A Comprehensive Systematic Review and Network Meta-analysis: The Role of anti- angiogenic agents in advanced epithelial ovarian cancer

doi:10.21203/rs.3.rs-1030229/v1

Download PDF

Research Article

A Comprehensive Systematic Review and Network Meta-analysis: The Role of anti- angiogenic agents in advanced epithelial ovarian cancer

https://doi.org/10.21203/rs.3.rs-1030229/v1

This work is licensed under a CC BY 4.0 License

Journal Publication

published 09 Mar, 2022

Read the published version in Scientific Reports →

You are reading this latest preprint version

Background

The efficacy of anti-angiogenic agents (AAAs) in epithelial ovarian cancer (EOC) remains unclear. Therefore, we conducted a systematic review and network meta-analysis (NMA) to synthesize evidence of their comparative effectiveness for improving overall survival (OS) among EOC patients.

Methods

We searched six databases for randomized controlled trials (RCTs) from their inception to February 2021. We performed a NMA with hazard ratios (HRs) and 95% confidence intervals (CIs) to evaluate comparative effectiveness among different AAAs in two disease settings, chemotherapy naïve, and recurrent EOC. P-score was used to provide an effectiveness hierarchy ranking. Sensitivity NMA was carried out by focusing on studies that reported high-risk disease chemotherapy-naïve, platinum-resistant, and platinum-sensitive EOC. The primary outcome was OS.

Findings

We identified 23 RCTs (n=11,560) which assessed effectiveness of eight different AAAs. NMA results showed no significant OS difference among anti-angiogenic agents in chemotherapy-naïve. In recurrent EOC, concurrent use of trebananib (10mg/kg) and chemotherapy was likely to be the best option (P-score: 0.88, NMA estimate versus chemotherapy: HR= 1.67, 95% CI: 0.94; 2.94). The sensitivity NMA indicated that bevacizumab plus chemotherapy with maintenance treatment (P-score: 0.99) and pazopanib plus chemotherapy (P-score: 0.79) had the highest probability of being the best intervention for improving OS in high-risk chemotherapy-naïve and platinum-resistant setting, respectively.

Interpretation

AAAs may not play a significant clinical role in chemotherapy-naïve and platinum-sensitive EOC. Conversely, the concurrent use of trebananib with chemotherapy was likely to be the best intervention in recurrent EOC.

Oncology

angiogenic agents

epithelial ovarian cancer

platinum-sensitive

Anti-angiogenic agents may not play a significant clinical role in chemotherapy naïve, and platinum-sensitive EOC.

Concurrent use of pazopanib or trebananib with chemotherapy yielded OS benefit in platinum-resistant or unclassified recurrent EOC settings, respectively.
Bevacizumab delivered concurrently with chemotherapy and maintenance treatment in high-risk chemotherapy naïve setting yielded an improvement in OS.

Epithelial ovarian cancer (EOC) is the 8^th most common female reproductive cancer-related cause of death¹. The majority of tumors relapse following platinum-based chemotherapy, which is associated with poor outcomes. Despite significant improvements in the management of relapsed high-grade serous ovarian cancer (HGSOC), the treatment options remain limited. Novel strategies have entered the clinic to manage recurrent EOC, including the use of anti-angiogenic therapies and PARP inhibitiors^2–6.

Approximately 70% of patients with EOC will eventually relapse following first-line systemic chemotherapy. The fifth Gynecologic Cancer Intergroup (GCIG) recommended re-categorizing platinum sensitivity based on platinum-free interval (PFI) duration (<1 month, 1–6 months, 6–12 months, and >12 months). These subsets corresponded to the previously widely used categories of platinum-refractory, platinum-resistant, partially platinum-sensitive, and fully platinum-sensitive, attempting to standardize second-line therapy^7,8. Patients with a PFI <6 months have fewer alternative treatment options and consequent poorer survival outcomes^9,10.

Anti-angiogenic agents have attained regulatory approval to manage a diverse spectrum of solid cancers. Angiogenesis is a key pathological^11–15 feature of EOC, and anti-angiogenic agents have dominated the field of drug development in EOC, particularly in the setting of recurrent disease. In EOC, bevacizumab is the only anti-angiogenic agent approved by the Food and Drug Administration (FDA) and European Medicines Agency (EMA). The FDA approved bevacizumab in platinum-resistant EOC² and platinum-sensitive EOC^3,16 combined with chemotherapy. Additionally, the EMA has approved bevacizumab's clinical use in EOC irrespective of disease state: chemotherapy-naïve^17,18; platinum-sensitive³ and platinum-resistant² disease.

