Outcome and Safety of Sorafenib in Metastatic Renal Cell Carcinoma ...

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Sep 30, 2015 - eTreatment was discontinued due to severe hematological toxicity. Sorafenib in. Dialysis. Patients. 4-. Clinical. Genitourinary. Cancer. Month.
Review

Outcome and Safety of Sorafenib in Metastatic Renal Cell Carcinoma Dialysis Patients: A Systematic Review Alessandro Leonetti,1 Melissa Bersanelli,1 Bruno Castagneto,2 Cristina Masini,3 Giovanni Di Meglio,4 Benedetta Pellegrino,1 Sebastiano Buti1 Abstract Few data are available about sorafenib use in patients with metastatic renal cell carcinoma (mRCC) undergoing hemodialysis. No systematic review has been previously performed about this issue. The objective of the present review is to investigate pharmacokinetics and clinical outcomes of sorafenib in mRCC patients undergoing hemodialysis. According to Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines, all the literature about mRCC dialysis patients receiving sorafenib, published from January 1946 to August 2015, was evaluated. Applying inclusion/exclusion criteria, 11 articles were selected for the analysis; 1 patient from our department was also included. The investigated outcomes were pharmacokinetics, toxicity, response rate, progression-free survival, and overall survival where available. A total of 36 patients were included. Median treatment duration was 6.0 months on overall population; median progression-free survival was 6.3 months (calculated on 19 patients); response rate was 22% (on 29 patients); median overall survival was 14.9 months (on 28 patients). Of note, 24 patients started sorafenib at reduced dose; 6 of 36 patients (17%) required dose reduction due to adverse events (AEs). Sorafenib treatment was discontinued in 7 patients (19%) because of AEs. Most of AEs were Grade 1-2; severe toxicities (Grade 4-5) included G4 anemia (1 case), G4 hypertension (1 case), G4 cerebellar hemorrhage (1 patient), and a case of G5 subarachnoid hemorrhage. This review confirmed the efficacy of sorafenib treatment in mRCC patients receiving hemodialysis. Nevertheless, drug toxicity seems to be increased in these patients, despite the initiation of therapy at reduced doses; therefore, sorafenib should be used with caution in dialysis patients. Clinical Genitourinary Cancer, Vol. -, No. -, --- ª 2016 Elsevier Inc. All rights reserved. Keywords: Hemodialysis, RCC, Renal failure, TKI, Treatment

Introduction Sorafenib (Nexavar) is an orally administered multi-kinase inhibitor, approved for the treatment of metastatic renal cell carcinoma (mRCC) and hepatocellular carcinoma. It shows antiangiogenic and anti-proliferative activities, through the inhibition of multiple targets involved in cancer cell signal transduction pathways: serine/threonine kinases c-Raf and b-Raf; vascular endothelial growth factor receptor (VEGFR-1, -2, and -3); plateletderived growth factor receptor (PDGFR-a and -b); FMS-like 1

Medical Oncology Unit, University Hospital of Parma, Parma, Italy Department of Oncology, San Giacomo Hospital Novi Ligure, Alessandria, Italy 3 Division of Medical Oncology, University Hospital of Modena, Modena, Italy 4 Medical Oncology Unit, Hospital of Bolzano, Bolzano, Italy 2

Submitted: Sep 30, 2015; Accepted: Jan 19, 2016 Address for correspondence: Dr. Sebastiano Buti, MD, Medical Oncology Unit, University Hospital of Parma, Via Gramsci 14, 43100 Parma, Italy E-mail contact: [email protected]

1558-7673/$ - see frontmatter ª 2016 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.clgc.2016.01.010

tyrosine kinase-3 (FLT3); stem cell growth factor receptor (SCFR or tyrosine-protein kinase KIT); rearranged during transfection (RET) receptor tyrosine kinase. This drug is effective for patients affected by mRCC who have received one prior systemic therapy, in terms of response rate (RR) and progression-free survival (PFS),1 but it did not show superiority over IFN-a in terms of PFS as first-line therapy.1 Sorafenib also seems to be less active than axitinib if used as first-line therapy.2 According to most guidelines worldwide, sorafenib is not currently recommended as the standard first-line therapy for mRCC.3-5 Renal tumors may involve both kidneys, as synchronous primitive bilateral sporadic tumor or as progression of the disease itself; in these cases, bilateral nephrectomy and hemodialysis may be necessary as life-saving treatments. Moreover, patients with end stage renal disease (ESRD) have an increased risk of developing renal cell carcinoma (RCC) in their native kidneys, proportionally related to hemodialysis treatment duration.6,7 Patients with mRCC and ESRD undergoing hemodialysis are often not included in

