A Systematic Review and Meta-Analysis: Safety and Efficacy of Cediranib in the Treatment of Cancer Patients

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Introduction
Irrespective of the level of human development, cancer is a signifcant cause of morbidity and mortality in every region of the world and threatens human health [1].More than 18 million new cancer cases were diagnosed in 2018, with more than 9.5 million deaths [2].Although most cancer patients experience efective treatment and diagnosis progression, the 5-year overall survival rate remains low, and other active treatment methods are required to improve the efectiveness of maintenance therapy [3].An essential step in tumor growth and metastasis is the process of new blood vessel formation and angiogenesis.Te VEGF binds to the VEGF receptor (VEGFR) on the cell surface, resulting in dimerization and passage through the cell phosphorylation of the internal tyrosine kinase region ultimately, which leads to the activation of the neovascularization cascade.Terefore, VEGF and VEGFR are essential targets for antitumor angiogenesis therapy and inhibiting vascular endothelial growth factor (VEGF) has become an essential strategy for cancer treatment.Tyrosine kinase inhibitors (TKIs) are molecules that bind to the intracellular ATP-binding catalytic site of the activated tyrosine kinase domain and block the latter, such as the vascular endothelial growth factor receptor (VEGFR), the epidermal growth factor receptor (EGFR), and the platelet-derived growth factor receptor (PDGFR), all of which play crucial roles in the pathophysiology of cancer [4].Regarding pharmacokinetics (PK), cediranib demonstrated a linear relationship in the dose range of 0.5-60 mg, with the maximum plasma concentration (C max ) observed 1 to 8 hours after administration [5].Patients typically have a terminal half-life of 12 to 36 hours, with an average terminal half-life of 22 [6].Cediranib belongs to the tyrosine kinase inhibitor that targets all three VEGFRs (VEGFR-1, VEGFR-2, and VEGFR-3) and c-Kit.It inhibits the VEGF signaling pathway in endothelial and cancer cells, resulting in antitumor activity in solid cancer patients.As a result, cediranib is regarded as a potentially efective drug added to standard chemotherapy [7].In previous studies, cediranib is efective in the following cancers: malignant pleural mesothelioma [8], biliary tract cancer [9], cervical cancer [10], nonsmall cell lung cancer [11], colorectal cancer [12], renal cell carcinoma [13], breast cancer [14], and glioblastoma [15].In addition, studies on the maintenance treatment of cediranib in recurrent ovarian cancer are ongoing (ClinicalTrials.gov:NCT03278717 and NCT03117933) [16,17].Furthermore, preclinical data show that antiangiogenic drugs may enhance the efcacy of PARP inhibitors [18], which is supported by two randomized phase II studies and a recent phase III trial.Combining antiangiogenic drugs with olaparib or olaparib resulted in more prolonged progression-free survival than PARP inhibitors alone [19][20][21].In this paper, we aimed to review the current evidence on the role of cediranib in solid cancer and to conduct a meta-analysis in order to evaluate the efcacy and safety of cediranib in those patients.

Electronic Search.
A systematic review and metaanalysis of cediranib were conducted for this study.A comprehensive search of PubMed, Embase, Cochrane Library, and Web of Science used medical subject heading (MeSH) terms and text words related to cediranib and neoplasms.Te search was completed through June 31, 2021.Relevant articles and abstracts from retrieved articles were browsed for additional eligible studies.

Study Selection.
Te selection of literature was performed independently by two reviewers as part of the assessment of research eligibility.Any discrepancies were discussed and resolved by consensus between both reviewers.According to PICOS criteria, relevant clinical studies of cediranib maintenance therapy for patients with solid malignant tumors were included if they met all of the following eligibility criteria: (1) P (population): patients with solid malignant tumors were included in the study; (2) I (Intervention) and C (comparison): participants were randomly assigned to cediranib-containing or control treatment; (3) O (outcome): studies reported the progression-free survival (PFS), overall survival (OS), and adverse events; (4) S (study design): the trial was designed as a randomized controlled trial (RCT); and (5) articles that have been published in English.Studies would be excluded for the following reasons: (1) studies with unclear outcome indicators; (2) not RCTs but retrospective trials, observational studies, or case reports; and (3) conferences, abstracts, guidelines, letters, meta-analyses, and reviews.When an unpublished date on cediranib could not be obtained, eforts were made to contact the trial authors.Single-armed studies were excluded due to the lack of control groups.Studies in which progression-free survival was not a primary or secondary endpoint and trials conducted in a frst-line setting were excluded.

