Vol 18, No 4 (2022)
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Evaluation of the effectiveness and tolerability of sunitinib and pazopanib in the first line treatment of metastatic renal cell carcinoma

Senar Ebinç1, Ziya Kalkan1, Zeynep Oruç1, Zuhat Urakçı1, Mehmet Küçüköner1, Muhammet Ali Kaplan1, Abdurrahman Işıkdoğan1
Oncol Clin Pract 2022;18(4):226-234.

Abstract

Introduction. It is known that sunitinib and pazopanib are effective in the first-line and subsequent treatment of metastatic renal cell carcinoma (mRCC). This study aims to investigate the effectiveness and tolerability of sunitinib and pazopanib in the first-line treatment of mRCC. 

Material and methods. This study included 78 patients followed up in our clinic due to a diagnosis of mRCC, who received pazopanib or sunitinib treatment between 2006 and 2020. Along with clinical and laboratory findings, survival times obtained with each treatment and medication side effects were assessed. Sunitinib and pazopanib were compared in terms of effectiveness (ORR, PFS and OS) and tolerability. 

Results. The patients’ median age at diagnosis was 55 years (25–81). In the first-line treatment, 54 patients (69.2%) received sunitinib and 24 (30.8%) received pazopanib. The comparison of sunitinib and pazopanib yielded an ORR of 66.7% vs. 45.8% (p = 0.08), PFS of 24 months vs. 19 months (p = 0.66) and OS of 27 months vs. 30 months (p = 0.73), respectively. The most common side effect was hypothyroidism in those on sunitinib (25.9%) and nausea-vomiting in those on pazopanib (41.7%). In our study, hemoglobin ≥ 13 g/dL, an ECOG PS of 0–1 and the occurrence of hypothyroidism as a medication side effect were found to be predictive factors of PFS for both agents. An International Metastatic RCC Database Consortium score corresponding to the poor risk group was associated with a poor PFS. 

Conclusions. This study, which provides current real-world data, confirms that sunitinib and pazopanib have similar effectiveness and side-effect profiles in the first-line treatment of mRCC.

ORIGINAL ARTICLE

Oncology in Clinical Practice

DOI: 10.5603/OCP.2022.0020

Copyright © 2022 Via Medica

ISSN 2450–1654

e-ISSN 2450–6478

Evaluation of the effectiveness and tolerability of sunitinib and pazopanib in the first line treatment of metastatic renal cell carcinoma

Senar EbinçZiya KalkanZeynep OruçZuhat UrakçıMehmet KüçükönerMuhammet Ali KaplanAbdurrahman Işnıkdoğa
Dicle University Faculty of Medicine, Department of Medical Oncology, Diyarbakır, Turkey

Address for correspondence:

Senar Ebinç, MD

Dicle University Faculty of Medicine,

Department of Medical Oncology,

Diyarbakır, Billstreet Sur, 21280 Diyarbakır;

Turkey

e-mail: senarebinc@gmail.com

Received: 02.02.2022 Accepted: 08.03.2022 Early publication date: 31.05.2022

ABSTRACT

Introduction. It is known that sunitinib and pazopanib are effective in the first-line and subsequent treatment of metastatic renal cell carcinoma (mRCC). This study aims to investigate the effectiveness and tolerability of sunitinib and pazopanib in the first-line treatment of mRCC.

Material and methods. This study included 78 patients followed up in our clinic due to a diagnosis of mRCC, who received pazopanib or sunitinib treatment between 2006 and 2020. Along with clinical and laboratory findings, survival times obtained with each treatment and medication side effects were assessed. Sunitinib and pazopanib were compared in terms of effectiveness (ORR, PFS and OS) and tolerability.