The approval of other anti-angiogenic agents by the regulatory authorities has been more challenging, with many awarded orphan designations until they receive marketing approval. The FDA and EMA assigned orphan designation for trebananib and cediranib to manage recurrent EOC, combined with chemotherapy. There is variation in the recommendations for the appropriate use and disease setting for anti-angiogenic agents in EOC. The National Comprehensive Cancer Network (NCCN)¹⁹ and the ESMO-ESGO Ovarian Cancer Consensus Conference Working Group²⁰ advocate for the clinical use of bevacizumab in both the chemotherapy-naïve setting and the recurrent disease setting. However, the National Institute for Health and Care Excellence (NICE)²¹ does not support the clinical use of bevacizumab in advanced EOC. Additionally, several meta-analyses were published to shed light on this clinical knowledge gap. Unfortunately, these studies further demonstrate the clinical uncertainty and show inconsistency in reporting regarding the clinical efficacy of anti-angiogenic agents in the EOC disease state spectrum^22–31 (Supplementary Table 2). We, therefore, a systematic review and network meta-analysis (NMA) to synthesize evidence of comparative effectiveness of different anti-angiogenic agents for improving overall survival (OS) among EOC patients

We performed a systematic review and NMA of the curated literature according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) extension statement for NMA³². A prospective protocol was registered in PROSPERO (registration: CRD42021240133)³³.

Eligibility criteria

To be eligible for inclusion in this review, a randomized controlled trial (RCT) should be published in English and satisfy the following criteria: patient, Intervention, comparison, and Outcome (PICO). Patients with either locally advanced or recurrent EOC were included. In addition, as defined in current evidence-based guidelines, anti-angiogenic agents, compared with placebo or any types of standard of care chemotherapy, were considered eligible. Included RCTs should report hazard ratio (HR) and 95% confidence intervals (CI) for the outcomes of overall survival (OS) or progression-free survival (PFS) in both intervention and control groups. The primary outcome of this systematic review was OS, while the secondary outcome was PFS.

Literature search

A systematic search was undertaken to identify RCTs using the following databases from inception to February 2021: EMBASE; PubMed; Ovid Medline; Cochrane Central Register of Controlled Trials (CCTR); Cochrane Database of Systematic Reviews (CDSR); and ClinicalTrials.gov (www.clinicaltrials.gov), ASCO and ESMO abstract database. Furthermore, we searched references of relevant articles retrieved from the electronic search for additional citations. No restrictions on publication status were imposed. The key search terms used were "ovarian cancer", "ovarian neoplasm” [MESH Term], "anti angiogenic agents", "angiogenesis inhibitors", "Bevacizumab", "Nintedanib", "Pazopanib", "Cediranib", "Trebananib", "Sorafenib", "platinum sensitive ovarian cancer", "platinum resistant ovarian cancer", "VEGF", "VEGFR", "PDGF", "PDGFR", "FGF", "FGFR", "TIE", "RET", "AXL", "FLT" and "FLT-3".

Study selection, data extraction, and quality assessment

After a comprehensive literature search, we used reference management software (EndNote) to identify and remove potential duplicate RCTs. Two review authors (AE, WLC) independently screened titles and abstracts of retrieved RCTs and assessed full texts for eligibility. Discrepancies were resolved through consensus; unsolved discrepancies were settled via consulting a third review author (ND). In the event of duplicate publications, priority was given to the publication reporting the most extended follow‐up associated with our primary and secondary outcomes. To be included in NMA, RCTs should share a common comparator that served as a bridge for indirect comparison of different anti-angiogenic agents.

Two review authors (AE, HC) collected the following information from each included RCT using an established data abstraction method: year of publication, country, disease settings, number of patients randomized, patient demographics, details of interventions and comparators, results of prespecified outcomes, and study funding sources. Data extracted was further independently evaluated by one author (CW).

Two review authors (AE, WLC) assessed the risk of bias of each eligible RCT independently using the Cochrane risk of bias tool 2³⁴. The following domains were assessed: bias arising from the randomization process; bias due to deviations from the intended interventions; bias due to missing outcome data; bias in the measurement of the outcome; and bias in selecting the reported results³⁶. The overall risk of bias of each trial was judged as low, some concerns, or high risk of bias³⁶. Disagreements were resolved through consensus; unsolved disagreements were settled via consulting a third review author (HC).

Data Analysis

NMA

NMA offered a set of methods to visualize and interpret a broader picture of current evidence and assessed comparative effectiveness among various interventions³⁵. It provided indirect evidence (estimates between various interventions via common comparators) when direct evidence (head-to-head estimates of various interventions) was not available³⁶. With the common comparators, we conducted indirect comparisons between different interventions on the primary and secondary outcomes. In this systematic review, NMA was performed to investigate the "relatively most" effective anti-angiogenic agent for improving OS and PFS among EOC patients in two disease settings, namely i) chemotherapy naïve, ii) recurrent EOC.

A network plot was generated for each disease setting to show all interventions included in the NMA^37,38. Comparative effectiveness results of all possible pairs of comparisons were summarized with an HR and 95% CI^37,38. P-score was used to provide an effectiveness hierarchy ranking^37,38. A higher P-score represents superior performance³⁹.

Given the potential impact of anti-angiogenic agents in i) high-risk group in the chemotherapy naïve setting⁴⁰, ii) platinum-resistant and iii) platinum-sensitive groups in recurrent EOC setting, sensitivity analyses of NMA were carried out by only including studies that explored the effectiveness of anti-angiogenic agents on primary and secondary outcomes in these three group of patients within the corresponding disease settings. High-risk disease was defined as FIGO stage IV or inoperable stage or sub-optimally (>1cm residual disease) resected FIGO stage III⁴¹.

