of Urology, Kobe University Graduate School of Medicine, 7-5-1 Kusunoki-cho, Chuo-ku, Kobe 6500017, Japan E-mail contact: [email protected]
1558-7673/$ - see frontmatter ª 2016 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.clgc.2015.08.002
patients with mRCC, novel molecular-targeted agents have been developed by intensive investigation of the molecular mechanisms mediating the progression of RCC. The recent introduction of these agents into clinical practice has resulted in a marked paradigm shift in the therapeutic strategy for mRCC.2 Of the several types of molecular-targeted agents, tyrosine kinase inhibitors (TKIs), which have been shown to mainly inactivate vascular endothelial growth factor (VEGF)-related pathways, are regarded as exerting powerful antitumor activities against mRCC according to the findings of pivotal randomized clinical trials.3-6 Therefore, TKIs currently play crucial roles in the treatment of patients with mRCC, in particular, as a first-line standard of care.7,8 Moreover, the favorable clinical outcomes on the use of TKIs against mRCC were confirmed in various studies evaluating these
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Lack of Correlation of Adverse Events Induced by Tyrosine Kinase Inhibitors agents in routine clinical settings.9-13 However, limited data are available with respect to sequencing therapy to determine the most effective second-line agent after the discontinuation of first-line TKIs, particularly for patients experiencing intolerable adverse events (AEs). It has been well-recognized that several common AEs are frequently observed during the treatment of mRCC patients with different TKIs.3-6,9-15 Accordingly, it has become a commonly held belief that patients who stop receiving first-line TKIs because of severe AEs should switch to an alternative agent with a mechanism of action different from that of TKIs to avoid the occurrence of AEs similar to those observed during first-line TKI therapy. However, this practice has not been based on reliable data with a high evidence level. Considering these findings, we retrospectively assessed the clinical outcomes of 154 consecutive patients with mRCC who had received second-line TKI therapy after the discontinuation of firstline TKI therapy. Our study focused on the association of AE profiles between the first- and second-line agents.
Patients and Methods
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We retrospectively reviewed the data from all patients with mRCC treated with molecular-targeted agents in a routine clinical setting at our institutions from April 2008 to December 2014. Of these, the present study included of 154 consecutive patients with mRCC who had received TKIs as first-line molecular-targeted agents and subsequently received a TKI different from that used as the first-line agent as second-line targeted therapy. Of the 154 patients, 9, who had not undergone radical nephrectomy, underwent needle biopsies of either the primary or the metastatic tumor to determine the histologic subtype. Therefore, all the included patients had a pathologic diagnosis of RCC. Each patient provided informed consent before participating in the present study, and the research ethics committee of our institution approved the study design. In the present series, immunotherapy using interferon-alfa and/or interleukin-2 was the only systemic therapy allowed before the introduction of first-line TKIs. TKIs were administered according to the following schedules: sorafenib, 400 mg orally, twice daily; sunitinib, 50 mg orally, once daily in repeated 6-week cycles consisting of 4 weeks on therapy, followed by 2 weeks off; and axitinib, 5 mg orally, twice daily. The administration of TKIs was continued until disease progression or intolerable AEs developed. As a rule, dose modification of TKIs was considered for patients with treatment-associated AEs corresponding to grade 3 as follows. For sorafenib, the dose was reduced from 800 to 400 mg once daily, followed by an additional dose reduction to a single 400-mg dose every other day. For sunitinib, the initial dose reduction was from 50 to 37.5 mg once daily, and then to 25 mg once daily. For axitinib, an increased dose of 7 mg twice daily was allowed for patients who had tolerated the standard dose for 2 weeks, unless the blood pressure was > 150/90 mm Hg or they were taking antihypertensive medication, and the dose was reduced to 3 mg twice daily and then further to 2 mg twice daily. As baseline evaluations, the clinicopathologic examinations and performance status were assessed using the International Union Against Cancer TNM classification system and Karnofsky performance status scale, respectively. Risk classification was conducted
Clinical Genitourinary Cancer February 2016
using both the Memorial Sloan Kettering Cancer Center and Heng’s risk classification systems.16,17 Before the initiation of TKI treatment, radiologic evaluations were performed for all patients by computed tomography of the brain, chest, and abdomen and radionuclide bone scanning. Tumor measurements were conducted by computed tomography before and every 12 weeks after the introduction of TKIs. Treatment responses and AEs were evaluated by the treating physician using the Response Evaluation Criteria in Solid Tumors, version 1.1, and the National Cancer Institute
Table 1 Patient Characteristics at Treatment Initiation of TKIs Characteristic
Value
Age (year) Median
61
Range
37-86
Gender Male Female
119 (77.3) 35 (22.7)
Previous nephrectomy Yes
144 (93.5)
No
9 (6.5)
Previous immunotherapy Yes
37 (24.0)
No
117 (76.0)
MSKCC risk classification Favorable
54 (35.1)
Intermediate
84 (54.5)
Poor
16 (10.4)
Heng risk classification Favorable
46 (29.9)
Intermediate
93 (60.4)
Poor
15 (9.7)
C-reactive protein <0.8 mg/dL
105 (68.2)
0.8 mg/dL
49 (31.8)
Metastatic organ Lung
98 (63.6)
Lymph node
33 (21.4)
Bone liver
16 (10.4)
Brain
8 (5.2)
No. of metastatic organs 1
82 (53.2)
2
62 (40.3)
>3
10 (6.5)
Histologic subtype Clear cell carcinoma Other
139 (90.3) 15 (9.7)
Sarcomatoid features Yes
15 (9.7)
No
139 (90.3)
Data presented as n (%), unless otherwise noted. Abbreviations: MSKCC ¼ Memorial Sloan Kettering Cancer Center; TKIs ¼ tyrosine kinase inhibitors.
