Impact of Anti-angiogenic Drugs on Severity of COVID-19 in Patients with Non-Small Cell Lung Cancer.

Introduction: The 2019 coronavirus disease (COVID-19) pandemic has reshaped oncology practice, but the impact of anti-angiogenic drugs on the severity of COVID-19 in patients with non-small cell lung cancer (NSCLC) remains unclear. Patients and Methods: We carried out a retrospective study involving 166 consecutive patients with NSCLC who were positive for COVID-19, aiming to determine the effects of anti-angiogenic drugs on disease severity, as defined by severe/critical symptoms, intensive care unit (ICU) admission/intubation, and mortality outcomes. Risk factors were identified using univariate and multivariate logistic regression models. Results: Of the participants, 73 had been administered anti-angiogenic drugs (termed the anti-angiogenic therapy (AT) group), while 93 had not (non-AT group). Comparative analyses showed no significant disparity in the rates of severe/critical symptoms (21.9% vs 35.5%, P = 0.057), ICU admission/intubation (6.8% vs 7.5%, P = 0.867), or death (11.0% vs 9.7%, P = 0.787) between these two groups. However, elevated risk factors for worse outcomes included age ≥ 60 (odds ratio (OR): 2.52, 95% confidence interval (CI): 1.07-5.92), Eastern Cooperative Oncology Group performance status of 2 or higher (OR: 21.29, 95% CI: 4.98-91.01), chronic obstructive pulmonary disease (OR: 7.25, 95% CI: 1.65-31.81), hypertension (OR: 2.98, 95% CI: 1.20-7.39), and use of immunoglobulin (OR: 5.26, 95% CI: 1.06-26.25). Conclusion: Our data suggests that the use of anti-angiogenic drugs may not exacerbate COVID-19 severity in NSCLC patients, indicating their potential safe application even during the pandemic period.

Visual outcomes of intraocular inflammation after brolucizumab injection in Japanese patients with neovascular age-related macular degeneration.

PURPOSE: This study investigates the visual outcomes of neovascular age-related macular degeneration (nAMD) patients who developed intraocular inflammation (IOI) after intravitreal brolucizumab injection (IVBr). METHODS: We studied 285 eyes of 279 cases diagnosed with nAMD and focused on 18 eyes (6.3%) of 17 cases which developed IOI after IVBr. IVBr was performed either on the initial treatment or for switching of other anti-vascular endothelial growth factor agents during January 2020 to December 2021. We evaluated clinical features and the course of treatment of a 6-month follow-up after IOI occurred. RESULTS: Of 17 cases, 9 cases were male, 8 cases were female. Baseline logarithm of the minimum angle of resolution(logMAR) best-corrected visual acuity (BCVA) was 0.36, BCVA before IOI occurred was 0.30, and BCVA when IOI occurred was 0.43. 16 eyes (88.9%) had symptoms such as visual loss or floaters when IOI occurred. On the other hand, the remaining 2 eyes (11.1%) had no symptoms. 11 eyes (61.1%) had only IOI, while the remaining 7 eyes (38.9%) had IOI and perivascular sheathing. Steroid sub-tenon injection was performed on 1 eye (5.6%), steroid eye drops were used in 11 eyes (61.1%), and 6 eyes (33.3%) were followed-up without treatment. Neovascular AMD recurred in 16 eyes (88.9%) after IOI occurred and were treated with aflibercept. VA at 3 and 6 months after IOI occurred were significantly improved to 0.34 and 0.30, respectively (P = 0.09 at 3 months and P = 0.02 at 6 months). The symptoms of patients were improved in all cases. We were able to stop steroid treatment in all cases. CONCLUSIONS: IOI occurred in 6.3% of nAMD patients after IVBr treatment. All of which showed significant improvement from logMAR of 0.43 to 0.30 with steroid treatment or without any treatment. We should consider the possibility of IOI after IVBr as a complication, however, they have a relatively good prognosis if treated at an early stage.

Intravitreal aflibercept 8 mg in neovascular age-related macular degeneration (PULSAR): 48-week results from a randomised, double-masked, non-inferiority, phase 3 trial.