Results. The patients’ median age at diagnosis was 55 years (2581). In the first-line treatment, 54 patients (69.2%) received sunitinib and 24 (30.8%) received pazopanib. The comparison of sunitinib and pazopanib yielded an ORR of 66.7% vs. 45.8% (p = 0.08), PFS of 24 months vs. 19 months (p = 0.66) and OS of 27 months vs. 30 months (p = 0.73), respectively. The most common side effect was hypothyroidism in those on sunitinib (25.9%) and nausea-vomiting in those on pazopanib (41.7%). In our study, hemoglobin13 g/dL, an ECOG PS of 01 and the occurrence of hypothyroidism as a medication side effect were found to be predictive factors of PFS for both agents. An International Metastatic RCC Database Consortium score corresponding to the poor risk group was associated with a poor PFS.

Conclusions. This study, which provides current real-world data, confirms that sunitinib and pazopanib have similar effectiveness and side-effect profiles in the first-line treatment of mRCC.

Key words: renal cell carcinoma, sunitinib, pazopanib, VEGFR inhibitors

Oncol Clin Pract 2022; 18, 4: 227234

Introduction

Although the prevalence of renal cell carcinoma varies across regions, it is estimated to have a worldwide annual incidence of 403,000 and 175,000 patients lose their lives due to renal cancer every year [1]. Renal cancers are more common in males and in the 6th8th decade [2]. Surgery constitutes a curative treatment approach in early-stage renal cell carcinomas, while systemic treatment options take precedence in advanced-stage disease. However, the excision of the primary tumor can sometimes result in the spontaneous regression of metastases [3].

Systemic treatment approaches include programmed cell death 1 protein (PD-1), programmed cell death ligand 1 (PD-L1), vascular endothelial growth factor receptor (VEGFR) inhibitors and anti-cytotoxic T-lymphocyte-associated protein (CTLA-4) antibodies [4]. The core treatment of intermediate and poor prognostic groups of metastatic renal cell carcinoma consists of an immunotherapy combination or a combination of VEGFR inhibitors with immunotherapy. This would also remain a treatment option for the favorable prognostic group. On the other hand, VEGFR inhibitors can be used alone in situations where immunotherapy is not appropriate or accessible in later lines of treatment. The effect mechanisms of these medications rely on the interruption of the VEGF signaling pathway, which causes physiological escape [5, 6]. Sunitinib is an oral tyrosine kinase inhibitor (TKI) that inhibits the endothelial growth factor receptor (VEGFR) and the platelet derived growth factor receptor (PDGFR) [7]. Similarly, pazopanib is an oral angiogenesis inhibitor that targets the VEGFR, PDGFR and c-kit [8]. Both agents have been used as single agents in the treatment of renal cell carcinoma for many years. In the recent years, immunotherapy and immunotherapy-TKI combinations have been introduced to the treatment algorithm. However, particularly in places where immunotherapy is not accessible as first-line treatment, single use of TKIs is still among the treatment options. In this study, we investigated the effectiveness and tolerability of pazopanib and sunitinib in the first-line treatment of metastatic renal cell carcinoma. Our study evaluated the response rates, PFS and OS times obtained with pazopanib and sunitinib in the first-line treatment of mRCC. It was investigated whether or not the two agents were different in terms of response rates, survival times or side effects.

Material and methods

In this study, the files of patients who presented to the Medical Oncology Clinic of Dicle University, Faculty of Medicine between 2006 and 2020 and received pazopanib or sunitinib as first-line treatment for a diagnosis of metastatic renal cell cancer were retrospectively reviewed. Data of a total of 78 patients who received pazopanib [24 (30.8%)] or sunitinib [54 (69.2%)] in the first-line treatment could be retrieved. Data concerning age, gender, smoking, ECOG PS (Eastern Cooperative Oncology Group performance status), IMDC (International Metastatic RCC Database Consortium) score, comorbidities, previous nephrectomy, tumor histology, primary tumor localization (right/left), metastatic sites (liver, lung, bone), hemoglobin levels, albumin levels, treatment agent used in the first-line treatment (pazopanib/sunitinib), and drug-induced side effects were obtained from the patient files. The effects of tumor characteristics and clinical parameters on the clinical outcomes and the effectiveness and tolerability of the first-line agent were evaluated. Treatment response was assessed at 3-month intervals based on clinical and radiological data. Radiological response to treatment was evaluated according to the Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST 1.1).