Hideaki Miyake et al Common Terminology Criteria for Adverse Events, version 3.0, respectively. All statistical analyses were performed using Statview, version 5.0, software (Abacus Concepts, Inc, Berkley, CA), and P < .05 was considered significant. Differences in the incidence of AEs during treatment with second-line TKIs were compared according to the AE profile during first-line TKI therapy using the c2 test. The progression-free survival (PFS) and OS rates from the introduction of the second-line TKIs were calculated using the Kaplan-Meier method, and differences were determined using the log-rank test.
Association of AE Profiles Between First- and Second-Line TKI Therapies According to the profile of each AE observed during first-line TKI therapy, the 154 patients were divided into 3 groups as follows: patients without AEs, those with grade 2 AEs, and those with grade 3 AEs. For all 5 AEs assessed in the present study, no significant difference was seen in the proportion of patients experiencing AEs or those that were grade 3 during second-line TKI therapy among the 3 groups (Table 3).
Effect of AE Profiles During First-Line TKI Therapy on Prognosis After Second-Line TKI Therapy
Results Patient Characteristics and AE Profiles The detailed characteristics of the 154 patients included in the present study are listed in Table 1. Of the 154 patients, 56 (36.4%) and 98 (63.6%) were treated with sorafenib and sunitinib, respectively, as first-line agents, and 14 (9.1%), 52 (33.8%), and 88 (57.1%) received sunitinib, axitinib, and sorafenib, respectively, as second-line agents. In the present study, we focused on diarrhea, fatigue, hand-foot syndrome, hypertension, and hypothyroidism because these are the common AEs frequently observed during treatment with different TKIs. The profiles of these 5 AEs according to the TKIs administered are summarized in Table 2. During treatment with first- and second-line TKIs, some of these AEs (grade 3) were observed in 49 (31.8%) and 54 (35.1%) patients, respectively.
To evaluate the effect of the occurrence of the 5 AEs (grade 3) during first-line TKI therapy on patient prognosis after the introduction of second-line TKI therapy, we compared the PFS and OS between the 105 patients without any of the 5 AEs and the 49 with some of these AEs (grade 3). As shown in Figure 1, no significant difference was seen in PFS or OS between these 105 and 49 patients.
Discussion Owing to the outcomes of pivotal randomized phase III clinical trials, TKI therapy is currently regarded as a new reference standard of care for the first-line treatment of patients with mRCC, except for those classified into the poor-risk group.2,4,6-8 Furthermore, the efficacies and tolerability of TKIs presented in the clinical trials were
Table 2 AE Profiles During First- and Second-Line Tyrosine Kinase Inhibitor Therapies Therapy
Diarrhea
Fatigue
Hand-Foot Syndrome
Hypertension
Hypothyroidism
All grades
22 (39.3)
13 (23.2)
38 (67.9)
20 (35.7)
31 (55.4)
Grade 3
3 (5.4)
2 (3.6)
10 (17.9)
10 (17.9)
4 (7.4)
All grades
52 (53.1)
53 (54.1)
49 (50.0)
47 (48.0)
58 (59.2)
Grade 3
8 (8.2)
20 (20.4)
13 (13.3)
10 (10.2)
8 (8.2)
All grades
74 (48.1)
66 (42.9)
87 (56.5)
67 (43.5)
89 (57.8)
Grade 3
11 (7.1)
22 (14.3)
23 (14.9)
20 (13.0)
12 (7.8)
First-line Sorafenib (n ¼ 56)
Sunitinib (n ¼ 98)
Total (n ¼ 154)
Second-line Sorafenib (n ¼ 14) All grades
4 (28.6)
5 (35.7)
7 (50.0)
4 (28.6)
5 (35.7)
Grade 3
1 (7.1)
1 (7.1)
2 (14.3)
1 (7.1)
1 (7.1)
All grades
24 (46.2)
30 (57.7)
20 (38.5)
18 (34.6)
31 (59.6)
Grade 3
4 (7.7)
12 (23.1)
5 (9.6)
5 (9.6)
4 (7.7)
All grades
47 (53.4)
33 (37.5)
43 (48.9)
46 (52.3)
30 (34.1)
Grade 3
7 (8.0)
7 (8.0)
8 (12.5)
28 (31.8)
1 (1.1)
All grades
75 (48.7)
68 (44.2)
70 (45.5)
68 (44.2)
66 (42.9)
Grade 3
12 (7.8)
20 (13.0)
15 (9.7)
34 (22.1)
6 (3.9)
Sunitinib (n ¼ 52)
Axitinib (n ¼ 88)
Total (n ¼ 154)
Data presented as n (%). Abbreviation: AE ¼ adverse event.
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Lack of Correlation of Adverse Events Induced by Tyrosine Kinase Inhibitors Table 3 Correlation of AE Profiles Between First- and Second-Line Tyrosine Kinase Inhibitor Therapies AE Profile During First-Line Therapy
AE
P Value
All Grades
Diarrhea
Grade ‡3
P Value
.55
.38
None
80
37 (46.3)
5 (6.3)
Grade 2
63
31 (49.2)
5 (7.9)
Grade 3
11
7 (63.6)
2 (18.2)
Fatigue
.44
.72
None
88
40 (45.5)
13 (14.8)
Grade 2
44
21 (47.7)
5 (11.4)
Grade >3
22
7 (31.8)
2 (9.1)
None
67
30 (44.8)
6 (9.0)
Grade 2
64
28 (43.8)
6 (9.4)
Grade >3
23
12 (52.1)
Hand-foot syndrome
.78
.84
3 (13.0)
Hypertension
.59
.71
None
87
41 (47.1)
20 (23.0)
Grade 2
47
20 (42.6)
11 (23.4)
Grade >3
20
7 (35.0)
3 (15.0)
Hypothyroidism
.42
.69
None
65
25 (38.5)
2 (3.1)
Grade 2
77
34 (44.2)
3 (3.9)
Grade >3
12
7 (58.3)
1 (8.3)
Data presented as n (%). Abbreviation: AE ¼ adverse event.