Consistency of direct and indirect evidence on the same comparison was a fundamental assumption of NMA⁴². Therefore, the separating indirect from direct evidence (SIDE) approach using the back-calculation method was performed for each comparison in the network, on which both direct and indirect evidence were available, to evaluate evidence consistency⁴³. The inconsistency with the p-value less than 0.05 was considered a significant concern. NMA was conducted using the "netmeta" package in R (version 4.1.1)^37,38.

Assessment of Publication bias

Publication bias on the primary outcome in each disease setting was assessed via a comparison-adjusted funnel plot produced by R (version 4.1.1)^37,38 when at least ten studies were included in NMA³⁴.

Study selection and characteristics of included RCTs

A total of 2,363 publications were identified through the initial literature search, and 1563 studies remained after duplications were excluded. Following the title and abstract screen, 1,392 publications were removed because they did not meet the study's hypothesis or were abstracts of full-text publications included in eligible articles review. One hundred seventy-one potentially relevant articles were identified for the comprehensive review. Following this process, 23 multicentre phase II-III RCTs were analyzed in this NMA. Details of literature search and selection for RCTs are presented in Supplementary Fig 1.

Characteristics of the 23 included RCTs are summarized in supplemtary table 1. They included a total of 11,560 patients, with sample sizes varying from 84 to 1873. Four RCTs were conducted in the chemotherapy naïve setting, three in the first-line maintenance setting, and 16 in the recurrent EOC setting. Eight different anti-angiogenic agents administered concurrently with chemotherapy, with or without maintenance treatment, were evaluated in all included trials, while the standard of care chemotherapy was reported as control intervention in 19 trials. All RCTs assessed OS and PFS, except that Duska et al.⁴⁴ and the East Asian Study⁴⁵ trials reported PFS only. Amongst these 23 RCTs, the overall risk of bias for 12 RCTs (52.2%) was rated as low and 11 (47.8%) as having some concerns (Supplementary table 3).

NMA results

Chemotherapy naïve setting

For improving OS and PFS, each network included one three-arm trial and three two-arm trials (Fig 1a, 1b, respectively). The standard of care chemotherapy in these networks was carboplatin combined with paclitaxel (Car/Pac). NMA results suggested no significant difference in OS and PFS among the concurrent use of anti-angiogenic agents and the standard of care chemotherapy with or without maintenance treatment (Fig 1c, 1d). Effectiveness hierarchy ranking results of the interventions are shown in Supplementary Fig 2. As the inconsistency p-values for the two comparisons in OS and PFS were 0.75 and 0.31, respectively (Fig 1e, 1f), there was no significant inconsistency in these two NMA.

High-risk group

There were four RCTs in the high-risk group of chemotherapy naïve setting. The ICON7 trial defined the high-risk disease as FIGO stage IV, inoperable, or sub-optimally (>1cm residual disease) resected FIGO stage III⁴¹. These criteria were shared with the TRINOVA-3⁴⁶, GOG-0218 trials ⁴⁷, and the AGO-OVAR 12⁴⁸. Results of sensitivity analysis of NMA supported the use of bevacizumab, administered concurrently with chemotherapy and maintenance treatment (Bev_CM), with an improved OS (P-score: 0.99, NMA estimate of Bev_CM versus Car/Pac: HR= 0.82, 95% CI: 0.70; 0.97) (Fig 2a, 2b) and PFS (P-score: 0.99, NMA estimate of Bev_CM versus Car/Pac: HR= 0.68, 95% CI: 0.59; 0.79) (Fig 2c, 2d). It was likely to be the best treatment option for both outcomes for this group of patients. Effectiveness hierarchy ranking results of the interventions for OS and PFS are shown in figure 2e, and 2f, respectively.

Recurrent EOC setting

For improving OS, the network included one three-arm trial and 13 two-arm trials (Fig 3a). The concurrent use of trebananib (10mg/kg) and chemotherapy (Tre_C10) was likely to be the best option (P-score: 0.88, NMA estimate of Standard of care chemotherapy (Chemo) versus Tre_C10: HR= 1.67, 95% CI: 0.94; 2.94), followed by sorafenib combined with chemotherapy and maintenance treatment (Sor_CM) (P-score: 0.87, NMA estimate of Chemo versus Sor_CM: HR= 1.54, 95% CI: 1.07; 2.21) (Fig 3b).

For improving PFS, the network included one three-arm trial and 14 two-arm trials (Fig 3c). The combination of chemotherapy and maintenance treatment with bevacizumab (Bev_CM) demonstrated more significant improvement when compared to standard of care chemotherapy (HR=0.48, 95% CI: 0.33; 0.70) (Fig 3d). It was also likely to be the most effective option (P-score: 0.89), followed by the concurrent use of Bevacizumab and chemotherapy (Bev_C) (P-score: 0.82, NMA estimate of Bev_C versus Chemo: HR= 0.54, 95% CI: 0.44; 0.67). Effectiveness hierarchy ranking results of the interventions for OS and PFS are shown in figure 3e, and 3f, respectively.

