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Research Papers:

Safety and efficacy profile of lenvatinib in cancer therapy: a systematic review and meta-analysis

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Oncotarget. 2016; 7:44545-44557. https://doi.org/10.18632/oncotarget.10019

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Chenjing Zhu _, Xuelei Ma, Yuanyuan Hu, Linghong Guo, Bo Chen, Kai Shen and Yue Xiao

Abstract

Chenjing Zhu1,*, Xuelei Ma1,*, Yuanyuan Hu2, Linghong Guo2, Bo Chen3, Kai Shen1, Yue Xiao2

1State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, and Collaborative Innovation Center for Biotherapy, Chengdu 610041, PR China

2West China School of Medicine, West China Hospital, Sichuan University, Chengdu 610041, PR China

3Department of Oncology, The First People’s Hospital of Chengdu City, Chengdu 610041, PR China

*These authors have contributed equally to this work

Correspondence to:

Xuelei Ma, email: drmaxuelei@gmail.com

Keywords: safety, efficacy, lenvatinib, cancer, meta-analysis

Received: January 30, 2016     Accepted: May 17, 2016     Published: June 14, 2016

ABSTRACT

To systematically review the safety and efficacy of lenvatinib in the treatment of patients, we retrieved all the relevant clinical trials on the adverse events (AEs) and survival outcomes of lenvatinib through PubMed, Medline, Embase, Web of Science and Cochrane Collaboration's Central register of controlled trial. Fourteen eligible studies involving a total of 978 patients were included in our analysis. The most common all-grade AEs observed in patients treated with lenvatinib were hematuria (56.6%), fatigue (52.2%) and decreased appetite (50.5%). The most frequently observed grade ≥3 AEs were thrombocytopenia (25.4%), hypertension (17.7%) and edema peripheral (15.5%). The incidences of both all-grade and high-grade hypertension were significantly increased. Meanwhile, the controlled trial suggested that progression free survival (PFS) was significantly longer in the lenvatinib group than the placebo group. Subgroup analyses showed that mean PFS for renal cell carcinoma was 10.933±1.828 months (95% CI 7.350-14.515, p < 0.001), and that for thyroid cancer was 18.344±0.083 months (95% CI 18.181-18.506, p < 0.001). In conclusion, lenvatinib is an effective agent in thyroid cancer. Early monitoring and effective management of side effects are crucial for the safe use of this drug.


Safety and efficacy profile of lenvatinib in cancer therapy: a systematic review and meta-analysis | Zhu | Oncotarget

INTRODUCTION

Angiogenesis is critical for the local invasion and progression of tumor cells [1]. The aberrant formation and proliferation of blood vessels is due to an imbalance in pro- and anti-angiogenic factors, with the first weighing more [2]. Vascular endothelial growth factor (VEGF), fibroblast growth factor (FGF), platelet-derived growth factor (PDGF) and epidermal growth factor (EGF) are several positive regulators of angiogenesis [3]. Over the last decade, multi-targeted tyrosine kinase inhibitors (TKIs) have been developed and approved in clinical oncology practice [4].

Lenvatinib (E7080) is an oral, multi-targeted tyrosine kinase inhibitor of VEGFR, FGFR, PDGFR and RET [5, 6]. With its anti-angiogenic activity, and a direct effect on tumor cells by preventing relevant signaling pathways [68], lenvatinib has been observed to have promising effects in clinical trials for thyroid cancer [9, 10]. In February 2015, US FDA has approved lenvatinib for the treatment of locally recurrent or metastatic, progressive, radioactive iodine-refractory differentiated thyroid cancer (RR-DTC) [9].

Lenvatinib has brought clinical benefits for patients, but adverse events (AEs) are inevitable such as hypertension, fatigue, proteinuria, nausea, decreased weight and abdominal pain, which may decrease the quality of life of patients and influence their acceptance of treatment [11, 12]. Therefore, we conducted a meta-analysis to estimate various AEs and clinical benefits of lenvatinib.