Taken together, we retrospectively assessed the clinical outcomes of 154 consecutive patients with mRCC who had been treated with both first- and second-line TKIs to evaluate the association of the AE profiles between first- and second-line TKI therapies. It is well-recognized that common AEs are frequently observed in patients with mRCC treated with different TKIs.3-6,9-15 For example, hypertension occurs in 17% to 45% of patients with mRCC treated with TKIs, with those of grade 3 reported in 3% to
subsequently confirmed in several studies targeting patients with mRCC who had received TKIs in routine clinical practice.9-13 However, the selection of optimal second-line molecular-targeted agents after the discontinuation of first-line TKIs remains controversial. Therefore, second-line agents have been likely to be selected with consideration of the treatment response or AE profile during first-line TKI therapy18,19 but with few published data to support such a practice, in particular, the data associated with the AE profile.
Figure 1 (A) Comparison of Progression-Free Survival After the Introduction of Second-Line Tyrosine Kinase Inhibitors (TKIs) Between Patients With Grade ‡ 3 Adverse Events (AEs), Including Diarrhea, Fatigue, Hand-Foot Syndrome, Hypertension, and Hypothyroidism, During Treatment With First-Line TKIs and Patients Without Any AEs. (B) Comparison of Overall Survival After the Introduction of Second-Line TKIs Between Patients With Grade ‡ 3 AEs, Including Diarrhea, Fatigue, Hand-Foot Syndrome, Hypertension, and Hypothyroidism, During Treatment With First-Line TKIs and Those Without Any AEs
B 100
100 P = 0.77
80 60 Without AEs ≥ grade 3 (n = 105)
40
20
0
-
P = 0.43 80 60 With AEs ≥ grade 3 (n = 49)
40 20
Without AEs ≥ grade 3 (n = 105)
With AEs ≥ grade 3 (n = 49)
0
e22
Overall survival (%)
Progression-free survival (%)
A
5
10 15 20 25 30 35 Observation period (months)
Clinical Genitourinary Cancer February 2016
0 40
0
10
20 30 40 50 60 Observation period (months)
70
Hideaki Miyake et al 16% of such patients. Hand-foot syndrome has been reported in 19% to 34% of patients with mRCC receiving TKIs, including those of grade 3 (range, 5%-9%).14,15 Of these AEs, we focused on 5 potential AEs, including diarrhea, fatigue, hand-foot syndrome, hypertension, and hypothyroidism. The incidence and severity of these 5 AEs in the present series, which included only Japanese patients, were marked compared with those in clinical trials mainly conducted in Western countries.3-6 Therefore, it is necessary to consider this point when interpreting the findings of our study. To date, some clinical trials have reported the prospectively collected data of AEs occurring during first- and second-line treatment with targeted agents, such as the SWITCH and RECORD-3.20,21 However, the association of the profile for each AE between the sequential treatments was not addressed in these studies. In the present series, therefore, we assessed the correlation of the profiles of 5 commonly observed AEs between firstand second-line TKIs. We found no significant effect of each AE profile during first-line TKI therapy on the subsequent incidence of AEs or grade 3 AEs. In particular, the proportion of patients who experienced identical grade 3 AEs during treatment with both first- and second-line TKIs was very low. This could be explained, at least in part, by the effective prevention of severe AEs during second-line TKI therapy and the continuous, skilled management of AEs that occurred during first-line TKI therapy at our institutions. However, these findings suggest that it might not be necessary to consider the AE profile from first-line TKI therapy when determining the agent to subsequently administer as second-line therapy. It is of interest to assess the prognosis of patients with mRCC who received both first- and second-line TKIs according to the AE profile during first-line TKI therapy. In the present series, no significant difference was found in the PFS or OS between patients with and without the 5 commonly observed grade 3 AEs during treatment with first-line TKIs. This finding indicates that the administration of TKIs as second-line agents to patients who experienced severe AEs during first-line TKI therapy might not have an unfavorable effect on the subsequent prognosis in such patients. Another point of interest is the selection of the optimal secondline agent for patients with mRCC after discontinuation of first-line TKI therapy based on the present findings. Currently, 2 agents are recommended as second-line targeted therapy with a high level of evidence for the treatment of mRCC after initial VEGF-targeted therapy.5,22 Everolimus, an orally available inhibitor of the mammalian target of rapamycin, is approved for use after failure of 1 VEGF-targeted therapies.22 Axitinib is a potent, specific inhibitor of VEGF receptors and has also been shown to improve PFS compared with sorafenib in patients who had received 1 previous systemic therapy for mRCC.5 To date, no randomized trial has directly compared the efficacies of these 2 agents as second-line therapeutic agents after first-line VEGF-targeted therapy for patients with mRCC. However, 2 recent studies clearly showed no significant correlation with disease control between first- and second-line TKIs, measured by the best response or PFS in patients with mRCC treated with second-line TKI therapy after failure of first-line TKI therapy.23,24 The results of the present study also suggest no significant correlation of the AE profiles between first- and second-line TKI therapies. Considering disease progression and intolerable AEs as 2 major factors causing the discontinuation of first-line TKIs, our
results have shown that the second-line agent can be selected regardless of the clinical course during treatment with first-line TKIs. The present study had several limitations. First, ours was a retrospective study of data from the medical records of previously treated patients. This usually makes it difficult to reliably capture toxicity data. Also, the sample size was not large enough to draw definitive conclusions. Second, our study included only Japanese patients with mRCC, who have been shown to exhibit profiles associated with the use of molecular-targeted agents different from those of Western populations.25 Accordingly, it might be difficult to apply the present findings to an overall cohort with mRCC. Third, owing to the timing of the approval of molecular-targeted agents in Japan, a significant proportion of patients were not treated because of the currently recommended strategy of sequential therapy against mRCC. Thus, 66 patients received sequential therapy with sorafenib and sunitinib. Fourth, the present study focused only on 5 representative AEs. It would be more suitable to conduct an intensive study involving a wide variety of AEs to precisely address the objective of our study. Finally, the AE profiles of patients receiving TKIs have recently been shown in several studies to be improved by modification of the administration schedule, such as the introduction of an alternative schedule of sunitinib with 2 weeks on and 1 week off.26,27 Thus, it will be necessary to investigate the topics of our study considering the updated data from patients with mRCC who have recently received TKIs.