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Sorafenib in Dialysis Patients Figure 1 Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) Flow Diagram Showing Literature Search Results

prospective trials because of their altered pharmacokinetics, and only a few cases have been described in the literature until now about the use of sorafenib in this setting. This evidence is not individually quite useful for the management of the drug in this situation, and no systematic review (SR) about efficacy and tolerability of sorafenib in mRCC dialysis patients has been previously performed. Therefore, the purpose of the present work is to perform a systematic review of available data about pharmacokinetics and clinical outcomes of sorafenib in patients with RCC undergoing hemodialysis.

Material and Methods

2

-

The review was performed according to Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA)

Clinical Genitourinary Cancer Month 2016

guidelines.8 The published literature was identified by searching in the National Library of Medicine Database MEDLINE (2000 to August 18, 2015) and Embase (2000 to August 18, 2015). The search items were (Sorafenib v Nexavar v Bay 43-9006) and (RCC v Renal Cancer v Kidney Cancer) and (Dialysis v Hemodialysis) and (PK v pharmacokinetics). Bibliographies of pertinent articles were hand-searched for additional relevant citations. Exclusion criteria were the following: articles not written in English, abstract only, and not pertinent. All authors from the included studies were contacted by email for missing additional data; data were included only when provided by the authors who responded to our request. To enrich the study population, 1 dialysis mRCC patient treated with sorafenib in our department was also included in the review. Baseline patient characteristics included gender, age, histology of tumor, prognostic score according to Memorial Sloan Kettering

Alessandro Leonetti et al Table 1 Baseline Patient Characteristics Number (%) Number of patients

36

Gender Male Female NR Median age at diagnosis, years (range)

26 (72) 2 (6) 8 (22) 59.5 (32-72) 8 NR

Histology Clear cell

26 (72)

Others

7 (20)

NR

3 (8)

MSKCC prognostic score Favorable Intermediate

3 (8) 20 (56)

Poor

6 (17)

NR

7 (19)

with reports of 35 patients overall were included in the systematic review together with our own patient11-21; 2 articles reported only parmacokinetics informations and were not included in clinical data collection (Figure 1). The great majority of the authors did not answer our request for additional data; this element allowed only a descriptive evaluation of efficacy/toxicity statistics and median OS calculation.

Patient Characteristics A total of 36 patients were included in the systematic review. Detailed information about available and lacking data are shown in Table 1. The median age of population with available data was 59.5 years (age not reported for 8 patients), and 26 were male. Histology was clear cell carcinoma in 26 patients (72%). Three patients (8%) had favorable risk, 20 (56%) had intermediate risk, 6 (17%) had poor risk disease according to MSKCC criteria, and 50% of patients included had at least  2 sites of metastasis at the beginning of sorafenib treatment.

Efficacy and Administered Treatment

Metastasis, number of sites 1

11 (31)

2

9 (25)

3

9 (25)

NR

7 (19)

Line of treatment First line

23 (64)

Second line

11 (30)

Third line

1 (3)

Fourth line

1 (3)

Abbreviations: MSKCC ¼ Memorial Sloan Kettering Cancer Center; NR ¼ not reported.

Cancer Center (MSKCC),9 number of sites of metastasis, and line of therapy. Outcome measures included response rate (RR), time of treatment (TOT), progression-free survival (PFS), overall survival (OS), and safety. TOT was defined as the time from the starting of sorafenib treatment until its discontinuation for any reason. PFS was defined as the time from the first day of treatment to the first evidence of disease progression or death, and it was calculated with the simple median count of all reported data. OS was defined as the time from start of treatment to death for any cause, and it was calculated according to Kaplan-Meier method. When reported, pharmacokinetic data were also collected. Of note, due to the heterogeneity and to the lack of data of the reviewed literature, statistical analyses were partially conducted with the available data.