BACKGROUND: Intravitreal aflibercept 8 mg could improve treatment outcomes and provide sustained disease control in patients with neovascular age-related macular degeneration (nAMD), with extended dosing compared with aflibercept 2 mg. METHODS: PULSAR is a phase 3, randomised, three-group, double-masked, non-inferiority, 96-week trial conducted across 223 sites worldwide. Adults with nAMD were randomised 1:1:1 to aflibercept 8 mg every 12 weeks (8q12), aflibercept 8 mg every 16 weeks (8q16), or aflibercept 2 mg every 8 weeks (2q8), following three initial monthly doses in all groups. From week 16, patients in the aflibercept 8 mg groups had their dosing interval shortened if pre-specified dose regimen modification criteria denoting disease activity were met. The primary endpoint was change from baseline in best-corrected visual acuity (BCVA) at week 48. All patients with at least one dose of study treatment were included in the efficacy and safety analyses. This trial is registered with ClinicalTrials.gov (NCT04423718) and is ongoing. FINDINGS: Of 1011 patients randomised to aflibercept 8q12 (n=336), 8q16 (n=338), or 2q8 (n=337) between Aug 11, 2020, and July 30, 2021, 1009 patients received study treatment (aflibercept 8q12 n=335; aflibercept 8q16 n=338; and aflibercept 2q8 n=336). Aflibercept 8q12 and 8q16 showed non-inferior BCVA gains versus aflibercept 2q8 (mean BCVA change from baseline +6·7 [SD 12·6] and +6·2 [11·7] vs +7·6 [12·2] letters). The least squares mean differences between aflibercept 8q12 versus 2q8 and 8q16 versus 2q8, respectively, were -0·97 (95% CI -2·87 to 0·92) and -1·14 (-2·97 to 0·69) letters (non-inferiority margin at 4 letters). The incidence of ocular adverse events in the study eye was similar across groups (aflibercept 8q12 n=129 [39%]; aflibercept 8q16 n=127 [38%]; and aflibercept 2q8 n=130 [39%]). INTERPRETATION: Aflibercept 8 mg showed efficacy and safety with extended dosing intervals, which has the potential to improve the management of patients with nAMD. FUNDING: Bayer AG and Regeneron Pharmaceuticals.

Efficacy and Safety of Anti-angiogenic Agents for Cancer Patients With Proteinuria or a History of Proteinuria: A Systematic Review.

BACKGROUND/AIM: The safety and efficacy of anti-angiogenic agents in patients with cancer with proteinuria and a history of proteinuria are not well established. This systematic review aimed to answer these questions. MATERIALS AND METHODS: We searched three electronic databases for articles published until June 18, 2021. The main outcomes used were "death", "renal impairment", and "proteinuria impairment". RESULTS: After screening 303 references in the PubMed, Cochrane Library, and ICHUSHI-web databases, this review included five studies on renal cell carcinoma (RCC). In patients with metastatic RCC, the hazard ratio of the presence of (or having) proteinuria (1+ or higher) at baseline was 0.82 (0.23-2.97); thus, proteinuria was not significantly associated with the outcome of death. No significant deterioration in kidney function was observed in patients with proteinuria. Although proteinuria at baseline was a significant risk factor for proteinuria progression during and after treatment, most patients maintained grade 1 or 2 proteinuria and continued treatment without dose reduction or discontinuation. CONCLUSION: While weak evidence suggests that proteinuria at the start of treatment with anti-angiogenic agents might be a risk factor for worsening proteinuria, it was not significantly associated with death or renal impairment.

The role of angiogenesis inhibitors associated with tyrosine kinase inhibitors in the first-line treatment for EGFR-mutated advanced lung cancer.

Tyrosine kinase inhibitors (TKIs) are the standard treatment for epidermal growth factor receptor mutant (EGFRm) advanced non-small cell lung cancer (NSCLC). Combining TKIs with an angiogenesis inhibitor has shown promise in pre-clinical studies. A systematic search of clinical trials found that combining erlotinib (a first-generation TKI) with bevacizumab or ramucirumab (angiogenesis inhibitors) improved progression-free survival (PFS) in EGFRm advanced NSCLC patients compared to TKI alone. However, no significant benefit in overall survival (OS) was observed in trials. Similar efficacy was seen in patients with specific EGFR mutations. Third generation TKIs were used as second-line therapy for patients with the T790M mutation. The combination treatment was associated with a higher incidence of severe adverse events. Overall, combining erlotinib or another TKI with an angiogenesis inhibitor is a safe and effective alternative for first-line treatment in EGFRm advanced NSCLC, particularly in countries without access to osimertinib and for patients with the EGFR L858R mutation.

Enhanced durability and evolution of retreatment criteria of intravitreal antivascular endothelial growth factor agents for diabetic macular edema.

PURPOSE OF REVIEW: The increasing prevalence of diabetic macular edema (DME) necessitates an updated review of treatment modalities. While the shift from laser to anti-vascular endothelial growth factor (anti-VEGF) therapy has transformed patient outcomes, benefits of these agents are not fully realized in real-world implementation relative to the setting of controlled clinical trials. This review outlines the evolution of intravitreal anti-VEGF treatment extension protocols for DME that reflect efforts to address treatment adherence challenges while optimizing visual outcomes. RECENT FINDINGS: Recent studies highlight the efficacy of extended-interval dosing with anti-VEGF agents in managing DME. Trials such as RISE/RIDE, VISTA/VIVID, and LUCIDATE have established the foundation of these regimens by demonstrating sustained visual gains with continuous treatment. However, newer trials including PROTOCOL T, KESTREL/KITE, YOSEMITE/RHINE, and PHOTON have furthered this concept, revealing that less frequent dosing of various anti-VEGF agents can maintain similar visual acuity and anatomical outcomes to traditional monthly injections. SUMMARY: The reviewed findings suggest a paradigm shift in DME treatment toward less frequent anti-VEGF injections. This has significant implications for clinical practice, potentially leading to greater adherence to treatment regimens and sustained visual function in patients, while minimizing treatment burden and healthcare costs. Further investigation into the long-term effects of extended dosing intervals is required.