Conclusion To our knowledge, this is the first study showing no significant correlation between the AE profiles of first- and second-line TKIs. We assessed the incidence of commonly observed AEs during treatment with different TKIs, including diarrhea, fatigue, handfoot syndrome, hypertension, and hypothyroidism, in 154 consecutive patients with mRCC who received second-line TKI therapy after discontinuation of first-line TKI therapy. Therefore, the AE profile during first-line TKI therapy might not be a useful criterion for selecting a second-line agent for mRCC.
Clinical Practice Points Several common AEs are frequently observed during treatment
with different TKIs, including diarrhea, fatigue, hand-foot syndrome, hypertension, and hypothyroidism, in patients with mRCC. In the present series assessing the clinical outcomes of 154 patients with mRCC who received TKIs as second-line agents after discontinuation of first-line TKIs, some grade 3 AEs were observed in 49 (31.8%) and 54 (35.1%) patients during treatment with first- and second-line TKIs, respectively. For all 5 AEs examined, no significant effect of the AE profile during first-line TKI therapy was seen on the incidence of AEs or grade 3 AEs during second-line TKI therapy in these patients. No significant difference was seen in PFS or OS after the introduction of second-line TKIs between patients with and without grade 3 AEs during treatment with first-line TKIs. Considering the findings of our study, AEs that occur during first-line TKI therapy should not affect the selection of the second-line targeted agent for patients with mRCC.
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Lack of Correlation of Adverse Events Induced by Tyrosine Kinase Inhibitors Disclosure The authors have stated that they have no conflicts of interest.
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15. Alasker A, Meskawi M, Sun M, et al. A contemporary update on rates and management of toxicities of targeted therapies for metastatic renal cell carcinoma. Cancer Treat Rev 2013; 39:388-401. 16. 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; 20:289-96. 17. Heng DY, Xie W, Regan MM, 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; 27:5794-9. 18. Busch J, Seidel C, Kempkensteffen C, et al. Sequence therapy in patients with metastatic renal cell carcinoma: comparison of common targeted treatment options following failure of receptor tyrosine kinase inhibitors. Eur Urol 2011; 60:1163-70. 19. Porta C, Paglino C, Imarisio I. Sequencing tyrosine kinase inhibitors or immediately switching to mTOR inhibitors in advanced kidney cancer: a critical review. Eur J Clin Med Oncol 2010; 2:1-6. 20. Eichelberg C, Vervenne WL, De Santis M, et al. SWITCH: a randomised, sequential, open-label study to evaluate the efficacy and safety of sorafenib-sunitinib versus sunitinib-sorafenib in the treatment of metastatic renal cell cancer [e-pub ahead of print]. Eur Urol http://dx.doi.org/10.1016/j.eururo.2015.04.017. 21. Motzer RJ, Barrios CH, Kim TM, et al. Phase II randomized trial comparing sequential first-line everolimus and second-line sunitinib versus first-line sunitinib and second-line everolimus in patients with metastatic renal cell carcinoma. J Clin Oncol 2014; 32:2765-72. 22. Motzer RJ, Escudier B, Oudard S, et al. Efficacy of everolimus in advanced renal cell carcinoma: a double-blind, randomised, placebo-controlled phase III trial. Lancet 2008; 372:449-56. 23. Al-Marrawi MY, Rini BI, Harshman LC, et al. The association of clinical outcome to first-line VEGF-targeted therapy with clinical outcome to second-line VEGFtargeted therapy in metastatic renal cell carcinoma patients. Target Oncol 2013; 8: 203-9. 24. Miyazaki A, Miyake H, Harada KI, Fujisawa M. No significant correlation of clinical outcomes between first- and second-line tyrosine kinase inhibitors in patients with metastatic renal cell carcinoma. Anticancer Res 2015; 35:3067-73. 25. Wada Y, Takahashi W, Kawano Y, Eto M. Current status of pharmacotherapy against metastatic renal cell carcinoma in Japan. Int J Urol 2012; 19:284-95. 26. Najjar YG, Mittal K, Elson P, et al. A 2 weeks on and 1 week off schedule of sunitinib is associated with decreased toxicity in metastatic renal cell carcinoma. Eur J Cancer 2014; 50:1084-9. 27. Miyake H, Harada K, Miyazaki A, Fujisawa M. Improved health-related quality of life of patients with metastatic renal cell carcinoma treated with a 2 weeks on and 1 week off schedule of sunitinib. Med Oncol 2015; 32:78.