The administered treatment included the use of 50 mg daily sunitinib (without regard to meals) for four weeks followed by two-week off or drug use for two weeks followed by one-week off (in case of adverse effects) in the sunitinib arm. In the pazopanib arm, 800 mg pazopanib (1 hour before or 2 hours after meals) was administered daily. Drug toxicity was assessed according to the Common Terminology Criteria for Adverse Events.

Statistics

Statistical analysis of the data used the SPSS 18.0 program package. Descriptive statistics were used to evaluate patient characteristics and the frequencies of parameters, Student’s t-test was used for normally distributed numeric variables and the Mann-Whitney U test was used for the analysis of non-normally distributed or non-parametric variables. For univariate analyses, the t-test, chi-square test, Fisher’s exact test and Mann-Whitney U test were used. A confidence interval of 95% and a p significance level < 0.05 were adopted. For survival analysis and subgroup analyses, the Kaplan-Meier method (log-rank, Breslow, Tarone-Ware tests) and Cox regression analysis were used. The parameters evaluated in subgroup analyses {gender, ECOG PS [≥ 2 vs. 01], smoking, tumor laterality [left/right], nephrectomy [yes/no], metastatic sites [liver, lung, bone), presence of comorbidity, histological subtype [clear-cell vs. non-clear-cell], albumin g/dL level [< 3.6 vs. 3.6], hemoglobin g/dL level [≥ 13 vs. < 13] [in ROC analysis, the cut-off value for albumin was determined as 3.6 g/dL (AUC = 0.735, p = 0.002) at 85% sensitivity and 53% specificity, the cut-off value for hemoglobin was determined as 13 g/dL (AUC = 0.667, p = 0.025) at 70% sensitivity and 50% specificity], drug-induced hypothyroidism, palmar-plantar erythrodysesthesia, hypertension and fatigue}, the first-line agent (pazopanib/sunitinib) were assessed with respect to the prediction of PFS.

Terminology

Overall survival (OS) was computed as the length of time from the occurrence of metastasis to death, progression-free survival (PFS) was computed as the duration of time from the initiation of first-line treatment to progression on this treatment or death from any cause. Objective response (OR) was accepted as the sum of complete responses and partial responses obtained at the third month of treatment. The IMDC scoring system included risk factors such as a duration of time from diagnosis to systemic therapy < 1 year, Karnofsky performance status < 80%, hemoglobin level < 12 g/dL, corrected serum calcium level > 10.2 mg/dL, platelet count > 400 × 109/L and neutrophil count > 7 × 109/L. Patients with no risk factors were accepted as the favorable risk group, patients with 12 risk factors as the intermediate risk group, and patients with risk factors3 as the poor risk group.

Results

Our study included a total of 78 patients with metastatic renal cell carcinoma, comprising 61 (78.2%) males and 17 (21.8%) females. The patients’ median age at diagnosis was 55 years (2581). ECOG PS at diagnosis was 01 in 66 (84.6%) patients,2 in 12 (15.4%) patients. There were 60 (76.9%) patients who smoked and 37 (47.4%) patients who had at least one comorbidity. The primary tumor was localized in the right kidney in 39 (50%) patients and in the left kidney in 39 (50%) patients. Fifty-nine (75.6%) patients had undergone nephrectomy at any stage of the disease. As to the metastatic localizations, metastases were found in the liver in 9 (11.6%) patients, in the lung in 52 (66.7%) patients, in the bone in 36 (46.2%) and in other localizations in 13 (16.7%) patients. Of our patients, 63 (80.8%) had clear-cell histology, while 15 (19.2%) had non-clear cell histology. In our study, 54 patients (69.2%) received sunitinib and 24 (30.8%) received pazopanib. When grouped with respect to the IMDC score, 3.8% patients (n = 3) were in the favorable risk group [1 (4.2%) on pazopanib, 2 (3.7%) on sunitinib], 57.7% patients (n = 45) were in the intermediate risk group [17 (70.8%) on pazopanib, 28 (51.9%) on sunitinib] and 38.5% patients (n = 30) were in the poor risk group [6 (25%) on pazopanib, 24 (44%) on sunitinib] (Tab. 1).