RESULTS

Literature search results

We ran an initial broad search that yielded 422 unique articles after deletion of duplicates. After title and abstract screening, 344 were excluded since they were narrative review articles or interviews, or completely not associated with clinical assessment of lenvatinib. Forty were further excluded for they were conference abstracts based on published clinical trials, leaving 38 potentially relevant studies for full review. After estimating the full texts of these articles, 24 articles were ruled out for insufficient information. Ultimately, 14 eligible studies [1326] involving a total of 978 patients met our meta-analysis criteria. Two articles [22, 26] with the same first author which had different study designs were both included in our study, one was a phase II trial, and the other was a phase III, randomized multicenter study. No additional unpublished trials were added to the literature search results. A flow diagram of the trial selection process is provided in Figure 1.

Flow diagram of the literature search and selection process.

Figure 1: Flow diagram of the literature search and selection process.

Study characteristics

Of the studies that were included in the final analysis, 3 studies were based on thyroid cancer patients, 5 evaluated advanced solid tumors, 1 evaluated non-small-cell lung cancer, 1 was based on melanoma, 2 were performed on metastatic renal cell carcinoma, 1 was on advanced hepatocellular carcinoma and 1 on healthy adults. Schlumberger M [22] compared lenvatinib with placebo in radioiodine-refractory thyroid cancer patients, and Motzer RJ [19] used lenvatinib—either in combination with everolimus or as a single agent in patients with metastatic renal cell carcinoma. The characteristics of each trial are summarized in Table 1.

Table 1: Basic characteristics of the included articles

First author

Year

Phase

Sample size

Gender

Age

Region

Histology

Treatment arm

Treatment regimen

Male

Female

Schlumberger M1

2015

II

59

37

22

Mean 52

United States, United Kingdom, Australia, France, Italy, and Poland

MTC or DTC

Lenvatinib

Lenvatinib 24 mg Qd, 28-day cycles

Hong DS1

2015

I

77

40

37

Median(range) 61.0(28–85)

USA

Advanced solid tumor; Melanoma

Lenvatinib

Lenvatinib 0.1–3.2 mg Bid (n=18); 3.2–12 mg Bid (n=33); 10 mg Bid (n=26)

Cabanillas ME

2015

II

58

34

24

Median(range) 63(34-77)

USA

RR-DTC

Lenvatinib

Lenvatinib 24 mg Qd, 28-day cycles

Schlumberger M2

2015

III

392(lenvatinib: n=261, placebo: n=131)

125, 75

136, 56

Lenvatinib: median 64, placebo: median 61

USA

RR-DTC

Lenvatinib/placebo

Lenvatinib 24 mg Qd, 28-day cycles/placebo

Dubbelman AC

2014

I

6

3

3

Median(range) 49(34–64)

Netherlands

Advanced solid tumors; lymphomas

Lenvatinib

Lenvatinib 24 mg Qd, 28-day cycles

Shumaker RC

2014

I

15

11

4

Median(range) 31(20–49)

USA

Healthy adult

Lenvatinib plus rifampicin

Lenvatinib 24 mg/coadministrate rifampicin 600 mg

Molina AM

2013

Ib

20

14

6

Mean(SD) 58.4(6.29)

Finland

Metastatic renal cell carcinoma

Lenvatinib plus everolimus

Lenvatinib [12 mg (n = 7); 18 mg (n = 11); 24 mg (n = 2)] plus everolimus 5 mg, 28-day cycles

Boss DS

2012

I

82

43

39

Median(range) 54(25–84)

USA

Advanced solid tumours

Lenvatinib

Dose cohorts from 0.2 to 32 mg, 28-day cycles

Nishio M

2013

I

28

21

7

Mean(range) 56.4(38-73)

Japan

Non-small-cell lung cancer

Lenvatinib

Lenvatinib 4/6 mg Bid

Yamada K

2011

I

27

10

17

Median(range) 53(26–70)

Japan

Advanced solid tumours

Lenvatinib

From 0.5 to 1, 2, 4, 6, 9, 13, 16, and 20 mg Bid

Nakamichi S

2015

I

9

2

7

Median(range) 41(30–59)

Japan

Advanced solid tumours

Lenvatinib

Lenvatinib [20 mg (n = 3); 24 mg (n = 6)], 28-day cycles

Hong DS2

2015

Ib

32

20

12

Median(range) 57.5(24-81)

USA

Advanced melanoma

Lenvatinib plus TMZ

Dose Level (DL)1: lenvatinib 20 mg, TMZ 100 mg/m2; DL2: lenvatinib 24 mg, TMZ 100 mg/m2; DL3: lenvatinib 24 mg, TMZ 150 mg/m2, 28-day cycles