Results The literature search identified 18 abstracts and titles. Of these, 7 articles were excluded according to the adopted criteria (not written in English, abstracts only, not pertinent); the study performed by Omae et al10 was excluded because of the risk of duplicate data compared with the previous study by Kennoki et al11 (authors did not respond to our request for additional data). A total of 11 articles

Twenty-three patients (64%) received sorafenib as first-line therapy, 11 (30%) as second-line, 1 (3%) as third-line, and 1 (3%) as fourth-line. Twenty-four patients (67%) started sorafenib at reduced dose, and only 12 patients (33%) started with full dose of 800 mg daily. Six patients (17%) required dose reduction because of adverse events (AEs), while the dose was increased during therapy in 13 patients (36%; Table 2). Median TOT was 6.0 months (range, 1.0-39.5 months) for 24 patients; for 2 patients, treatment duration was not reported. It was not possible to include 10 patients (Kennoki et al) in this count, because data were not reported separately; the median treatment duration for them was 11.3 months (range, 1.3-29.6 months). RR was 22% on 29 patients; the remaining 7 patients (Shetty et al) were not included in this count because RR was not reported separately for each drug evaluated in the case series, where Shetty et al reported a RR of 31% for 14 patients treated with several targeted therapies including sorafenib. Median PFS was 6.3 months (range, 1.5-39.0 months) on 19 patients. The PFS of 10 patients was not reported; the remaining 7 patients (Shetty et al) had a median PFS of 4.2 months (range, not reported), with no individual data. Median OS, calculated using the Kaplan-Meier method on data available for 28 patients (Figure 2), was 14.9 months (95% confidence interval (CI), 8.8-20.9). OS was not reported for 8 patients.

Safety Seven patients (17%) discontinued sorafenib treatment due to AEs (Table 2). Toxicities reported during sorafenib treatment are shown in Table 3. Most common grade 1-2 side effects were diarrhea and hypertension, and these both occurred in 21 patients (58%, any grade). A total of 17 patients showed hand-foot skin reaction (47%, any grade), and 11 patients had fatigue (31%, any grade). Hematological toxicities were frequently reported, including anaemia (47%, any grade), thrombocytopenia (36%, any grade), and leucopenia (14%, any grade). Severe toxicities (grade 4-5) were rare and included grade 4 anemia (1 case), grade 4 hypertension (1 case), grade 4 cerebellar hemorrhage (1 patient), and a case of

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Starting Daily Dose Czarnecka et al, 2015 Shetty et al, 2014 Masini et al, 2011 Kennoki et al, 2010 Shinsako et al, 2010 Castagneto et al, 2010 Ferraris et al, 2009 Ruppin et al, 2008 Rey et al, 2008 Our patient TOT

N

100 mg

200 mg

400 mg

600 mg

800 mg

N Dose Titration

3 7 8 10 1 1 2 1 2 1 36

0 1 0 0 0 0 0 0 0 0 1 (3%)

0 0 1 8 1 0 0 0 0 0 10 (28%)

1 1 3 2 0 0 0 1 2 0 10 (28%)

0 3 0 0 0 0 0 0 0 0 3 (8%)

2 2 4 0 0 1 2 0 0 1 12 (33%)

1 0 0 8 1 0 0 1 2 0 13 (36%)

Abbreviations: N ¼ Number; NR ¼ not reported; TOT ¼ time of treatment. a Dose was first reduced to 400 mg, than to 600 mg. b Treatment was discontinued due to hand-foot syndrome, intolerable fatigue and development of squamous cell skin cancer respectively. c Treatment was discontinued due to Grade 3 cardiac toxicity. d Treatment was discontinued due to myocardial ischemia. e Treatment was discontinued due to severe hematological toxicity.

Dose Titration 400 mg 0 0 0 8 0 0 0 0 0 0 8 (62%)

Dose Reduction

800 mg

N Dose Reduction

400 mg

600 mg

N Treatment Discontinuation

1 0 0 0 1 0 0 1 2 0 5 (38%)

0 2 1a 0 0 1 1 0 1 0 6 (17%)

0 1 1 0 0 1 1 0 NR 0 4 (11%)

0 1 1 0 0 0 0 0 NR 0 2 (5%)

1 3b 1c NR 0 0 1d 0 0 1e 7 (19%)

Sorafenib in Dialysis Patients

Clinical Genitourinary Cancer Month 2016

Table 2 Starting Dose of Sorafenib and Dose Modifications During Therapy

Alessandro Leonetti et al Figure 2 Overall Survival Calculated by Kaplan-Meier Method on Data Available for 28 Patients

grade 5 subarachnoid hemorrhage. Of note, 1 patient developed squamous cell skin cancer during sorafenib treatment.