Data Extraction.
Two independent reviewers extracted the data from eligible primary studies.Tey converted them into a standard data extraction form, and if disagreement occurred, it was resolved by two authors for consensus.Te following information was extracted from each trial: frst author, publication year, country, and clinical trials, Gov number, study design, number of patients enrolled, participant's age, primary treatment received, intervention details, the dosage of cediranib, duration of maintenance, median follow-up, PFS, OS, and adverse events.We also extracted the logarithm of the hazard ratio (log (HR)) and its standard error from each eligible study for time-to-event data (PFS).To estimate the risk ratio (RR) for binary outcomes (such as adverse events), we extracted the number of participants in each eligible trial who experienced this event.Wherever available, the complete protocol of each trial was included to verify relevant information regarding study design and execution.Te most recent or complete publication reporting the information of interest was considered for publications reporting results from the same trail.Adverse events were classifed using the National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE) (grade 1, mild; grade 2, moderate; grade 3, severe or medically signifcant; grade 4, life-threatening).

Assessment of Risk of Bias.
We assessed the risk of bias independently and in duplicate using the Cochrane Risk of Bias 2.0 tool for RCTs.We used the tool to assess the risk of bias (ROB) in the following domains: randomization process, deviations from intended interventions, missing outcome data, measurement of the outcome, and selection of the reported result.We rated each domain as "some concerns," "low," or "high."

Grading the Certainty of Evidence for Major Outcomes.
We assessed the certainty of the evidence for major outcomes based on the GRADE (Grading of Recommendations Assessment, Development, and Evaluation) approach.Tis approach incorporates fve key domains: (1) risk of bias, (2) inconsistency, (3) indirectness, (4) imprecision of the evidence, and (5) reporting bias.Two reviewers graded each domain for the major outcome and resolved diferences by consensus discussion.We documented all decisions regarding up-or downgrading the certainty of evidence to ensure transparency.

Data Handling and Statistical
Methods.Te efcacy of cediranib in the treatment of solid malignant tumors was determined by calculating pooled PFS, OS, and hazard ratio (HR) with 95% confdence intervals (CI) based on data from all trials.Furthermore, in terms of safety, the binary data (adverse events) were calculated using the risk ratio (RR), with a 95% confdence interval (CI).For data analysis, Stata 15.1 software packages were utilized.P < 0.05 was considered statistically signifcant for heterogeneity, representing the percentage of total variation across studies.A fxed-efect model was used when substantial heterogeneity or I 2 < 50% (P ≥ 0.1) was not observed.On the contrary, a random-efect model was adopted to obtain a more appropriate estimation of the average treatment efect in the case of between-study heterogeneity.A forest plot was used to display all the data analysis results.Moreover, sensitivity analyses were performed to assess the stability of the results by omitting individual studies sequentially, and publication bias was assessed using Begg's and Egger's tests.A P value <0.05 was considered statistically signifcant.

Patient and Public Involvement.
Given that this systematic review will be carried out based on published studies, patients and members of the public will not be involved directly.Only data from published literature and/or the aforementioned sources will be used.

Ethics and Dissemination.
Tis meta-analysis will be performed on published studies without involving any private and confdential patient data, so no approval is required from an ethics committee.Te results will be reported by publishing them in a peer-reviewed journal or disseminated in the relevant conferences.No ethical issues will be raised.

Search Results.
One thousand three hundred and seven potentially relevant studies were obtained electronically from PubMed, Cochrane Library, Embase, and Web of Science.Te inclusion and exclusion criteria for the excluded 1,293 studies were met by screening each record's titles, abstracts, and keywords.Tree hundred and ffty four duplicates and 939 articles that did not meet the criteria were excluded.Finally, 14 studies were further assessed for eligibility, and the latest publication of each trial was adopted for the meta-analysis.Te trial selection process was summarized in the PRISMA plot (Figure 1).

Study Characteristics.
In total, 4,387 patients from fourteen RCTs were included in this meta-analysis, of whom 546 patients were with ovarian cancer, 62 patients were with breast cancer, 69 patients were with cervical cancer, 644 patients were with nonsmall cell lung cancer, 2454 patients were with colorectal cancer, 71 patients were with renal cell cancer, 124 patients were with biliary tract cancer, 325 patients were with glioblastoma, and 92 patients were with malignant pleural mesothelioma.Te included trials included fve phase III RCTs and nine phase II RCTs.All studies reported sufcient data on PFS and adverse events, and nine reported sufcient data on OS.Cediranib dosages varied across fourteen RCTs, with nine trials administering 20 mg once daily, while the other fve trials gave participants 30 mg or 45 mg per day.Te characteristics of patients in the fourteen articles are shown in Table 1.