Ikeda M

2015

I

20

17

3

Median(range) 63.5(47–74)

Japan

Advanced hepatocellular carcinoma

Lenvatinib

Lenvatinib 8 mg, 12 mg, 16 mg, 25 mg Qd, 4-week cycles

Motzer RJ

2015

II

153(lenvatinib: n=52, everolimus: n=50, lenvatinib plus everolimus: n=51)

112

41

Median(range) 59(37–77)

Czech Republic, Poland, Spain, the UK, and the USA

Metastatic renal cell carcinoma

Lenvatinib

Lenvatinib (24 mg/day), everolimus (10 mg/day), or lenvatinib plus everolimus (18 mg/day and 5 mg/day, respectively), 28-day cycles

MTC: medullary thyroid cancer; RR-DTC: radioiodine-refractory, differentiated thyroid cancer

Schlumberger M1 and 2: the former was a single-arm trial, while the latter was a controlled trial

Adverse drug reactions analyses

To evaluate the safety of lenvatinib, we calculated the rates of all-grade and grade 3 or more serious adverse events in the overall population. In single-arm trials with all-grade AEs, homogeneity existed in upper abdominal pain, arthralgia, constipation and peripheral edema etc., which were further analysed with a fixed-effects model (Figure 2a, Table 2). Others were analysed using a random-effects model (Figure 2b, Table 2). Hematuria (56.6%, 95% CI 0.193-0.877), fatigue (52.2%, 95% CI 0.384-0.657), palmar-plantar erythrodysesthesia syndrome (47.2%, 95% CI 0.201-0.761), hypertension (47.0%, 95% CI 0.354-0.589) and diarrhea (46.2%, 95% CI 0.362-0.605) were common in a random-effects model (Figure 2b, Table 2). Increased alanine aminotransferase occurred in 42% of the patients using a fixed-effects model (42.0%, 95% CI 0.294-0.556). The most frequent grade ≥ 3 treatment-related adverse events were thrombocytopenia (25.4%, 95% CI 0.055-0.665, random model), hypertension (17.7%, 95% CI 0.102-0.289, random model), peripheral edema (15.5%, 95% CI 0.020-0.622, random model) and increased aspartate aminotransferase (12.6%, 95% CI 0.061-0.242, fixed model) (Figure 2c, 2d, Table 2).

Forest plot of all-grade and grade &#x2265; 3 AEs in single-arm trials.

Figure 2: Forest plot of all-grade and grade ≥ 3 AEs in single-arm trials. a. The all-grade adverse event rates and 95% CIs using a fixed-effects model; b. The all-grade adverse event rates and 95% CIs using a random-effects model; c. The grade ≥ 3 adverse event rates and 95% CIs using a fixed-effects model; d. The grade ≥ 3 adverse event rates and 95% CIs using a random-effects model.

Table 2: Summary results of the all-grade and grade ≥ 3 adverse events (AEs) with 95% confidence intervals

All-grade adverse events

Model

Event rate with 95% CI

Abdominal pain upper

Fixed model

0.287 (0.214-0.372)

Alanine aminotransferase increased

Fixed model

0.420 (0.294-0.556)

Alkaline phosphatase increased

Fixed model

0.418 (0.269-0.583)

Arthralgia

Fixed model

0.343 (0.264-0.431)

Constipation

Fixed model

0.214 (0.161-0.278)

Cough

Fixed model

0.403 (0.317-0.494)

Dry skin

Fixed model

0.205 (0.139-0.292)

Dyspnea

Fixed model

0.265 (0.203-0.339)

Edema peripheral

Fixed model

0.350 (0.250-0.466)

Epistaxis

Fixed model

0.269 (0.183-0.378)

Hypoalbuminemia

Fixed model

0.316 (0.172-0.507)

Hypothyroidism

Fixed model

0.416 (0.276-0.570)

Musculoskeletal pain

Fixed model

0.267 (0.195-0.356)

Pain in extremity

Fixed model

0.292 (0.216-0.381)

Thrombocytopenia

Fixed model

0.263 (0.168-0.388)

Rash

Fixed model

0.380 (0.224-0.566)

Stomatitis

Fixed model

0.325 (0.257-0.400)

Vomiting

Fixed model

0.337 (0.285-0.393)

Abdominal pain

Random model

0.239 (0.144-0.368)