Pharmacokinetics Patients receiving hemodialysis have an increased risk of drug accumulation due to decreased renal excretion. Sorafenib is primarily metabolized in the liver, and approximately 19% of the drug is excreted in urine almost exclusively as glucuronide conjugates of the parent drug or metabolites.22 The most accredited suggestion is that pharmacokinetic of sorafenib would not be affected by renal impairment because of the low quantity of the drug eliminated by the kidney: no significant relationships were found between creatinine clearance and the area under the curve (AUC) of sorafenib in 54 patients with renal dysfunction,18 and pharmacokinetic parameters of sorafenib in dialysis patients did not appear to significantly differ from those of patients with normal renal function.16,18 Nevertheless, a phase I and pharmacokinetic study of sorafenib in patients with hepatic or renal impairment suggested that the empiric starting dose of the drug would be 200 mg daily in patients receiving hemodialysis, encouraging clinicians to carefully consider dose escalation only if the drug is well-tolerated.18 Moreover, 3 other pharmacokinetic studies demonstrated that sorafenib plasma concentration increased during hemodialysis sessions,11,16,19 due to the apparent absence of clearance of sorafenib and its metabolite M2 from plasma by the dialyzer.11 This could be explained by the fact that the large protein-drug complex could be unable to pass through the dialysis membrane.16 In conclusion, the possibility of a higher exposure to sorafenib due to renal failure and/or to hemodialysis session cannot be ruled out, despite the prevalent hepatic metabolism of the drug.

Discussion Dialysis patients are often excluded from clinical studies because of their altered metabolism and expectancy of increased drug toxicity, and few data are available about outcomes and safety of sorafenib in this setting of patients, mostly limited to

case series reported by reference centers. Toxicities are not often investigated, and the few available data suggest to start treatment at lower doses,18 resulting in a difficult clinical decision. This is the first systematic review performed on this issue, with the aim to provide additional information potentially useful for the management of the decision algorithm. We showed that RCC dialysis patients treated with sorafenib had a median PFS of 6.3 months and a median OS of 14.9 months, with a RR of 22% on 29 patients and with 44% of patients achieving stable disease, showing an overall disease control rate of 67% and demonstrating the efficacy of sorafenib in this setting of patients, with the limit of the small sample size and the lack of additional data. Our results are in line with those reported by Omae et al in a recent retrospective study of 20 mRCC patients treated with sorafenib undergoing hemodialysis, with a median PFS of 6.3 months, a median OS of 14.2 months, and a RR of 15%.10 In our study, 23 of 36 analyzed patients (64%) received sorafenib as first-line therapy; this is in contrast with the recommendations of the most popular guidelines for first-line mRCC therapy3-5 and with the results of the phase III randomized trial of sorafenib versus interferon-a (IFN-a)1 that showed no superiority of sorafenib treatment as first-line therapy compared with IFN-a. Moreover, sorafenib seems to be less active than axitinib in the first-line setting.2 However, the choice for sorafenib as first-line treatment could be explained by the expected good tolerability of the drug and the lower incidence of AEs compared with sunitinib.1,23 Although 67% of patients started treatment at reduced dose; furthermore, 17% of them required dose reduction due to AEs. Of note, sorafenib treatment in general was not well-tolerated, resulting in relevant toxicities and treatment discontinuation in 7 patients (19%). Common drug-related AEs were more frequent than reported in the large expanded-access study conducted with sorafenib on 1159 mRCC patients,24 and hematological toxicity was not entirely negligible; unexpected Grade > 3 toxicities were observed, including 2 cases of myocardial ischemia and 2 severe hemorrhages. Pharmacokinetic studies showed that sorafenib parameters are not different than those reported for patients with normal renal function,11,16 but there seems to be no clearance of the drug from plasma by the dialyzer.11 According to our findings, the increased toxicity could be expression of the recurrent increased exposure to the drug during the hemodialysis session. The limits of this review are represented by the small sample size and the descriptive analysis conducted mainly on the literature, often without access to the original source of data. Further studies are needed to give clinical guidance about the safety of treatment of mRCC patients receving hemodialysis.