Risk of Bias and Certainty of Evidence for Major Outcomes.
Among the fourteen RCTs we included, the word "random" was mentioned in all articles, and specifc random methods were mentioned in nine RCTs, such as a computer program.Te seven RCTs described allocation concealment in great detail.Te RCTs have complete outcome data, and none were selectively reported.A detailed risk of bias assessment is described in Figure 2. Te GRADE assessment indicated a moderate quality for PFS and OS.

Progression-Free Survival.
All studies reported the outcome of PFS.Te combined HR for PFS was 0.75 (95% CI 0.69-0.82,P < 0.001; Figure 3), indicating that cediranib-containing treatment signifcantly improved PFS compared to the control therapy.Te pooled HR was calculated using the fxed-efect model because there was signifcant heterogeneity among trials (I 2 � 37.7%, P � 0.083).

Overall Survival.
Te pooled HR was calculated using a fxed-efect model since nine out of fourteen trials reported data on OS, which showed no signifcant between-study heterogeneity among trials (overall: I-squared � 0.0%, P � 0.724).In addition, patients receiving cediranibcontaining therapy had a statistically signifcant improvement in OS (HR: 0.91; 95% CI 0.84-1.00;P � 0.041; Figure 4) compared to control therapy.
Furthermore, there was no diference in the risk of occurrence of these adverse events in the cediranibcontaining group and the control group for nausea, anemia, sensory neuropathy, dyspnea, leukopenia, epistaxis, and venous thromboembolism (Table 3).

Sensitivity Analysis.
We conducted a sensitivity analysis to evaluate the stability and reliability of the pooled HR (for PFS and OS) and RR (for all-grade adverse events).As shown in Figure 5, the horizontal box plot of the leaveone-out method confrmed a study (Schmoll, 2012) that afects the aggregate HR of PFS.Before removing this article, the combined HR for PFS was 0.75 (95% CI 0.65-0.87,P < 0.001), and after removing it, PFS was 0.75 (95% CI 0.69-0.82,P < 0.001).However, the horizontal box plot of the leave-one-out method confrmed that no single study had a qualitative infuence on the pooled HR of OS.Simultaneously, we performed a sensitivity analysis for allgrade adverse events, and after excluding each study in turn, the overall RR value remained unchanged.
3.8.Publication Bias.Tis meta-analysis performed a funnel chart analysis on the outcome indicators (PFS and OS) and included adverse events with subgroups ≥10.We utilized Begg's adjusted rank correlation test and Egger's test to assess the publication bias of works of literature.Te Z-value (continuity corrected) of Begg's adjusted rank correlation test was 1.77 (P � 0.077) on PFS (Figure 6(a)), and Egger's test (P > |t| � 0.128) was used to detect publication bias (Figure 6(b)).In addition, Begg's test (Pr > |z| � 0.175; Figure 6(c)) and Egger's test (P > |t| � 0.141; Figure 6(d)) were used to detect the publication bias of OS and found no publication bias.Te publication bias results for adverse events with subgroups ≥10 showed that the funnel charts of these outcome indicators were symmetrical.Terefore, the present results were statistically steady and robust.