Anorexia

Random model

0.401 (0.293-0.519)

Aspartate aminotransferase increased

Random model

0.441 (0.207-0.706)

Blood TSH increased

Random model

0.381 (0.203-0.597)

Diarrhea

Random model

0.462 (0.326-0.605)

Dysphonia

Random model

0.358 (0.266-0.463)

Fatigue

Random model

0.522 (0.384-0.657)

Headache

Random model

0.383 (0.228-0.565)

Hematuria

Random model

0.566 (0.193-0.877)

Hypertension

Random model

0.470 (0.354-0.589)

Hypertriglyceridemia

Random model

0.276 (0.034-0.803)

Nausea

Random model

0.399 (0.324-0.478)

Palmar-plantar erythrodysesthesia syndrome

Random model

0.472 (0.201-0.761)

Proteinuria

Random model

0.430 (0.309-0.560)

Weight loss

Random model

0.378 (0.224-0.562)

Grade ≥ 3 adverse events

Model

Event rate with 95% CI

Abdominal pain

Fixed model

0.024 (0.008-0.073)

Abdominal pain upper

Fixed model

0.017 (0.004-0.066)

Alkaline phosphatase increased

Fixed model

0.074 (0.028-0.182)

Anemia

Fixed model

0.083 (0.038-0.173)

Anorexia

Fixed model

0.049 (0.026-0.090)

Arthralgia

Fixed model

0.039 (0.015-0.100)

Aspartate aminotransferase increased

Fixed model

0.126 (0.061-0.242)

diarrhea

Fixed model

0.094 (0.065-0.134)

Dyspnea

Fixed model

0.045 (0.014-0.131)

Fatigue

Fixed model

0.067 (0.043-0.103)

Headache

Fixed model

0.031 (0.010-0.093)

Hyponatremia

Fixed model

0.052 (0.017-0.149)

Nausea

Fixed model

0.047 (0.024-0.093)

Proteinuria

Fixed model

0.077 (0.053-0.109)

Vomiting

Fixed model

0.040 (0.013-0.118)

Weight loss

Fixed model

0.080 (0.050-0.127)

Edema peripheral

Random model

0.155 (0.020-0.622)

Hypertension

Random model

0.177 (0.102-0.289)

Palmar-plantar erythrodysesthesia syndrome

Random model

0.076 (0.017-0.284)

Thrombocytopenia

Random model

0.254 (0.055-0.665)

Survival outcomes and subgroup analysis

The efficacy analysis of lenvatinib was mainly based on the controlled trial of lenvatinib in patients with thyroid cancer [22]. The median progression-free survival was 18.3 months in the lenvatinib group and 3.6 months in the placebo group (hazard ratio for progression or death 0.21, 99% CI 0.14-0.31, P < 0.001). In addition, Motzer RJ [19] reported that median PFS was 7.4 months (95% CI 5.6-10.2) for single-agent lenvatinib in patients with metastatic renal cell carcinoma and 5.5 months (95% CI 3.5-7.1) for single-agent everolimus, representing the significantly prolonged PFS of lenvatinib compared with everolimus alone (HR 0.61, 95% CI 0.38-0.98, p = 0.048). Seven trials [13, 15, 16, 19, 22, 25, 26] reported encouraging response rates, median time to response, or PFS observed in patients with different types of tumors, demonstrating the anti-tumour efficacy of lenvatinib (Table 3). We further carried out subgroup analyses according to tumor types. Mean PFS for renal cell carcinoma was 10.933 ± 1.828 months (95% CI 7.350-14.515, p < 0.001), and that for thyroid cancer was 18.344±0.083 months (95% CI 18.181-18.506, p < 0.001) (Table 4). Further large-scale studies are still needed to assess the PFS of patients with melanoma and non-small-cell lung cancer.