Platinum resistant group

There were three RCTs in the platinum-resistant group of recurrent EOC setting. Results of sensitivity analysis of NMA showed that the concurrent use of pazopanib and chemotherapy (Paz_C) had the highest probability of being the best intervention for improving OS (P-score: 0.79, NMA estimate of Chemo versus Paz_C: HR= 1.67, 95% CI: 0.89; 3.13), followed by sorafenib combined with chemotherapy and maintenance treatment (Sor_CM) (P-score: 0.76, NMA estimate of Chemo versus Sor_CM: HR= 1.54, 95% CI: 1.07; 2.21) (Fig 4a, 4b). The former intervention (Paz_C) was also likely to be the most effective intervention for improving PFS (p-score: 0.85, NMA estimate of Chemo versus Paz_C: HR= 2.38, 95% CI: 1.43; 3.96) (Fig 4c, 4d). Effectiveness hierarchy ranking results of the interventions for OS and PFS are shown in figure 4e, and 4f, respectively

Platinum sensitive group

There were four RCTs in the platinum-sensitive group of recurrent EOC setting. Sensitivity analysis of NMA results showed no significant difference in OS among the use of anti-angiogenic agents and standard of care chemotherapy (Fig 5a, 5b). Nonetheless, the combination of chemotherapy and maintenance treatment with i) bevacizumab (Bev_CM) and ii) cediranib (Ced_CM), as well as iii) bevacizumab combined with chemotherapy alone (Bev_C) were significantly more effective than chemotherapy in improving PFS, with HRs of 0.48 (95% CI: 0.36; 0.66), 0.56 (95% CI: 0.41; 0.77) and 0.58 (95% CI: 0.47; 0.70) respectively (Fig 5c, 5d). Amongst these interventions, bevacizumab combined with chemotherapy and maintenance treatment (Bev_CM) had the highest probability of being the best option for prolonging PFS (p-score: 0.85). Effectiveness hierarchy ranking results of the interventions for OS and PFS are shown in figure 5e, and 5f, respectively

Publication bias assessment

Based on the visual inspection of comparison-adjusted funnel plot of 15 included RCTs on the primary outcome of OS in the recurrent EOC setting, there was no evidence of funnel plot asymmetry (Egger's test: p= 0.8347, Supplementary Fig 3), indicating absence of publication bias. However, for other NMAs on the OS outcome in chemotherapy naïve, publication bias could not be assessed due to insufficient number of included studies.

To our knowledge, this is the most comprehensive NMA which explores the clinical impact of anti-angiogenic agents in EOC. We demonstrate the probable lack of efficacy of anti-angiogenic agents in non-high-risk chemotherapy naïve, and platinum-sensitive EOC. Furthermore, in the absence of a predictive biomarker for response to anti-angiogenic agents, we highlight their probable positioning in managing high-risk chemotherapy naïve and platinum-resistant EOC.

The variation in OS outcomes reported in the high-risk chemotherapy naïve disease setting may make it difficult to infer any recommendations regarding the role of anti-angiogenic agents in this disease setting. Data interpreted of the ICON7 trial demonstrated that high-risk disease is associated with an OS benefit (p=0·01, HR: 0·78; 95% CI: 0·63-0·97)⁴⁹. Conversely, the AGO-OVAR 12 study reported that OS in the high-risk group did not favor nintedanib (HR: 1·14; 95% CI: 0·89–1·45)⁴⁸. Additionally, the GOG-0218, FIGO stage IV disease favored the concurrent bevacizumab and chemotherapy followed by bevacizumab maintenance arm (HR: 0·72; 95% CI: 0·53–0·97)⁵⁰. When used concurrently with chemotherapy followed by maintenance until progression, we demonstrate that bevacizumab was associated with the highest probability of OS (Fig 2b) and PFS (Fig 2d) benefit in high-risk chemotherapy naïve EOC. Furthermore, we demonstrate that anti-angiogenic agents may not play a role in managing non-high-risk chemotherapy naïve EOC.

Interestingly, primary platinum resistance was associated with significant PFS and OS benefit from adding anti-angiogenic agents to chemotherapy. In addition, we identified that in the setting of platinum-resistant disease, Pazopanib (P-score=0·79) and Sorafenib (P-score=0·76), administered concurrently with chemotherapy, resulted in clinically significant improvements in OS (Fig 4).

The FDA defines clinical outcomes as a direct measure of benefit from an intervention in a trial, while a surrogate end-point is used as a predictive substitute for clinical benefit. Nevertheless, surrogate outcome measures play a notable role in solid cancers⁵¹. PFS is the most commonly used primary end-point and surrogate marker for OS in solid cancer^52,53, and the prevalence of its use is growing. The FDA has approved many cancer drugs based on surrogate end-point data. Among those receiving regulatory approval, 57% of cancer drugs did not demonstrate an OS benefit⁵⁴.