Discussion
Cediranib is an oral, potent, small molecule antitumor drug developed by Astra Zeneca in the United States.Cediranib is an efective ATP-competitive VEGF signaling inhibitor that can inhibit in vivo and in vitro and prevent VEGF-induced angiogenesis vivo [23].It can also inhibit tumor cell growth by inhibiting lymphangiogenesis, which VEGFR-3 mediates [24].Previously, many researchers such as Chen et al. in 2021 were concerned about the efcacy and safety of Cediranib in treating malignant tumors.Te combination of cediranib and lomustine showed the highest incidence of grade 3-4 adverse events [25].Te combination of antiangiogenesis VEGF-induced angiogenesis while increasing VEGF2 phosphorylation, indicating that using PARP inhibitors in combination with antiangiogenic drugs has a synergistic efect [27].Our previous publication revealed the efcacy and safety of olaparib in the treatment of platinum-sensitive recurrent ovarian cancer [28].Furthermore, the efcacy of cediranib and olaparib combined maintenance therapy for recurrent ovarian cancer after platinum therapy is still being investigated [14].Te research found that cediranib may have antitumor activity in metastatic castration-resistant  100.00 Overall (I 2 = 37.7%, p = 0.083) .26 1 prostate cancer (mCRPC) cells [29].Meanwhile, cediranib is also being tested in a large-scale clinical trial, and it is expected to improve the treatment of solid malignant tumors in the future.As the most promising oral tyrosine kinase inhibitor, cediranib has undergone systematic clinical evaluation as both a single agent and in combination therapy in various malignant tumors.Until now, cediranib has shown a stable response in ovarian, nonsmall cell lung cancer, and so on [9,14].We systematically evaluated the efcacy and safety of cediranib in cancer patients for the frst time.Several new RCTs of cediranib in ovarian cancer and malignant pleural mesothelioma have recently been completed, and thus the efcacy and safety of cediranib should be evaluated.As a result, we systematized the available information in order to conduct this meta-analysis on the role of cediranib in cancer treatment.Tis meta-analysis examined nine types of tumor, including ovarian cancer [30,31], breast cancer [12], cervical cancer [8], nonsmall cell lung cancer [9,32,33], colorectal cancer [10,34,35], renal cell carcinoma [11], biliary tract cancer [7], glioblastoma [13], and malignant pleural mesothelioma [6].We evaluated the survival data of 4,387 cancer patients treated with cediranib, and 14 diferent studies were systematically included.In summary, the results indicated that the cediranibcontaining group had a signifcantly better PFS than the control group (HR: 0.75; 95% CI � 0.69-0.82;P < 0.001), and the pooled OS of the cediranib-containing group was signifcantly Terefore, more research is needed to determine the most benefcial population and the best treatment plan, while reducing adverse reactions and overcoming resistance, which can maximize the prognosis of patients and reduce the potential negative impact on life.
Despite the clinical potential of cediranib therapy, several limitations should be considered in our meta-analysis.First, there were potential diferences among the studies included, such as drug doses, diferent types of malignancies, race, age, and even study quality, making interpreting a meta-analysis more difcult.Second, not all OS data and AEs have been reported, or OS was not the primary endpoint for most studies, which may lead to immature data for OS and AEs.Tird, the exclusion of non-English articles may have infuenced our meta-analysis.Although we conducted a comprehensive search, some data will inevitably be lost.Finally, due to the limited number of included studies, this study did not perform the subgroup analysis, which may lead to diferences in the   antitumor efects of cediranib on diferent malignancies.As a result of the limitations of this meta-analysis, more comprehensive perspectives and large-scale sample studies are required to assess cediranib's efcacy and safety.
In conclusion, our meta-analysis demonstrates that cediranib treatment has a better treatment response than noncediranib therapy.Even though cediranib is associated with an increased risk of specifc treatment-related toxicities such as diarrhea and fatigue, cediranib signifcantly improved the quality of life and patient outcomes in multiple clinical trials, providing a new potential therapeutic option for cancer patients.Trials on cediranib, the most promising oral antiangiogenic tyrosine kinase inhibitor, are currently in progress.In the future, the ongoing randomized, double-masked phase II/III clinical trials will help to understand better the role of cediranib in the treatment of solid malignant tumors, and toxicities associated with its use should be given more attention in order to provide stricter monitoring and management and continuously improve the prognosis of patients.

Figure 2 :
Figure 2: (a) Risk of bias graph: review authors' judgments on each risk of bias item presented as percentages across all included studies.(b) Risk of bias summary: review authors' judgments on each risk of bias item for each included study.(c) Certainty of evidence for major outcomes.

Figure 3 :
Figure 3: Forest plots of pooled HRs for PFS by the fxed-efect model.HR, hazard ratio; PFS, progression-free survival.

Table 1 :
Baseline characteristics of included studies in the meta-analysis.
Abbreviations: NSCLC: nonsmall cell lung cancer; CRC: colorectal cancer; RCC: renal cell carcinoma; BC: breast cancer; GB: glioblastoma; CC: cervical cancer; BTC: biliary tract cancer; MPM: malignant pleural mesothelioma; OC: ovarian cancer; PC: paclitaxel-carboplatin; mFOLFOX6: modifed FOLFOX6; FOLFOX/CAPOX: fuorouracil, leucovorin, and oxaliplatin/capecitabine and oxaliplatin; GC: gemcitabine-carboplatin; GP: gemcitabine-cisplatin; PP: pemetrexed-platinum; m: months.and phase III clinical trials to evaluate the role of cediranib in solid malignant tumors are underway.Cediranib has an excellent clinical efect but exploring the best combination of chemotherapy and other targets is more important.Research on the combination of cediranib and PARP inhibitors has gradually increased.PARP inhibitors can reduce