Absence of Significant Correlation of Adverse Events Between First- and Second-Line Tyrosine Kinase Inhibitors in Patients With Metastatic Renal Cell Carcinoma Hideaki Miyake, Satoshi Imai, Ken-ichi Harada, Masato Fujisawa Abstract Several adverse events (AEs) are known to be commonly observed during treatment with different tyrosine kinase inhibitors (TKIs) in patients with metastatic renal cell carcinoma (mRCC) patients. However, no significant correlation appears present in the profiles of such AEs between first- and second-line TKI therapies. Therefore, a second-line targeted agent for patients with mRCC could be selected irrespective of the AE profile during first-line TKI therapy. Background: Several adverse events (AEs) commonly observed during treatment with different tyrosine kinase inhibitors (TKIs). The objective of the present study was to investigate whether the appearance of such AEs during treatment with first-line TKIs significantly affects the occurrence of AEs during second-line TKI therapy for patients with metastatic renal cell carcinoma (mRCC). Patients and Methods: The present study included 154 consecutive patients with mRCC treated with second-line TKIs after the discontinuation of first-line TKIs. The association of AEs, including diarrhea, fatigue, hand-foot syndrome, hypertension, and hypothyroidism, between first- and second-line therapies was analyzed in these 154 patients. Results: For all 5 AEs assessed in the present study, the proportion of patients experiencing AEs or those grade 3 during second-line TKI therapy was not significantly different among the following 3 groups: patients without AEs, those with grade 2 AEs, and those with grade 3 AEs during first-line TKI therapy. Furthermore, no significant difference was seen in progression-free or overall survival after the introduction of second-line TKIs between patients with and without grade 3 AEs during treatment with first-line TKIs. Conclusion: The incidence of AEs or grade 3 AEs during second-line TKI therapy are not dependent on the profiles of AEs during first-line TKI therapy in patients with mRCC. Therefore, AEs that occur during first-line TKI therapy should not affect the selection of second-line targeted agents for patients with mRCC. Clinical Genitourinary Cancer, Vol. 14, No. 1, e19-24 ª 2016 Elsevier Inc. All rights reserved. Keywords: Adverse events, First-line, Metastatic renal cell carcinoma, Second-line, Tyrosine kinase inhibitors
Introduction Until recently, immunotherapy using cytokines had been the mainstay of systemic therapy for patients with metastatic renal cell carcinoma (mRCC). However, this treatment could provide only limited efficacy, with a median overall survival (OS) of approximately 1 year.1 To overcome the poor prognostic outcomes of Division of Urology, Kobe University Graduate School of Medicine, Kobe, Japan Submitted: May 22, 2015; Revised: Aug 2, 2015; Accepted: Aug 8, 2015; Epub: Aug 15, 2015 Address for correspondence: Hideaki Miyake, MD, PhD, Division of Urology, Kobe University Graduate School of Medicine, 7-5-1 Kusunoki-cho, Chuo-ku, Kobe 6500017, Japan E-mail contact: [email protected]
1558-7673/$ - see frontmatter ª 2016 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.clgc.2015.08.002
patients with mRCC, novel molecular-targeted agents have been developed by intensive investigation of the molecular mechanisms mediating the progression of RCC. The recent introduction of these agents into clinical practice has resulted in a marked paradigm shift in the therapeutic strategy for mRCC.2 Of the several types of molecular-targeted agents, tyrosine kinase inhibitors (TKIs), which have been shown to mainly inactivate vascular endothelial growth factor (VEGF)-related pathways, are regarded as exerting powerful antitumor activities against mRCC according to the findings of pivotal randomized clinical trials.3-6 Therefore, TKIs currently play crucial roles in the treatment of patients with mRCC, in particular, as a first-line standard of care.7,8 Moreover, the favorable clinical outcomes on the use of TKIs against mRCC were confirmed in various studies evaluating these
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Lack of Correlation of Adverse Events Induced by Tyrosine Kinase Inhibitors agents in routine clinical settings.9-13 However, limited data are available with respect to sequencing therapy to determine the most effective second-line agent after the discontinuation of first-line TKIs, particularly for patients experiencing intolerable adverse events (AEs). It has been well-recognized that several common AEs are frequently observed during the treatment of mRCC patients with different TKIs.3-6,9-15 Accordingly, it has become a commonly held belief that patients who stop receiving first-line TKIs because of severe AEs should switch to an alternative agent with a mechanism of action different from that of TKIs to avoid the occurrence of AEs similar to those observed during first-line TKI therapy. However, this practice has not been based on reliable data with a high evidence level. Considering these findings, we retrospectively assessed the clinical outcomes of 154 consecutive patients with mRCC who had received second-line TKI therapy after the discontinuation of firstline TKI therapy. Our study focused on the association of AE profiles between the first- and second-line agents.
Patients and Methods
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We retrospectively reviewed the data from all patients with mRCC treated with molecular-targeted agents in a routine clinical setting at our institutions from April 2008 to December 2014. Of these, the present study included of 154 consecutive patients with mRCC who had received TKIs as first-line molecular-targeted agents and subsequently received a TKI different from that used as the first-line agent as second-line targeted therapy. Of the 154 patients, 9, who had not undergone radical nephrectomy, underwent needle biopsies of either the primary or the metastatic tumor to determine the histologic subtype. Therefore, all the included patients had a pathologic diagnosis of RCC. Each patient provided informed consent before participating in the present study, and the research ethics committee of our institution approved the study design. In the present series, immunotherapy using interferon-alfa and/or interleukin-2 was the only systemic therapy allowed before the introduction of first-line TKIs. TKIs were administered according to the following schedules: sorafenib, 400 mg orally, twice daily; sunitinib, 50 mg orally, once daily in repeated 6-week cycles consisting of 4 weeks on therapy, followed by 2 weeks off; and axitinib, 5 mg orally, twice daily. The administration of TKIs was continued until disease progression or intolerable AEs developed. As a rule, dose modification of TKIs was considered for patients with treatment-associated AEs corresponding to grade 3 as follows. For sorafenib, the dose was reduced from 800 to 400 mg once daily, followed by an additional dose reduction to a single 400-mg dose every other day. For sunitinib, the initial dose reduction was from 50 to 37.5 mg once daily, and then to 25 mg once daily. For axitinib, an increased dose of 7 mg twice daily was allowed for patients who had tolerated the standard dose for 2 weeks, unless the blood pressure was > 150/90 mm Hg or they were taking antihypertensive medication, and the dose was reduced to 3 mg twice daily and then further to 2 mg twice daily. As baseline evaluations, the clinicopathologic examinations and performance status were assessed using the International Union Against Cancer TNM classification system and Karnofsky performance status scale, respectively. Risk classification was conducted
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using both the Memorial Sloan Kettering Cancer Center and Heng’s risk classification systems.16,17 Before the initiation of TKI treatment, radiologic evaluations were performed for all patients by computed tomography of the brain, chest, and abdomen and radionuclide bone scanning. Tumor measurements were conducted by computed tomography before and every 12 weeks after the introduction of TKIs. Treatment responses and AEs were evaluated by the treating physician using the Response Evaluation Criteria in Solid Tumors, version 1.1, and the National Cancer Institute
Table 1 Patient Characteristics at Treatment Initiation of TKIs Characteristic
Value
Age (year) Median
61
Range
37-86
Gender Male Female
119 (77.3) 35 (22.7)
Previous nephrectomy Yes
144 (93.5)
No
9 (6.5)
Previous immunotherapy Yes
37 (24.0)
No
117 (76.0)
MSKCC risk classification Favorable
54 (35.1)
Intermediate
84 (54.5)
Poor
16 (10.4)
Heng risk classification Favorable
46 (29.9)
Intermediate
93 (60.4)
Poor
15 (9.7)
C-reactive protein <0.8 mg/dL
105 (68.2)
0.8 mg/dL
49 (31.8)
Metastatic organ Lung
98 (63.6)
Lymph node
33 (21.4)
Bone liver
16 (10.4)
Brain
8 (5.2)
No. of metastatic organs 1
82 (53.2)
2
62 (40.3)
>3
10 (6.5)
Histologic subtype Clear cell carcinoma Other
139 (90.3) 15 (9.7)
Sarcomatoid features Yes
15 (9.7)
No
139 (90.3)
Data presented as n (%), unless otherwise noted. Abbreviations: MSKCC ¼ Memorial Sloan Kettering Cancer Center; TKIs ¼ tyrosine kinase inhibitors.