Furthermore, Pasalic et al. and Prasad et al. highlight the suboptimal predictive value of PFS as a surrogate for OS^55,56. Additionally, in EOC, the predictive value of PFS was further refuted as a surrogate for OS⁵⁷. Furthermore, interpretation of the result findings presented in this NMA show that PFS falls short of being a substitute for OS in EOC. Therefore, we consider that the findings presented in this NMA are collectively significant and highlight the importance of selecting the appropriate EOC patient group, high-risk, and platinum resistant disease, that are likely to derive OS benefit from anti-angiogenic agents. Consequently, regulators need to cautiously interpret trials that report PFS benefits without mature OS data.

To date, there are no clinically approved predictive molecular biomarkers that may have clinical utility in selecting the subtype of patients likely to benefit from anti-angiogenic agents. However, there is a clear clinical unmet need. Nevertheless, there has been a significant drive to identify patients who benefit from bevacizumab. Bentink et al. identified molecular subtypes (split 1 – 4) in HGSOC, generated from 129 FFPE patient tumor samples. Split 1 was associated with angiogenesis and extracellular matrix proteins, termed the angiogenic subtype, corresponding with the Tothill C1 and TCGA mesenchymal subtypes⁵⁸.

Backen et al. identified that high Ang1/low Tie2 serum values were associated with significantly improved PFS for bevacizumab-treated patients in the ICON7 trial (median, 23.0 months vs. 16.2; p = 0.003)⁵⁹. In addition, Gourley et al. developed a gene signature to identify angiogenic molecular subtypes in ovarian cancer⁶⁰. These findings were validated in the ICON7 trial and demonstrated that bevacizumab had a favorable PFS impact on patient tumors harboring the angiogenic subtype⁶⁰.

Collinson et al. identified three potentially predictive biomarkers, mesothelin, fms-like tyrosine kinase-4 (FLT4), and α₁-acid glycoprotein (AGP), from serum samples of patients recruited to the ICON7 trial. These biomarkers identified the subgroup of patients likely to benefit from bevacizumab, predominantly leading to an improvement in median PFS of 5.5 months in the signature positive subgroup (p=0.001))⁶¹. In the GOG218 trial, Birrer et al. demonstrated a correlation between microvessel density (MVD), tumor VEGF-A (tVEGF-A) expression, and survival outcome in the bevacizumab arm. Comparing chemotherapy with bevacizumab versus chemotherapy alone, higher MVD showed predictive value for PFS (p= 0.018) and OS (p= 0.0069). tVEGF-A expression showed potential predictive value for OS (and PFS) (p= 0.023)⁶². However, the results described above need to be independently validated in more extensive trials before clinical practice implementation.

We identified a few limitations of this study. It is essential to highlight that the small sample size in the MITO-11 trial⁶³ and the TRIAS trial⁶⁴ may impact the interpretation of the OS results illustrated in Fig 4. Therefore, making it challenging to definitively assess the impact of pazopanib on OS in platinum-resistant disease. Furthermore, not all the trials identified in the recurrent disease setting reported separate PFS and OS based on PFI. This, therefore, reduced the number of trials included in the sensitivity analysis for each pre-defined PFI cohort

Following our observations, we suggest a potential treatment approach (Supplementary Fig 4) for EOC. In high-risk treatment naïve disease, bevacizumab combined with standard chemotherapy and followed maintenance may provide the best PFS and OS. On recurrence, anti-angiogenic agents, particularly pazopanib in combination with chemotherapy, may be most appropriate in managing platinum-resistant EOC. In contrast, PARP inhibitors combined with anti-angiogenic agents may play a more critical role than anti-angiogenic agent monotherapy in platinum-sensitive EOC⁶⁵. The level IA evidence presented in this study further emphasizes the need for better patient selection for anti-angiogenic agents in EOC.

Acknowledgements:

Author Disclosures:

Professor Richard Kennedy is employed by Almac as the Medical Director. RDK
No author disclosures for the remaining authors: AE, CW, HC, WLC, ND, SWKS, KKC, HYSN, RKCN

Author contributions:

Conceptualization: AE
Methodology: AE, CW, HC, WLC, ND, RDK
Formal analysis: AE, CW, HC
Writing – original draft: AE
Writing – review & editing: AE, CW, HC, WLC, ND, SWKS, KKC, HYSN, RKCN, RDK

Funding: This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors

1. World Health Organization. Globocan 2020. Int. Agency Res. (2020).

2. Pujade-Lauraine, E. et al. Bevacizumab combined with chemotherapy for platinum-resistant recurrent ovarian cancer: The AURELIA open-label randomized phase III trial. J. Clin. Oncol. 32, 1302–8 (2014).

3. Aghajanian, C. et al. OCEANS: a randomized, double-blind, placebo-controlled phase III trial of chemotherapy with or without bevacizumab in patients with platinum-sensitive recurrent epithelial ovarian, primary peritoneal, or fallopian tube cancer. J. Clin. Oncol. 30, 2039–45 (2012).

4. Coleman, R. L. et al. Bevacizumab after bevacizumab in platinum-sensitive recurrent ovarian cancer: A subgroup analysis of GOG0213. J. Clin. Oncol. 34, (2016).