Table 1. General characteristics of patients

All patients

Pazopanib

Sunitinib

N (%)

78

24 (30.8)

54 (69.2)

Age, yrs (median, range)

55 (2581)

57 (28-81)

55 (2578)

ECOG PS

01

66 (84.6)

19 (79.2)

47 (87)

2

12 (15.4)

5 (20.8)

7 (13)

Gender

Male

61 (78.2)

14 (58.3)

47 (87)

Female

17 (21.8)

10 (41.7)

7 (13)

Comorbidities

Yes

37 (47.4)

15 (62.5)

22 (40.7)

No

41 (52.6)

9 (37.5)

32 (59.3)

Smoking

Yes

60 (76.9)

14 (58.39

46 (85.2)

No

18 (23.1)

10 (41.7)

8 (14.8)

Nephrectomy

Yes

59 (75.6)

18 (75)

41 (75.9)

No

19 (24.4)

6 (25)

13 (24.1)

Metastasis site

Liver

9 (11.6)

2 (2.6)

7 (9)

Lung

52 (66.7)

18 (23.1)

34 (43.6)

Bone

36 (46.2)

11 (14.1)

25 (32.1)

Others

13 (16.7)

5 (6.4)

8 (10.3)

Histological type

Clear cell

63 (80.8)

20 (83.3)

43 (79.6)

Non-Clear cell

15 (19.2)

4 (16.7)

11 (20.4)

Tumor location

Left

39 (50)

15 (62.5)

24 (44.4)

Right

39 (50)

9 (37.5)

30 (55.6)

IMDC score

Favorable

3 (3.8)

1 (4.2)

2 (3.7)

İntermediate

45 (57.7)

17 (70.8)

28 (51.9)

Poor

30 (38.5)

6 (25)

24 (44.4)

With regard to the three-month treatment response rates, partial response was obtained in 11 (45.8%) patients and stable disease was observed in 13 (54.2%) patients on pazopanib, with no cases of complete response or progressive disease. In the sunitinib arm, complete response was obtained in 2 (3.7%) patients, partial response was obtained in 34 (63%) patients, and stable disease was observed in 18 (33.3%) patients. Progressive disease was also not encountered in this arm. With regard to the objective response rates (ORR), an ORR of 45.8% (n = 11) was obtained in the pazopanib arm and an ORR of 66.7% (n = 36) was obtained in the and sunitinib arm, with no statistically significant difference between the two arms (p = 0.08). When evaluated with regard to survival, PFS was 19 months [95% CI: (8.429.5)] in thepazopanib arm and 24 months [95% CI: (16.131.9)] in the sunitinib arm and there was no statistically significant difference between the two groups in terms of PFS [HR, 0.88; 95% CI, 0.501.55], (p = 0.66), (Fig. 1). OS was 30 months [95% CI: (24.535.4)] in the pazopanib arm as opposed to 27 months [95% CI: (15.938)] in the sunitinib arm [HR, 1.10; 95% CI, 0.611.97], (p = 0.73) (Fig. 2). For the entire study group, the first-line treatment was associated with a PFS of 22 months [95% CI (15.228.7)] and an OS of 30 months [95% CI (21.638.3)] (Tab. 2).