Hideaki Miyake et al Common Terminology Criteria for Adverse Events, version 3.0, respectively. All statistical analyses were performed using Statview, version 5.0, software (Abacus Concepts, Inc, Berkley, CA), and P < .05 was considered significant. Differences in the incidence of AEs during treatment with second-line TKIs were compared according to the AE profile during first-line TKI therapy using the c2 test. The progression-free survival (PFS) and OS rates from the introduction of the second-line TKIs were calculated using the Kaplan-Meier method, and differences were determined using the log-rank test.
Association of AE Profiles Between First- and Second-Line TKI Therapies According to the profile of each AE observed during first-line TKI therapy, the 154 patients were divided into 3 groups as follows: patients without AEs, those with grade 2 AEs, and those with grade 3 AEs. For all 5 AEs assessed in the present study, no significant difference was seen in the proportion of patients experiencing AEs or those that were grade 3 during second-line TKI therapy among the 3 groups (Table 3).
Effect of AE Profiles During First-Line TKI Therapy on Prognosis After Second-Line TKI Therapy
Results Patient Characteristics and AE Profiles The detailed characteristics of the 154 patients included in the present study are listed in Table 1. Of the 154 patients, 56 (36.4%) and 98 (63.6%) were treated with sorafenib and sunitinib, respectively, as first-line agents, and 14 (9.1%), 52 (33.8%), and 88 (57.1%) received sunitinib, axitinib, and sorafenib, respectively, as second-line agents. In the present study, we focused on diarrhea, fatigue, hand-foot syndrome, hypertension, and hypothyroidism because these are the common AEs frequently observed during treatment with different TKIs. The profiles of these 5 AEs according to the TKIs administered are summarized in Table 2. During treatment with first- and second-line TKIs, some of these AEs (grade 3) were observed in 49 (31.8%) and 54 (35.1%) patients, respectively.
To evaluate the effect of the occurrence of the 5 AEs (grade 3) during first-line TKI therapy on patient prognosis after the introduction of second-line TKI therapy, we compared the PFS and OS between the 105 patients without any of the 5 AEs and the 49 with some of these AEs (grade 3). As shown in Figure 1, no significant difference was seen in PFS or OS between these 105 and 49 patients.
Discussion Owing to the outcomes of pivotal randomized phase III clinical trials, TKI therapy is currently regarded as a new reference standard of care for the first-line treatment of patients with mRCC, except for those classified into the poor-risk group.2,4,6-8 Furthermore, the efficacies and tolerability of TKIs presented in the clinical trials were
Table 2 AE Profiles During First- and Second-Line Tyrosine Kinase Inhibitor Therapies Therapy
Diarrhea
Fatigue
Hand-Foot Syndrome
Hypertension
Hypothyroidism
All grades
22 (39.3)
13 (23.2)
38 (67.9)
20 (35.7)
31 (55.4)
Grade 3
3 (5.4)
2 (3.6)
10 (17.9)
10 (17.9)
4 (7.4)
All grades
52 (53.1)
53 (54.1)
49 (50.0)
47 (48.0)
58 (59.2)
Grade 3
8 (8.2)
20 (20.4)
13 (13.3)
10 (10.2)
8 (8.2)
All grades
74 (48.1)
66 (42.9)
87 (56.5)
67 (43.5)
89 (57.8)
Grade 3
11 (7.1)
22 (14.3)
23 (14.9)
20 (13.0)
12 (7.8)
First-line Sorafenib (n ¼ 56)
Sunitinib (n ¼ 98)
Total (n ¼ 154)
Second-line Sorafenib (n ¼ 14) All grades
4 (28.6)
5 (35.7)
7 (50.0)
4 (28.6)
5 (35.7)
Grade 3
1 (7.1)
1 (7.1)
2 (14.3)
1 (7.1)
1 (7.1)
All grades
24 (46.2)
30 (57.7)
20 (38.5)
18 (34.6)
31 (59.6)
Grade 3
4 (7.7)
12 (23.1)
5 (9.6)
5 (9.6)
4 (7.7)
All grades
47 (53.4)
33 (37.5)
43 (48.9)
46 (52.3)
30 (34.1)
Grade 3
7 (8.0)
7 (8.0)
8 (12.5)
28 (31.8)
1 (1.1)
All grades
75 (48.7)
68 (44.2)
70 (45.5)
68 (44.2)
66 (42.9)
Grade 3
12 (7.8)
20 (13.0)
15 (9.7)
34 (22.1)
6 (3.9)
Sunitinib (n ¼ 52)
Axitinib (n ¼ 88)
Total (n ¼ 154)
Data presented as n (%). Abbreviation: AE ¼ adverse event.