Table 3: The median PFS of the included trials

Study

Sample
size

Tumor types

Median PFS (95%CI)
(Months)

Mean

SD

Overall median OS

Boss DS 2012

9

renal cell carcinoma

15.9 (9.3-18.63)

14.93

2.75

14

melanoma

7.23 (3.63-12.63)

7.68

2.61

Schlumberger M1 2015

59

MTC

9.0 (7-16.6)

6.25

2.4

16.6 (16.4-NE)

Cabanillas ME 2015

58

RR-DTC

12.6 (9.9-16.1)

12.8

1.55

Molina AM 2014

20

renal cell carcinoma

11 (5.23-14.87)

10.525

2.41

Nishio M 2013

28

non-small-cell lung cancer

9.0 (6.5-9.5)

8.5

0.75

Schlumberger M2 2015

392

RR-DTC

18.3 (15.2-26)

19.45

1.8

Motzer RJ 2015

153

renal cell carcinoma

7.4 (5.6-10.2)

7.65

0.77

SD: Standard deviation estimation

MTC: medullary thyroid cancer

RR-DTC: radioiodine-refractory, differentiated thyroid cancer

Martin schlumberger 1 and 2: the former was a single-arm trial, while the latter was a controlled trial

Table 4: Subgroup analysis for survival outcomes

First author

Model

Mean

Standard error

Variance

95% CI

Z-Value

P-Value

Histology

lower limit

upper limit

Cabanillas ME 2015

12.800

0.204

0.041

12.401

13.199

62.892

RR-DTC

Schlumberger M2 2015

19.450

0.091

0.008

19.272

19.628

213.933

RR-DTC

Overall

Random

18.344

0.083

0.007

18.181

18.506

220.987

< 0.001

Molina AM 2014

10.525

0.539

0.290

9.469

11.581

19.531

RCC

Boss DS 2012

14.930

0.917

0.840

13.133

16.727

16.287

RCC

Motzer RJ 2015

7.650

0.062

0.004

7.528

7.772

122.890

RCC

Overall

Random

10.933

1.828

3.341

7.350

14.515

5.981

< 0.001

MTC: medullary thyroid cancer

RR-DTC: radioiodine-refractory, differentiated thyroid cancer

RCC: Renal cell carcinoma

Schlumberger M1 and 2: the former was a single-arm trial, while the latter was a controlled trial

Risk of bias and quality assessment

The risk of bias and quality assessments of the included studies are outlined in Figure 3a, 3b. Overall, the quality of the studies was satisfactory.

Risk of bias and quality assessment.

Figure 3: Risk of bias and quality assessment. a. Risk of bias graph: review authors' judgments about each risk of bias item presented as percentages across all included studies; b. Risk of bias summary: review authors' judgments about each risk of bias item for each included study.

DISCUSSION

To the best of our knowledge, this is the first study to evaluate both the safety and efficacy of the novel antitumor agent lenvantinib in different types of tumors systematically. The adverse events of lenvatinib were tyrosine kinase inhibitor-related and were also seen in other TKIs. In one meta-analysis [27], the VEGFR-TKIs group (cediranib and axitinib) was associated with higher rates of diarrhea, fatigue, hypertension and thrombocytopenia compared with bevacizumab. Vandetanib [28], a dual VEGFR and EGFR inhibitor, yielded an improvement in PFS but more frequent grade 3 or greater hypertension. Although the incidence of hematuria was high, most people experienced low grade (grade 0) hematuria.

It should be noted that lenvatinib was associated with a significantly increased risk in all-grade (47.0%) and high-grade (17.7%) hypertension. The mechanism of lenvatinib-associated hypertension has not been clarified, and may be due to a possible perturbation of endothelial cell function in patients treated with VEGF-targeting agents [29]. It has been documented upon administration of bevacuzimab and cediranib, and several other inhibitors of the VEGF signalling pathway [3032]. All of these suggest that patients who were administered lenvatinib should be monitored for high blood pressure, and managed with antihypertensive drugs or dose reductions when necessary.

Grade ≥ 3 thrombocytopenia was experienced in about a quarter of patients. Through binding to PDGFR, PDGF promotes the recovery of platelets and the formation of bone marrow colony-forming unit-megakaryocyte [33, 34], thus the inhibition of PDGFR by lenvatinib might cause thrombocytopenia. Hematopoietic growth factors and transfusions [35] could be used to deal with persistent toxicities on platelets, but the effects of them on tumor cells remain to be explored.

In February 2015, US FDA has approved lenvatinib for the treatment of radioiodine-refractory thyroid cancer [9] based on the randomized controlled trial [22] included in our analysis. We find a similar mean PFS (18.344±0.083 months, 95% CI 18.181-18.506, p < 0.001) for thyroid cancer in our pooled analysis. However, our results of adverse events (Figure 4a, 4b) are different, since the relatively larger sample size may allow us to better determine the AE values. Survival outcomes of other tumors are mainly based on phase I and phase II trials, and more subsequent randomized, controlled phase III trials are needed.