Figure 1. Progression-free survival for sunitinib and pazopanib
Figure 2. Overall survival for sunitinib and pazopanib
Table 2. Response rates and survivall for pazopanib and sunitinib

All patients

Pazopanib

Sunitinib

P value

Responses

0.17

CR no. (%)

2 (2.6%)

0 (0%)

2 (3.7%)

PR no. (%)

45 (57.7%)

11 (45.8%)

34 (63%)

SD no. (%)

31 (39.7%)

13 (54.2%)

18 (33.3%)

PD no. (%)

0 (0%)

0 (0%)

0 (0%)

ORR no. (%)

47 (60.3%)

11 (45.8%)

36 (66.7%)

0.08

PFS (mo) median (95% CI)

22 (15.228.7)

19 (8.429.5)

24 (1928.9)

0.58

OS (mo) median (95% CI)

30 (21.638.3)

30 (24.535.4)

27 (15.938)

0.73

It was found that ECOG PS, hemoglobin levels, IMDC scores (intermediate/poor) and the occurrence of drug-induced hypothyroidism predicted PFS for both drugs. Median PFS was 5 months (2.08.0) in patients with an ECOG PS2, as opposed to 24 months (18.129.8) in patients with an ECOG PS 01 (Log-rank p = 0.001). Median PFS was 25 months (14.135.8) in patients with a hemoglobin level13 g/dL, while it was 22 months in those with a hemoglobin level < 13 g/dL (14.929) (Log-rank p = 0.030). Median PFS was 24 months in patients with an intermediate IMDC score as opposed to 12 months in patients with a poor IMDC score (Log Rank p = 0.045). The majority of our patients were categorized in the intermediate or poor IMDC risk group. PFS was 30 months (27.332.7) in patients who developed hypothyroidism as a side effect, as opposed to 15 months (7.822.1) in others (Log-Rank p = 0.016). Other parameters listed above (gender, smoking, tumor laterality (right/left), nephrectomy (yes/no), metastatic sites (liver, lung, bone), presence of comorbidity, histological subtype (clear-cell vs. non-clear-cell), albumin g/dL level (< 3.6 vs. 3.6), drug-induced palmar-plantar erythrodysesthesia, hypertension and fatigue) were not found to predict PFS with statistical significance. Univariate and multivariate analysis results are specified in Table 3.

Table 3. Univariate and multivariate analysis results of factors affecting progression-free survival in first line therapy

Univariate Analysis

Multivariate Analysis

HR

95% CI

P value

HR

95% CI

P value

Age

0.99

0.971.02

0.96

ECOG PS (01/≥ 2)

4.77

2.1010.83

< 0.001

9.86

3.0132.2

< 0.001

Gender (male/female)

0.72

0.381.34

0.30

Hemoglobin (< 13/≥ 13 g/dL)

0.52

0.290.95

0.03

0.51

0.260.99

0.05

Albumin (< 3.6/≥ 3.6 g/dL)

0.78

0.451.34

0.37

1.35

0.691.74

0.38

Palmar-plantar erythrodysesthesa

0.78

0.351.7

0.55

Hypothyroidism

0.48

0.260.89

0.02

0.46

0.240.89

0.02

Fatigue

1.33

0.622.84

0.45

Hypertension

0.67

0.301.49

0.32

Comorbidities (no/yes)

0.82

0.481.39

0.46

Smoking (no/yes)

0.97

0.521.82

0.94

Nefrektomi (no/yes)

0.67

0.341.33

0.25

Metastasis site

Liver (no/yes)

1.64

0.733.66

0.22

Lung (no/yes)

1.09

0.601.95

0.77

Bone (no/yes)

1.21

0.702.07

0.48

Histological type (clear cell/non-clear cell)

0.86

0.421.78

0.69

0.77

0.341.74

0.54

Tumor location (left/right)

1.09

0.641.84

0.75

IMDC score (poor/intermediate)