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Lack of Correlation of Adverse Events Induced by Tyrosine Kinase Inhibitors Table 3 Correlation of AE Profiles Between First- and Second-Line Tyrosine Kinase Inhibitor Therapies AE Profile During First-Line Therapy
AE
P Value
All Grades
Diarrhea
Grade ‡3
P Value
.55
.38
None
80
37 (46.3)
5 (6.3)
Grade 2
63
31 (49.2)
5 (7.9)
Grade 3
11
7 (63.6)
2 (18.2)
Fatigue
.44
.72
None
88
40 (45.5)
13 (14.8)
Grade 2
44
21 (47.7)
5 (11.4)
Grade >3
22
7 (31.8)
2 (9.1)
None
67
30 (44.8)
6 (9.0)
Grade 2
64
28 (43.8)
6 (9.4)
Grade >3
23
12 (52.1)
Hand-foot syndrome
.78
.84
3 (13.0)
Hypertension
.59
.71
None
87
41 (47.1)
20 (23.0)
Grade 2
47
20 (42.6)
11 (23.4)
Grade >3
20
7 (35.0)
3 (15.0)
Hypothyroidism
.42
.69
None
65
25 (38.5)
2 (3.1)
Grade 2
77
34 (44.2)
3 (3.9)
Grade >3
12
7 (58.3)
1 (8.3)
Data presented as n (%). Abbreviation: AE ¼ adverse event.
Taken together, we retrospectively assessed the clinical outcomes of 154 consecutive patients with mRCC who had been treated with both first- and second-line TKIs to evaluate the association of the AE profiles between first- and second-line TKI therapies. It is well-recognized that common AEs are frequently observed in patients with mRCC treated with different TKIs.3-6,9-15 For example, hypertension occurs in 17% to 45% of patients with mRCC treated with TKIs, with those of grade 3 reported in 3% to
subsequently confirmed in several studies targeting patients with mRCC who had received TKIs in routine clinical practice.9-13 However, the selection of optimal second-line molecular-targeted agents after the discontinuation of first-line TKIs remains controversial. Therefore, second-line agents have been likely to be selected with consideration of the treatment response or AE profile during first-line TKI therapy18,19 but with few published data to support such a practice, in particular, the data associated with the AE profile.
Figure 1 (A) Comparison of Progression-Free Survival After the Introduction of Second-Line Tyrosine Kinase Inhibitors (TKIs) Between Patients With Grade ‡ 3 Adverse Events (AEs), Including Diarrhea, Fatigue, Hand-Foot Syndrome, Hypertension, and Hypothyroidism, During Treatment With First-Line TKIs and Patients Without Any AEs. (B) Comparison of Overall Survival After the Introduction of Second-Line TKIs Between Patients With Grade ‡ 3 AEs, Including Diarrhea, Fatigue, Hand-Foot Syndrome, Hypertension, and Hypothyroidism, During Treatment With First-Line TKIs and Those Without Any AEs
B 100
100 P = 0.77
80 60 Without AEs ≥ grade 3 (n = 105)
40
20
0
-
P = 0.43 80 60 With AEs ≥ grade 3 (n = 49)
40 20
Without AEs ≥ grade 3 (n = 105)
With AEs ≥ grade 3 (n = 49)
0
e22
Overall survival (%)
Progression-free survival (%)
A
5
10 15 20 25 30 35 Observation period (months)
Clinical Genitourinary Cancer February 2016
0 40
0
10
20 30 40 50 60 Observation period (months)
70
Hideaki Miyake et al 16% of such patients. Hand-foot syndrome has been reported in 19% to 34% of patients with mRCC receiving TKIs, including those of grade 3 (range, 5%-9%).14,15 Of these AEs, we focused on 5 potential AEs, including diarrhea, fatigue, hand-foot syndrome, hypertension, and hypothyroidism. The incidence and severity of these 5 AEs in the present series, which included only Japanese patients, were marked compared with those in clinical trials mainly conducted in Western countries.3-6 Therefore, it is necessary to consider this point when interpreting the findings of our study. To date, some clinical trials have reported the prospectively collected data of AEs occurring during first- and second-line treatment with targeted agents, such as the SWITCH and RECORD-3.20,21 However, the association of the profile for each AE between the sequential treatments was not addressed in these studies. In the present series, therefore, we assessed the correlation of the profiles of 5 commonly observed AEs between firstand second-line TKIs. We found no significant effect of each AE profile during first-line TKI therapy on the subsequent incidence of AEs or grade 3 AEs. In particular, the proportion of patients who experienced identical grade 3 AEs during treatment with both first- and second-line TKIs was very low. This could be explained, at least in part, by the effective prevention of severe AEs during second-line TKI therapy and the continuous, skilled management of AEs that occurred during first-line TKI therapy at our institutions. However, these findings suggest that it might not be necessary to consider the AE profile from first-line TKI therapy when determining the agent to subsequently administer as second-line therapy. It is of interest to assess the prognosis of patients with mRCC who received both first- and second-line TKIs according to the AE profile during first-line TKI therapy. In the present series, no significant difference was found in the PFS or OS between patients with and without the 5 commonly observed grade 3 AEs during treatment with first-line TKIs. This finding indicates that the administration of TKIs as second-line agents to patients who experienced severe AEs during first-line TKI therapy might not have an unfavorable effect on the subsequent prognosis in such patients. Another point of interest is the selection of the optimal secondline agent for patients with mRCC after discontinuation of first-line TKI therapy based on the present findings. Currently, 2 agents are recommended as second-line targeted therapy with a high level of evidence for the treatment of mRCC after initial VEGF-targeted therapy.5,22 Everolimus, an orally available inhibitor of the mammalian target of rapamycin, is approved for use after failure of 1 VEGF-targeted therapies.22 Axitinib is a potent, specific inhibitor of VEGF receptors and has also been shown to improve PFS compared with sorafenib in patients who had received 1 previous systemic therapy for mRCC.5 To date, no randomized trial has directly compared the efficacies of these 2 agents as second-line therapeutic agents after first-line VEGF-targeted therapy for patients with mRCC. However, 2 recent studies clearly showed no significant correlation with disease control between first- and second-line TKIs, measured by the best response or PFS in patients with mRCC treated with second-line TKI therapy after failure of first-line TKI therapy.23,24 The results of the present study also suggest no significant correlation of the AE profiles between first- and second-line TKI therapies. Considering disease progression and intolerable AEs as 2 major factors causing the discontinuation of first-line TKIs, our
results have shown that the second-line agent can be selected regardless of the clinical course during treatment with first-line TKIs. The present study had several limitations. First, ours was a retrospective study of data from the medical records of previously treated patients. This usually makes it difficult to reliably capture toxicity data. Also, the sample size was not large enough to draw definitive conclusions. Second, our study included only Japanese patients with mRCC, who have been shown to exhibit profiles associated with the use of molecular-targeted agents different from those of Western populations.25 Accordingly, it might be difficult to apply the present findings to an overall cohort with mRCC. Third, owing to the timing of the approval of molecular-targeted agents in Japan, a significant proportion of patients were not treated because of the currently recommended strategy of sequential therapy against mRCC. Thus, 66 patients received sequential therapy with sorafenib and sunitinib. Fourth, the present study focused only on 5 representative AEs. It would be more suitable to conduct an intensive study involving a wide variety of AEs to precisely address the objective of our study. Finally, the AE profiles of patients receiving TKIs have recently been shown in several studies to be improved by modification of the administration schedule, such as the introduction of an alternative schedule of sunitinib with 2 weeks on and 1 week off.26,27 Thus, it will be necessary to investigate the topics of our study considering the updated data from patients with mRCC who have recently received TKIs.