5. J.A., L. et al. Randomised double-blind phase III trial of cediranib (AZD 2171) in relapsed platinum sensitive ovarian cancer: Results of the ICON6 trial. Eur. J. Cancer 49, S5–S6 (2013).

6. Ledermann, J. et al. Olaparib Maintenance Therapy in Platinum-Sensitive Relapsed Ovarian Cancer. New England Journal of Medicine vol. 366 1382–1392 (2012).

7. Wilson, M. K. et al. 5th Ovarian Cancer Consensus Conference of the Gynecologic Cancer InterGroup: Recurrent Disease. Ann. Oncol. mdw663 (2016) doi:10.1093/annonc/mdw663.

8. Friedlander, M. et al. Clinical trials in recurrent ovarian cancer. Int. J. Gynecol. Cancer 21, 771–775 (2011).

9. Cannistra, S. A. Cancer of the Ovary. N Engl J Med 35124351, 2519–29 (2004).

10. Naumann, R. W. & Coleman, R. L. Management strategies for recurrent platinum-resistant ovarian cancer. Drugs 71, 1397–1412 (2011).

11. Folkman, J. & Folkman, J. Angiogenesis: an organizing principle for drug discovery? Nat. Rev. Drug Discov. 6, 273–86 (2007).

12. Oklu, R., Walker, T. G., Wicky, S. & Hesketh, R. Angiogenesis and current anti-angiogenic strategies for the treatment of cancer. Journal of Vascular and Interventional Radiology vol. 21 1791–1805 (2010).

13. Folkman, J. Tumor angiogenesis: therapeutic implications. N. Engl. J. Med. 285, 1182–1186 (1971).

14. Bergers, G. & Benjamin, L. E. Tumorigenesis and the angiogenic switch. Nat. Rev. Cancer 3, 401–410 (2003).

15. Carmeliet, P. & Jain, R. K. Molecular mechanisms and clinical applications of angiogenesis. Nature 473, 298–307 (2011).

16. Coleman, R. L. et al. Bevacizumab and paclitaxel-carboplatin chemotherapy and secondary cytoreduction in recurrent, platinum-sensitive ovarian cancer (NRG Oncology/Gynecologic Oncology Group study GOG-0213): A multicentre, open-label, randomised, phase 3 trial. The Lancet Oncology (2017) doi:10.1016/S1470-2045(17)30279-6.

17. Perren, T. J. et al. A phase 3 trial of bevacizumab in ovarian cancer. N. Engl. J. Med. 365, 2484–96 (2011).

18. Burger, R. a et al. GOG 218 - Incorporation of bevacizumab in the primary treatment of ovarian cancer. N. Engl. J. Med. 365, 2473–83 (2011).

19. Cancer, O. NCCN.org NCCN Guidelines for Patients ® available at www.nccn.org/patients NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines ® ). www.nccn.org/patients (2021).

20. Colombo, N. et al. ESMO-ESGO consensus conference recommendations on ovarian cancer: Pathology and molecular biology, early and advanced stages, borderline tumours and recurrent disease. Ann. Oncol. 30, 672–705 (2019).

21. Managing advanced (stage II-IV) ovarian cancer - NICE Pathways. https://pathways.nice.org.uk/pathways/ovarian-cancer#path=view%3A/pathways/ovarian-cancer/managing-advanced-stage-ii-iv-ovarian-cancer.xml&content=view-node%3Anodes-second-line-and-subsequent-chemotherapy.

22. Wang, H., Xu, T., Zheng, L. & Li, G. Angiogenesis Inhibitors for the Treatment of Ovarian Cancer: An Updated Systematic Review and Meta-analysis of Randomized Controlled Trials. International Journal of Gynecological Cancer (2018) doi:10.1097/IGC.0000000000001258.

23. Wu, Y. S., Shui, L., Shen, D. & Chen, X. Bevacizumab combined with chemotherapy for ovarian cancer: an updated systematic review and meta-analysis of randomized controlled trials. Oncotarget 8, 10703–10713 (2017).

24. Marchetti, C. et al. Efficacy and toxicity of bevacizumab in recurrent ovarian disease: An update meta-analysis on phase III trials. Oncotarget 7, 13221–13227 (2016).

25. Jiang, Y., Sun, X., Kong, B. & Jiang, J. Antiangiogenesis therapy in ovarian cancer patients: An updated meta-analysis for 15 randomized controlled trials. Medicine (Baltimore). (2018) doi:10.1097/MD.0000000000011920.

26. Li, J., Zhou, L., Chen, X. & Ba, Y. Addition of bevacizumab to chemotherapy in patients with ovarian cancer: a systematic review and meta-analysis of randomized trials. Clin. Transl. Oncol. 17, 673–683 (2015).

27. Zhou, M., Yu, P., Qu, X., Liu, Y. & Zhang, J. Phase III trials of standard chemotherapy with or without bevacizumab for ovarian cancer: A meta-analysis. PLoS One 8, (2013).