Conclusion Despite the prevalent hepatic metabolism of the drug, it is not possible to certainly exclude that renal failure and/or hemodialysis procedure could increase the exposure to sorafenib and subsequently its toxicity. This hypothesis is also supported by the observation of the relevant drug activity even in the first-line setting despite not negligible dose reductions (often upfront) and of a toxicity more relevant than expected. For these reasons, in contrast with other authors,12 in our opinion, sorafenib should be used with caution in

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6

Fatigue

Nausea/Vomiting

Gastritis

Anorexia

Diarrhea

Hypertension

Myocardial Ischemia

N

G1-2

G3

G4-5

G1-2

G3

G4-5

G1-2

G3

G4-5

G1-2

G3

G4-5

G1-2

G3

G4-5

G1-2

G3

G4-5

G1-2

G3

Czarnecka et al, 2015

3

NR

NR

NR

NR

NR

NR

NR

NR

NR

NR

NR

NR

NR

NR

NR

NR

NR

1

NR

NR

G4-5 NR

Shetty et al, 2014

7

3

1

0

NR

NR

NR

NR

NR

NR

NR

NR

NR

2

0

0

2

0

0

NR

NR

NR

Masini et al, 2012

8

4

1

0

3

0

0

NR

NR

NR

0

0

0

5

1

0

5

0

0

0

1

0

Kennoki et al, 2011

10

NR

NR

NR

2

0

0

NR

NR

NR

NR

NR

NR

4

4

0

5

5

0

NR

NR

NR

Shinsako et al, 2010

1

NR

NR

NR

NR

NR

NR

NR

NR

NR

NR

NR

NR

0

0

0

0

0

0

NR

NR

NR

Castagneto et al, 2010

1

0

0

0

0

0

0

0

0

0

0

0

0

0

0

0

0

0

0

0

0

0

Ferraris et al, 2009

2

0

1

0

0

0

0

0

1

0

0

0

0

2

0

0

1

0

0

0

1

0

Ruppin et al, 2008

1

0

0

0

0

0

0

0

0

0

0

0

0

1

0

0

1

0

0

0

0

0

Rey et al, 2008

2

0

0

0

0

0

0

0

0

0

0

0

0

1

0

0

2

0

0

0

0

0

Our patient

1

1

0

0

1

0

0

0

0

0

1

0

0

1

0

0

0

1

0

0

0

0

N events (%)

8 (22%)

3 (8%)

0 (0%)

6 (17%)

0 (0%)

0 (0%)

0 (0%)

1 (3%)

0 (0%)

1 (3%)

0 (0%)

0 (0%)

16 (44%)

5 (14%)

0 (0%)

15 (42%)

6 (17%)

1 (3%)

0 (0%)

2 (6%)

0 (0%)

NR (%)

14 (39%) 14 (39%) 14 (39%) 11 (31%) 11 (31%) 11 (31%) 29 (81%) 29 (81%) 29 (81%) 21 (58%) 21 (58%) 21 (58%)

3 (8%)

3 (8%)

3 (8%)

3 (8%)

3 (8%)

0 (0%)

Hand-Foot Skin Reaction

Skin Rash

G3

NR

NR

NR

NR

NR

NR

NR

NR

NR

NR

NR

NR

NR

NR

NR

NR

NR

NR

NR

NR

NR

NR

NR

NR

Shetty et al, 2014

7

3

1

0

NR

NR

NR

NR

NR

NR

NR

NR

NR

NR

NR

NR

NR

NR

NR

NR

NR

NR

NR

NR

NR

Masini et al, 2012

8

5

0

0

1

1

0

NR

NR

NR

NR

NR

NR

NR

NR

NR

NR

NR

NR

NR

NR

NR

NR

NR

NR

Kennoki et al, 2011

10

5

1

0

2

NR

NR

5

NR

NR

NR

NR

NR

0

1

0

1

0

0

NR

NR

NR

2

0

2

Shinsako et al, 2010

1

0

0

0

NR

NR

NR

NR

NR

NR

NR

NR

NR

NR

NR

NR

NR

NR

NR

0

0

0

NR

NR

NR

Castagneto et al, 2010

1

1

0

0

0

0

0

0

0

0

0

0

0

0

0

0

0

0

0

0

0

0

0

0

0

Ferraris et al, 2009

2

0

0

0

1

0

0

0

0

0

0

1

0

0

0

0

0

0

0

0

0

0

0

0

0

Ruppin et al, 2008

1

0

0

0

0

0

0

0

0

0

0

0

0

0

0

0

0

0

0

0

0

0

0

0

0

Rey et al, 2008

2

0

1

0

0

0

0

0

0

0

0

0

0

0

0

0

0

0

0

0

0

0

0

0

0

Our patient

1

0

0

0

0

0

0

0

0

0

0

0

0

0

0

0

0

0

0

0

0

0

0

0

0

0 (0%)

4 (11%)

1 (3%)

0 (0%)

5 (14%)

0 (0%)

0 (0%)

0 (0%)

1 (3%)

0 (0%)

0 (0%)

1 (3%)

0 (0%)

1 (3%)

0 (0%)