Conclusion To our knowledge, this is the first study showing no significant correlation between the AE profiles of first- and second-line TKIs. We assessed the incidence of commonly observed AEs during treatment with different TKIs, including diarrhea, fatigue, handfoot syndrome, hypertension, and hypothyroidism, in 154 consecutive patients with mRCC who received second-line TKI therapy after discontinuation of first-line TKI therapy. Therefore, the AE profile during first-line TKI therapy might not be a useful criterion for selecting a second-line agent for mRCC.
Clinical Practice Points Several common AEs are frequently observed during treatment
with different TKIs, including diarrhea, fatigue, hand-foot syndrome, hypertension, and hypothyroidism, in patients with mRCC. In the present series assessing the clinical outcomes of 154 patients with mRCC who received TKIs as second-line agents after discontinuation of first-line TKIs, some grade 3 AEs were observed in 49 (31.8%) and 54 (35.1%) patients during treatment with first- and second-line TKIs, respectively. For all 5 AEs examined, no significant effect of the AE profile during first-line TKI therapy was seen on the incidence of AEs or grade 3 AEs during second-line TKI therapy in these patients. No significant difference was seen in PFS or OS after the introduction of second-line TKIs between patients with and without grade 3 AEs during treatment with first-line TKIs. Considering the findings of our study, AEs that occur during first-line TKI therapy should not affect the selection of the second-line targeted agent for patients with mRCC.
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Lack of Correlation of Adverse Events Induced by Tyrosine Kinase Inhibitors Disclosure The authors have stated that they have no conflicts of interest.
References 1. Parton M, Gore M, Eisen T. Role of cytokine therapy in 2006 and beyond for metastatic renal cell cancer. J Clin Oncol 2006; 24:5584-92. 2. Figlin R, Sternberg C, Wood CG. Novel agents and approaches for advanced renal cell carcinoma. J Urol 2012; 188:707-15. 3. Escudier B, Eisen T, Stadler WM, et al. Sorafenib in advanced clear-cell renal-cell carcinoma. N Engl J Med 2007; 356:125-34. 4. Motzer RJ, Hutson TE, Tomczak P, et al. Sunitinib versus interferon alfa in metastatic renal-cell carcinoma. N Engl J Med 2007; 356:115-24. 5. Rini BI, Escudier B, Tomczak P, et al. Comparative effectiveness of axitinib versus sorafenib in advanced renal cell carcinoma (AXIS): a randomised phase 3 trial. Lancet 2012; 378:1931-9. 6. Motzer RJ, Hutson TE, Cella D, et al. Pazopanib versus sunitinib in metastatic renal-cell carcinoma. N Engl J Med 2013; 369:722-31. 7. Motzer RJ, Jonasch E, Agarwal N, et al. Kidney cancer, version 3.2015. J Natl Compr Cancer Netw 2015; 13:151-9. 8. Escudier B, Porta C, Schmidinger M, et al. Renal cell carcinoma: ESMO clinical practice guidelines for diagnosis, treatment and follow-up. Ann Oncol 2014; 25(suppl 3):iii49-56. 9. Gore ME, Szczylik C, Porta C, et al. Safety and efficacy of sunitinib for metastatic renal-cell carcinoma: an expanded-access trial. Lancet Oncol 2009; 10:757-63. 10. Harshman LC, Xie W, Bjarnason GA, et al. Conditional survival of patients with metastatic renal-cell carcinoma treated with VEGF-targeted therapy: a populationbased study. Lancet Oncol 2012; 13:927-35. 11. Beck J, Procopio G, Bajetta E, et al. Final results of the European Advanced Renal Cell Carcinoma Sorafenib (EU-ARCCS) expanded-access study: a large open-label study in diverse community settings. Ann Oncol 2011; 22:1812-23. 12. Choueiri TK, Duh MS, Clement J, et al. Angiogenesis inhibitor therapies for metastatic renal cell carcinoma: effectiveness, safety and treatment patterns in clinical practice-based on medical chart review. BJU Int 2010; 105:1247-54. 13. Miyake H, Miyazaki A, Harada K, et al. Assessment of efficacy, safety and quality of life of 110 patients treated with sunitinib as first-line therapy for metastatic renal cell carcinoma: experience in real-world clinical practice in Japan. Med Oncol 2014; 31:978. 14. Cohen RB, Oudard S. Antiangiogenic therapy for advanced renal cell carcinoma: management of treatment-related toxicities. Invest New Drugs 2012; 30:2066-79.
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