28. Ye, Q. & Chen, H. L. Bevacizumab in the treatment of ovarian cancer: A meta-analysis from four phase III randomized controlled trials. Arch. Gynecol. Obstet. 288, 655–666 (2013).

29. Li, J., Li, S., Chen, R., Yu, H. & Lu, X. The prognostic significance of anti-angiogenesis therapy in ovarian cancer: a meta-analysis. J. Ovarian Res. (2015) doi:10.1186/s13048-015-0181-z.

30. Li, X., Zhu, S., Hong, C. & Cai, H. Angiogenesis inhibitors for patients with ovarian cancer: A meta-analysis of 12 randomized controlled trials. Curr. Med. Res. Opin. 32, 555–562 (2016).

31. Wang, T. S. et al. A meta-analysis of bevacizumab combined with chemotherapy in the treatment of ovarian cancer. Indian J. Cancer 51, e95–e98 (2014).

32. Hutton, B. et al. The PRISMA extension statement for reporting of systematic reviews incorporating network meta-analyses of health care interventions: checklist and explanations. Ann. Intern. Med. 162, 777–784 (2015).

33. Booth, A. et al. The nuts and bolts of PROSPERO: An international prospective register of systematic reviews. Syst. Rev. (2012) doi:10.1186/2046-4053-1-2.

34. Higgins, J., Savović, J., Page, M. J. & Sterne, J. A. C. RoB 2: A revised Cochrane risk-of-bias tool for randomized trials. British Medical Journal (2019).

35. Lu, G. & Ades, A. E. Combination of direct and indirect evidence in mixed treatment comparisons. Stat. Med. 23, 3105–3124 (2004).

36. Mills, E. J., Thorlund, K. & Ioannidis, J. P. A. Demystifying trial networks and network meta-analysis. BMJ 346, (2013).

37. Neupane, B., Richer, D., Bonner, A. J., Kibret, T. & Beyene, J. Network meta-analysis using R: a review of currently available automated packages. PLoS One 9, e115065 (2014).

38. Rucker, G., Krahn, U., Konig, J., Efthimiou, O., Papakonstantinou, T., & Schwarzer, G. Package ‘ netmeta ’. Network Meta-Analysis using Frequentist Methods. (2021) doi:10.1007/978-3-319-21416.

39. Rücker, G. & Schwarzer, G. Ranking treatments in frequentist network meta-analysis works without resampling methods. BMC Med. Res. Methodol. 15, 58 (2015).

40. Monk, B. J., Minion, L. E. & Coleman, R. L. Anti-angiogenic agents in ovarian cancer: Past, present, and future. Ann. Oncol. (2016) doi:10.1093/annonc/mdw093.

41. Colomban, O. et al. Bevacizumab for Newly Diagnosed Ovarian Cancers: Best Candidates Among High-Risk Disease Patients (ICON-7). JNCI Cancer Spectr. 4, (2020).

42. Veroniki, A. A., Vasiliadis, H. S., Higgins, J. P. T. & Salanti, G. Evaluation of inconsistency in networks of interventions. Int. J. Epidemiol. 42, 332–345 (2013).

43. van Valkenhoef, G., Dias, S., Ades, A. E. & Welton, N. J. Automated generation of node-splitting models for assessment of inconsistency in network meta-analysis. Res. Synth. Methods 7, 80–93 (2016).

44. Duska, L. R. et al. A randomized phase II evaluation of weekly gemcitabine plus pazopanib versus weekly gemcitabine alone in the treatment of persistent or recurrent epithelial ovarian, fallopian tube or primary peritoneal carcinoma. in Gynecologic Oncology (2020). doi:10.1016/j.ygyno.2019.10.014.

45. Zang, R. et al. Pazopanib (Paz) monotherapy in Asian women who have not progressed after first-line chemotherapy for advanced ovarian, Fallopian tube, or primary peritoneal carcinoma. J. Clin. Oncol. 31, 5512–5512 (2013).

46. Vergote, I. et al. Trebananib or placebo plus carboplatin and paclitaxel as first-line treatment for advanced ovarian cancer (TRINOVA-3/ENGOT-ov2/GOG-3001): a randomised, double-blind, phase 3 trial. Lancet Oncol. 20, 862–876 (2019).

47. Coleman, R. et al. Analysis of survivorship in high-risk patients on treated on GOG-218. Gynecol. Oncol. 130, e112–e113 (2013).

48. Ray‐Coquard, I. et al. Final results from GCIG/ENGOT/AGO‐OVAR 12, a randomised placebo‐controlled phase III trial of nintedanib combined with chemotherapy for newly diagnosed advanced ovarian cancer. Int. J. Cancer 146, 439–448 (2020).

49. Oza, A. M. et al. Standard chemotherapy with or without bevacizumab for women with newly diagnosed ovarian cancer (ICON7): Overall survival results of a phase 3 randomised trial. Lancet Oncol. 16, 928–936 (2015).

50. Randall, L. et al. Outcome differences in patients with advanced epithelial ovarian, primary peritoneal and fallopian tube cancers treated with and without bevacizumab. Gynecol. Oncol. 130, e33–e34 (2013).