The odds ratios (ORs) of adverse events (AEs) in a controlled trial comparing lenvatinib and placebo.

Figure 4: The odds ratios (ORs) of adverse events (AEs) in a controlled trial comparing lenvatinib and placebo. a. OR and 95% CIs of all-grade AEs using a random-effects model; b. OR and 95% CIs of grade ≥ 3 AEs using a fixed-effects model.

The dose of lenvatinib administered in patients with solid tumors varied in different situations, but in 8 [15, 16, 1820, 22, 23, 26] of the 14 included studies, patients received lenvatinib at a daily dose of 24 mg per day in 28-day cycles, and two studies [18, 20] demonstrated that the 24-mg QD dose of lenvatinib was determined to be tolerable with encouraging anti-tumor activity in patients with solid tumors.

The heterogeneity in our analysis could arise from different tumor types, the very heterogeneous study population with pre-treated disease and the ethnicity difference. In addition, there are several limitations of our study. Firstly, because lenvatinib is a relatively new drug, reports about it are few and are mostly phase I and II studies. Secondly, only one study provided the overall survival data, so prolonged follow-ups are needed. Thirdly, we did not perform subgroup analysis of melanoma and non-small-cell lung cancer because of lack of enough information.

In conclusion, lenvatinib has clinically meaningful benefits in survival outcomes of patients with thyroid cancer. The pooled analyses suggest that patients should be monitored for potential thrombocytopenia and increases in blood pressure, and dose reductions or delays or antihypertensive drugs are needed accordingly. Correct estimates of treatment-related toxicities and the efficacy of lenvatinib are fundamental to provide appropriate guidance and to conduct ongoing trials.

MATERIALS AND METHODS

Search strategy

We performed a literature search of PubMed, Medline, Embase, Web of Science and The Cochrane Library for all the relevant clinical trials on the safety and efficacy of lenvatinib (until April 26, 2016, 201). In order to ensure the completeness of the results, we expanded the search scope by using the search terms “lenvatinib” or “E7080” or “lenvima”. We also carried out further searches for relevant unpublished trials in the clinical trial registry (http://www.clinicaltrials.gov). Papers in all languages were sought and translated where appropriate to reduce the chances of bias.

Inclusion and exclusion criteria

To be included in the analysis, patients must be diagnosed with histologically confirmed tumors, survival outcomes and toxicities were mandatory to be reported. All phase clinical trials were eligible for inclusion if they evaluated the side effects and efficacy of lenvatinib. Studies were excluded if they did not provide enough data for toxicities and survival outcomes. They were also excluded for which full-text reports were not available.

Selection process and data extraction

Two reviewers selected studies independently. Any disagreements were resolved through discussion with another author. We excluded those studies that clearly did not meet the inclusion criteria, and made efforts to rule out duplicated studies by comparing author lists, publication year, and the main contents if necessary. Articles with the same author(s) or medical center(s) were carefully reviewed and discussed for eligibility.

Data extracted from all eligible articles included the first author, year of publication, sample size, study phase, tumor type, treatment regime, progression-free survival (PFS), hazard ratio (HR) and adverse events. ADRs were graded using the National Cancer Institute (Washington, DC, USA) Common Toxicity Criteria, version 3.0.

Data analysis

We used patients' all-grade and grade ≥ 3 Common Toxicity Criteria Adverse Events (CTCAE) counts to calculate the incidence rates of AEs and the corresponding 95% confidence intervals (CIs). I-squared was calculated to test heterogeneity of the studies, and I2 > 50% and P ≤ 0.1 indicated strong heterogeneity between the studies. All the analysis was carried out using the software Comprehensive Meta-Analysis (CMA) program 2 (Biostat, Englewood, NJ) and Review manager 5.3 (Copenhagen, Sweden).

Risk of bias and quality assessment

To evaluate the risk of bias and quality of the studies, QUADAS-2 was used as a systematic review assessment method, which consisted of four key domains: patient selection, index test, reference standard and flow and timing [36]. Risk of bias was rated as high/low/unclear. The assessment was measured using Review Manager 5.3 (Copenhagen, Sweden).

CONFLICTS OF INTEREST

All authors declare no conflicts of interest

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