0.09

0.06

Favorable

1.49

0.346.50

0.58

0.22

0.361.40

0.10

Intermediate

0.56

0.320.99

0.049

0.46

0.220.92

0.03

Poor

Reference

Reference

When the two agents, sunitinib and pazopanib, were compared with regard to PFS, [HR = 0.88, 95% CI (0.501.55), p = 0.66] no statistically significant difference was found in terms of PFS. When the parameters that influenced the PFS times obtained with pazopanib and sunitinib were inspected in subgroups, no statistically significant difference was found between the two agents in terms of gender, smoking, nephrectomy (yes/no), metastatic sites (liver, lung, bone), histological subtype (clear-cell vs. non-clear-cell), drug-induced hypothyroidism, hypertension, palmar-plantar erythrodysesthesia, albumin g/dL level (< 3.6) hemoglobin g/dL level (< 13) and IMDC score (intermediate/poor) (Tab. 4, Fig. 3).

Table 4. Results of pazopanib vs. Sunitinib comparison subgroup analysis

Pazopanib vs. Sunitinib

HR

95% CI

P value

All patient

0.88

0.501.55

0.66

Gender

Male

0.94

0.461.93

0.88

Female

0.77

0.252.39

0.66

Smoking (yes)

0.99

0.491.98

0.98

Nephrectomy (yes)

1.06

0.552.03

0.84

Albumin (< 3.6 g/dL)

0.63

0.241.63

0.34

Hemoglobin (< 13 g/dL)

1.14

0.433.00

0.77

Metastasis site

Liver

0.27

0.031.96

0.19

Lung

0.71

0.212.32

0.57

Bone

0.85

0.361.97

0.70

Hypothyroidism

0.57

0.191.69

0.31

Hypertension

0.73

0.124.31

0.73

Palmar-plantar erythrodysesthesa

1.55

0.1713.7

0.69

Histological type

Clear cell

0.96

0.521.78

0.90

Non-clear cell

0.52

0.122.22

0.38

IMDC score (poor/intermediate)

Intermediate

0.70

0.351.41

0.32

Poor

1.31

0.444.11

0.60

Figure 3. Subgroup analysis of factors affecting progression-free survival for sunitinib and pazopanib

When evaluated with regard to medication side effects, the most common side effects of any grade were nausea-vomiting, hypothyroidism, hypertension and skin reactions in the pazopanib arm and hypothyroidism, nausea-vomiting, palmar-plantar erythrodysesthesia and hypertension in the sunitinib arm. Although the side effects associated with the two agents were similar, nausea-vomiting was encountered at a higher rate in the pazopanib arm when compared with sunitinib [respectively 41.7% vs. 14.8%, (p = 0.01)]. Medication side effects are specified in detail in Table 5.

Table 5. Treatment-related side effects

Any grade n(%)

All patients

Pazopanib

Sunitinib

P value

Hypothyroidism

19 (24.4)

5 (20.8)

14 (25.9)

0.62

Hyperthyroidism

1 (1.3)

0 (0)

1 (1.9)

0.69

Pruritus

1. (1.3)

1 (4.2)

0 (0)

0.30

Palmar-plantar erythrodysesthesa

8 (10.3)

1 (4.2)

7 (13)

0.23

Nausea/vomiting

18 (23.1)

10 (41.7)

8 (14.8)

0.01

Diarrhea

5 (6.4)

1 (4.2)

4 (7.4)

0.50

Hypertension

8 (10.3)

2 (8.3)

6 (11.1)

0.71

Neutropenia

2 (2.6)

0 (0)

2 (3.7)

0.47

Anemia

0 (0)

0 (0)

0 (0)

Thrombocytopenia

4 (5.1)

0 (0)

4 (7.4)

0.22

Mucositis

5 (6.4)

1 (4.2)

4 (7.4)

0.59

Fatigue

9 (11.5)

2 (8.3)

7(13)

0.55

Skin reaction

3 (3.8)

2 (8.3)

1 (1.9)