0 (0%)

0 (0%)

0 (0%)

0 (0%)

2 (6%)

0 (0%)

2 (6%)

3 (8%)

G3

G4-5 G1-2

G3

G4-5 G1-2

G3

G4-5 G1-2

G3

Hemorrhage

G1-2

3 (8%)

G4-5 G1-2

Liver Dysfunction Increased Amylase

3

NR (%)

G3

Pneumonitis

N

14 (39%) 3 (8%)

G4-5 G1-2

Dyspnea

Czarnecka et al, 2015

N events (%)

G4-5 G1-G2 G3

Alopecia

21 (58%) 21 (58%) 21 (58%)

G4-5 G1-2

G3

G4-5

3 (8%) 11 (31%) 11 (31%) 11 (31%) 19 (53%) 29 (81%) 29 (81%) 29 (81%) 29 (81%) 29 (81%) 19 (53%) 19 (53%) 19 (53%) 19 (53%) 19 (53%) 19 (53%) 28 (78%) 28 (78%) 28 (78%) 19 (53%) 19 (53%) 19 (53%)

Hypothyroidism

Sepsis

Mucositis

Anemia

Trombocytopenia

Leucopenia

Others

N

G1-2

G3

G4-5

G1-2

G3

G4-5

G1-2

G3

G4-5

G1-2

G3

G4-5

G1-2

G3

G4-5

G1-2

G3

G4-5

Any Grade

Czarnecka et al, 2015

3

NR

NR

NR

NR

NR

NR

NR

NR

NR

NR

NR

NR

NR

NR

NR

NR

NR

NR

NR

Shetty et al, 2014

7

NR

NR

NR

NR

NR

NR

NR

NR

NR

NR

NR

NR

NR

NR

NR

NR

NR

NR

1a

Masini et al, 2012

8

0

0

0

NR

NR

NR

NR

NR

NR

6

0

0

3

0

0

2

0

0

0

Kennoki et al, 2011

10

NR

NR

NR

0

1

0

NR

NR

NR

3

6

0

8

0

0

1

0

0

2b

Shinsako et al, 2010

1

NR

NR

NR

NR

NR

NR

NR

NR

NR

0

0

1

0

1

0

0

1

0

0

Castagneto et al, 2010

1

0

0

0

0

0

0

0

0

0

0

0

0

0

0

0

0

0

0

0

Ferraris et al, 2009

2

0

0

0

0

0

0

0

0

0

0

0

0

0

0

0

0

0

0

0

Ruppin et al, 2008

1

0

0

0

0

0

0

0

0

0

0

0

0

0

0

0

0

0

0

0

Sorafenib in Dialysis Patients

Clinical Genitourinary Cancer Month 2016

Table 3 Toxicities Due to Sorafenib Treatment

3 (8%)

Abbreviations: G ¼ Grade; N ¼ number; NR ¼ not reported. a Squamous cell skin cancer. b Pulmonary nose; central nervous system toxicity. c Headache G1.

4 (11%) 0 (0%)

10 (28%)

1 (3%)

10 (28%)

4 (11%)

10 (28%) 10 (28%)

0 (0%) 1 (3%)

10 (28%) 10 (28%)

12 (33%) 1 (3%)

10 (28%) 10 (28%)

7 (19%) 9 (25%)

10 (28%) 29 (81%)

0 (0%) 0 (0%)

29 (81%) 29 (81%)

1 (3%)

References

19 (53%)

0 (0%)

The authors have stated that they have no conflicts of interest.

19 (53%)

1 (3%)

Disclosure

19 (53%)

0 (0%)

dialysis patients and we suggest starting therapy with reduced doses (ie, 400 mg/day).

21 (58%)

0 (0%) 0 (0%)

NR (%)

21 (58%)

0 (0%)

21 (58%)

N events (%)

0

1c

0

0

0

0

0

0 0

0 1

0 0

0 1

0 0

0 0

0 0

0 0

1 0

0 0

0 0

0 0

0 0

0 Our patient

0

2

1

Rey et al, 2008

0

1

0

Any Grade G4-5 G3 G4-5 G3 G1-2 G3 G3 G3 G4-5 G3 G1-2 N

Table 3 Continued

Hypothyroidism

G1-2

Sepsis

G4-5

G1-2

Mucositis

G4-5

G1-2

Anemia

G4-5

Trombocytopenia

G1-2

Leucopenia

Others

Alessandro Leonetti et al

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Clinical Genitourinary Cancer Month 2016

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