51. Shi, Q. & Sargent, D. J. Meta-analysis for the evaluation of surrogate endpoints in cancer clinical trials. International Journal of Clinical Oncology vol. 14 102–111 (2009).

52. Kay, A., Higgins, J., Day, A. G., Meyer, R. M. & Booth, C. M. Randomized controlled trials in the era of molecular oncology: Methodology, biomarkers, and end points. Ann. Oncol. 23, 1646–1651 (2012).

53. S, D., P, T. & A, C. A Review of Studies Examining the Relationship between Progression-Free Survival and Overall Survival in Advanced or Metastatic Cancer. A Review of Studies Examining the Relationship between Progression-Free Survival and Overall Survival in Advanced or Metastatic Cancer (2012).

54. Kim, C. & Prasad, V. Cancer drugs approved on the basis of a surrogate end point and subsequent overall survival: An analysis of 5 years of us food and drug administration approvals. JAMA Internal Medicine vol. 175 1992–1994 (2015).

55. Pasalic, D. et al. Progression-free survival is a suboptimal predictor for overall survival among metastatic solid tumour clinical trials. Eur. J. Cancer 136, 176–185 (2020).

56. Prasad, V., Kim, C., Burotto, M. & Vandross, A. The strength of association between surrogate end points and survival in oncology: A systematic review of trial-level meta-analyses. JAMA Intern. Med. 175, 1389–1398 (2015).

57. Paoletti, X. et al. Assessment of Progression-Free Survival as a Surrogate End Point of Overall Survival in First-Line Treatment of Ovarian Cancer: A Systematic Review and Meta-analysis. JAMA Netw. open 3, e1918939 (2020).

58. Bentink, S. et al. Angiogenic mRNA and microRNA gene expression signature predicts a novel subtype of serous ovarian cancer. PLoS One 7, (2012).

59. Backen, A. et al. The combination of circulating Ang1 and Tie2 levels predicts progression-free survival advantage in bevacizumab-treated patients with ovarian cancer. Clin. Cancer Res. 20, 4549–4558 (2014).

60. Gourley, C. et al. Molecular subgroup of high-grade serous ovarian cancer (HGSOC) as a predictor of outcome following bevacizumab. | 2014 ASCO Annual Meeting | Abstracts | Meeting Library. J. Clin. Oncol. 32, Abstract 5502 (2014).

61. Collinson, F. et al. Predicting response to bevacizumab in ovarian cancer: A panel of potential biomarkers informing treatment selection. Clin. Cancer Res. 19, 5227–5239 (2013).

62. Michael J. Birrer, YounJeong Choi, Mark F. Brady, Robert S. Mannel, Robert Allen Burger, WEI WEI, Amreen Husain, Carlos Bais, NRG Oncology/Gynecologic Oncology Group; Massachusetts General Hospital/Dana Farber Cancer Center, Boston, MA; Genentech, Inc., S, M. Retrospective analysis of candidate predictive tumor biomarkers (BMs) for efficacy in the GOG-0218 trial evaluating front-line carboplatin–paclitaxel (CP) ± bevacizumab (BEV) for epithelial ovarian cancer (EOC). J Clin Oncol 33, 2015 (suppl; abstr 5505).

63. Pignata, S. et al. Pazopanib plus weekly paclitaxel versus weekly paclitaxel alone for platinum-resistant or platinum-refractory advanced ovarian cancer (MITO 11): A randomised, open-label, phase 2 trial. Lancet Oncol. 16, 561–568 (2015).

64. Chekerov, R. et al. Sorafenib plus topotecan versus placebo plus topotecan for platinum-resistant ovarian cancer (TRIAS): a multicentre, randomised, double-blind, placebo-controlled, phase 2 trial. Lancet Oncol. 19, 1247–1258 (2018).

65. Ray-Coquard, I. et al. Olaparib plus Bevacizumab as First-Line Maintenance in Ovarian Cancer. N. Engl. J. Med. (2019) doi:10.1056/nejmoa1911361.

Competing interest reported. Author Disclosures: • Professor Richard Kennedy is employed by Almac as the Medical Director. RDK • No author disclosures for the remaining authors: AE, CW, HC, WLC, ND, SWKS, KKC, HYSN, RKCN

Download PDF

Journal Publication

published 09 Mar, 2022

Read the published version in Scientific Reports →

Editorial decision: Major revision
31 Dec, 2021
Reviews received at journal
29 Nov, 2021
Reviewers agreed at journal
29 Nov, 2021
Reviewers invited by journal
26 Nov, 2021
Editor assigned by journal
26 Nov, 2021
Editor invited by journal
15 Nov, 2021
Submission checks completed at journal
15 Nov, 2021
First submitted to journal
29 Oct, 2021

You are reading this latest preprint version

A Comprehensive Systematic Review and Network Meta-analysis: The Role of anti- angiogenic agents in advanced epithelial ovarian cancer

Status:

Journal Publication

Version 1

Abstract

Figures

Key Points

Introduction

Methods

Results

Discussion

Declarations

References

Additional Declarations

Supplementary Files

Status:

Journal Publication

Version 1