0.22

Discussion

This study compared the effectiveness and tolerability of pazopanib and sunitinib in the first-line treatment of metastatic renal cell carcinoma. In a study that compared sunitinib with interferon alpha in the treatment of treatment-naive metastatic renal cell carcinoma, it was shown to be superior to interferon alfa in terms of both PFS (11 months vs. 5 months) and the objective response rate (31% vs. 6%) [9]. When considered with regard to OS, the overall survival achieved in the sunitinib arm was 26.4 months, while the OS obtained in the interferon alpha arm was 21.8 months [10]. In our study, an OS of 27 months, PFS of 24 months and ORR of 66.7 were obtained with sunitinib as the first-line treatment of metastatic renal cell carcinoma. Both the response rates and the PFS values showed better outcomes in our study when compared with the literature.

In a controlled phase-III study, in which pazopanib was given as first line therapy or subsequent to cytokine therapy in locally advanced or metastatic renal cell carcinoma, it was shown to be superior to placebo in terms of both PFS (11.1 months vs. 2.8 months, respectively) and the ORR (30% vs. 3%, respectively). In our study, PFS was 19 months and the ORR was 45.8% in the pazopanib arm [11]. The PFS and ORR values obtained in our study were more favorable compared with the literature.

In the prospective COMPARZ study, which included 1100 patients and compared pazopanib and sunitinib in the first-line treatment of mRCC (clear-cell histology), a PFS of 10.5 months was obtained with pazopanib and a PFS of 10.2 months was obtained with sunitinib, and the two groups were evaluated to be similar with respect to PFS (HR, 1.00; 95% CI, 0.861.15). However, this study reported pazopanib to be more tolerable according to the side effect profiles [12]. On the other hand, OS data from another study that compared pazopanib and sunitinib in the first-line treatment of mRCC showed pazopanib to be non-inferior to sunitinib, with median OS times for pazopanib and sunitinib reported as 26.9 months (95% CI, 23.135.6) and 26.1 months (95% CI, 20.731.6), respectively [13]. Considering the real-life data, in the study of Isik U. et al. [14], sunitinib and pazopanib data were evaluated in first-line treatment in metastatic clear cell renal cell carcinoma. A median PFS of 24.3 months was observed in the sunitinib arm, while a median PFS of 34.2 months was observed in the pazopanib arm. There was no statistically significant difference between the two drugs in terms of PFS [14]. In our study, the sunitinib and pazopanib arms were associated with a PFS of 24 months and 19 months, (p = 0.66) and an OS of 27 months and 30 months, (p = 0.73), respectively. The results of our study were consistent with real-life data. The present study confirms that these two agents have comparable effectiveness in terms of PFS and OS.

Previously, prognostic models such as the Memorial Sloan-Kettering Cancer Center (MSKCC) and IMDC risk scores have been used in metastatic RCC. Such models have used hemogram parameters (hemoglobin, platelet count, neutrophil count), lactate dehydrogenase and calcium levels, performance status and the duration of the disease-free interval. Prognostic value was shown by scoring systems [15, 16]. In another study, parameters such as nephrectomy, albumin levels, hemoglobin levels and presence of bone metastasis were investigated as prognostic factors associated with the effectiveness of sunitinib [17]. In the literature, side effects such as hypertension and hypothyroidism were reported to be linked to the survival associated with pazopanib [18, 19]. Again, there exist studies reporting that fatigue and palmar-plantar erythrodysesthesia are related to the effectiveness of TKIs [20, 21]. In the present study, we compared the PFS outcomes of pazopanib and sunitinib in terms of gender, IMDC score (intermediate/poor), smoking, metastatic sites (liver, lung, bone), history of nephrectomy (yes/no), histological subtype (clear-cell vs. non-clear-cell), albumin g/dL level (< 3.6) hemoglobin g/dL level (< 13) drug-induced palmar-plantar erythrodysesthesia, hypertension, and hypothyroidism. Subgroup analyses showed that these parameters did not cause a significant difference between the two agents (Tab. 4, Fig. 3). However, a hemoglobin level13 g/dL, an ECOG PS of 01 and the occurrence of hypothyroidism induced by pazopanib or sunitinib were found to be factors predicting a longer PFS for both agents. Also, PFS times of the patients in the poor IMDC risk group were shorter compared with those in the intermediate risk group. Diverging from the studies in the literature, the present study did not observe a relationship between the occurrence of hypertension and drug effectiveness. Our study had fewer patients in the favorable risk group when compared with the literature. We reasoned that this might be attributable to the late attendance of the patients due to the region our center is located in.

The effect of nephrectomy in mRCC was investigated in the CARMENA and SURTIME studies. In the CARMENA study, sunitinib alone was compared with the nephrectomy + sunitinib arm in the first-line treatment of intermediate- or poor-risk mRCC. This study obtained an OS of 18.4 months with sunitinib alone, as opposed to 13.9 months in the nephrectomy + sunitinib arm (HR: 0.89, 95% CI: 0.711.10) [22]. In the SURTIME study, upfront nephrectomy and deferred nephrectomy (after 3 cycles of sunitinib) were compared in mRCC patients with intermediate MSKCC risk, and deferred nephrectomy was determined to be associated with better survival outcomes in terms of OS (32 months vs. 15 months) [23]. In our study, most of the patients with a history of nephrectomy had undergone nephrectomy in a localized disease stage. However, the comparison of the nephrectomy subgroups revealed that the history of nephrectomy did not predict PFS in patients on TKI.

In the PISCES study with a prospective, cross-over design, which compared pazopanib and sunitinib with regard to their side effect profiles, sunitinib mostly resulted in diarrhea, vomiting, hypertension, and palmar-plantar erythrodysesthesia and patients on pazopanib demonstrated similar side-effects, except for lower rates of palmar-plantar erythrodysesthesia than sunitinib. In this study, pazopanib was reported to be more preferable by patients in terms of the side effect profile and its side effects were reported to be more tolerable compared with sunitinib [24]. In the comparison of pazopanib and sunitinib in our study with respect to their side effect profiles, the most common side effects were nausea-vomiting (41.7%), hypothyroidism (20.8%) and hypertension (8.3%) in the pazopanib arm, as opposed to hypothyroidism (25.9%), nausea-vomiting (14.8%) and palmar-plantar erythrodysesthesia (13%) in the sunitinib arm. When the two groups were compared with regard to side effects, nausea-vomiting was more frequent in the pazopanib arm (p = 0.01), while the other side effects were comparable (Tab. 5). In our study, a significant difference was not determined between the two groups in terms of the side effects.

Previous studies have shown that the mode of sunitinib administration influenced its side effect profile. Daily use of the drug for two weeks followed by one week off was reported to reduce the rate of grade-3 and higher side effects from 45.7% to 8.2% when compared with a four-week-on/two-week-off scheme [25]. In our study, the treatment scheme of some patients (in case of adverse effects) in the sunitinib arm included drug use for two weeks, followed by one week off. Medication side effects could not be evaluated in detail for either of the agents due to the retrospective nature of our study and the lack of details in the patient files.

The single-center, retrospective design of our study and the low number of patients constituted the limitations of our study.

Conclusions

In conclusion, the use of pazopanib and sunitinib in the first-line treatment of patients diagnosed with mRCC yielded a better PFS outcome in our study when compared with the previous studies. No difference was found between the two agents in terms of PFS, OS and ORR. The side effect profiles were comparable. Pazopanib and sunitinib had similar effectiveness in terms of PFS in the investigated subgroups. In agreement with the literature, both agents obtained longer PFS times in patients with a hemoglobin level13 g/dL, an ECOG PS of 01, an intermediate IMDC score and drug-induced hypothyroidism.

Ethics approval

All analyses were performed in accordance with the principles of the Declaration of Helsinki.

Conflict of interest

Authors declare that they have no conflict of interest.

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