Cardiac and Nephrological Complications Related to the Use of Antiangiogenic and Anti-Programmed Cell Death Protein 1 Receptor/Programmed Cell Death Protein 1 Ligand Therapy.

The ability to undergo neoangiogenesis is a common feature with all cancers. Signaling related to vascular endothelial growth factors (VEGF) and their receptors (VEGFR) plays a key role in the process of tumor neoangiogenesis. A close relationship has been demonstrated between excessive VEGF levels and the induction of immunosuppression in the tumor microenvironment. The use of drugs blocking the VEGF function, apart from the anticancer effect, also result in adverse effects, in particular related to the circulatory system and kidneys. Cardiac toxicity associated with the use of such therapy manifests itself mainly in the form of hypertension, thromboembolic episodes and ischemic heart disease. In the case of renal complications, the most common symptoms include renal arterial hypertension, proteinuria and microangiopathy. Although these complications are reversible in 60-80% of cases after cessation of VSP (VEGF pathway inhibitor) therapy, in some cases they can lead to irreversible changes in renal function, whereas cardiac complications may be fatal. Also, the use of PD-1/PD-L1 inhibitors may result in kidney and heart damage. In the case of cardiac complications, the most common symptoms include myocarditis, pericarditis, arrhythmia, acute coronary syndrome and vasculitis, while kidney damage most often manifests as acute kidney injury (AKI), nephrotic syndrome, pyuria or hematuria. The decision whether to resume treatment after the occurrence of cardiovascular and renal complications remains a problem.

Evaluation of bevacizumab biosimilar on wound healing complications in patients with colorectal cancer undergoing endoscopic mucosal resection: A systematic review and meta-analysis in anorectal medicine.

Complications related to wound healing pose substantial obstacle in the management of colorectal cancer (CRC), specifically in the field of anorectal medicine. Biosimilars of bevacizumab have emerged as crucial therapeutic agents in the management of these complications. With the particular emphasis on effects of Bevacizumab Biosimilar Plus on wound healing among patients diagnosed with CRC, this review underscores the potential of this anorectal medication to improve patient outcomes and was aimed to assess the safety and efficacy of Bevacizumab Biosimilar Plus in relation to complications associated with wound healing in patients with CRC. The assessment centers on its therapeutic potential and safety profile within the domain of anorectal medicine. In accordance with the PRISMA guidelines, a comprehensive literature search was performed, resulting in the identification of 19 pertinent studies out of an initial 918. Priority was given to assessing the safety and adverse effects of Bevacizumab Biosimilar Plus in conjunction with its effectiveness in wound healing. The extracted data comprised the following: study design, patient demographics, comprehensive treatment regimens, wound healing-specific outcomes and adverse effects. The evaluation of study quality was conducted utilizing the instruments provided by the Cochrane Collaboration and the Newcastle-Ottawa Scale (NOS). Bevacizumab Biosimilar Plus demonstrates efficacy in the management of wound healing complications among patients with CRC, with a safety and efficacy profile similar to that of the original Bevacizumab, according to the analysis. Notably, several studies reported improved rates of wound healing in relation to the biosimilar. The safety profiles exhibited similarities to the anticipated anti-VEGF agent effects. In wound management, the biosimilar also demonstrated advantages in terms of prolonged efficacy. In addition, analyses of cost-effectiveness suggested that the use of biosimilars could result in cost reductions. Bevacizumab Biosimilar Plus exhibited potential as an anorectal medication for the effective management of wound healing complications in patients with CRC. This has substantial ramifications for improving the quality of patient care, encompassing the affordability and effectiveness of treatments.

Efficacy and safety of intravitreal faricimab for neovascular age-related macular degeneration: a systematic review and meta-analysis.

We conducted a systematic review and meta-analysis to evaluate the visual, anatomical, and safety outcomes of the intravitreal faricimab, a novel vascular endothelial growth factor (VEGF)/angiopoietin-2 (Ang-2) bispecific agent, in neovascular age-related macular degeneration (nAMD) patients. The follow-up times in the included studies ranged from a minimum of 36 weeks to a maximum of 52 weeks. EMBASE, Ovid-Medline, Cochrane Central Register of Controlled Trials (CENTRAL), Web of Science, Scopus, the WHO ICTRP, ClinicalTrial.gov, the EU Clinical Trials Register, and Chinese Clinical Trial Registry (ChiCTR) were searched (The last literature search was performed on August 17, 2023) for randomized controlled trials (RCTs) comparing faricimab with control groups for neovascular age-related macular degeneration (nAMD). The risk of bias for eligible RCTs was independently assessed using the Cochrane Risk of Bias Tool by two authors (W.-T.Y. and C.-S.W.). The meta-analysis was conducted using Review Manager 5.4 software. The mean best corrected visual acuity (BCVA), central subfield thickness (CST), total choroidal neovascularization (CNV) area, and total lesion leakage were analyzed as continuous variables and the outcome measurements were reported as the weighted mean difference (WMD) with a 95% confidence interval (CI). The ocular adverse events and ocular serious adverse events were analyzed as dichotomous variables and the outcome measurements were analyzed as the odds ratios (ORs) with a 95% CI. Random-effects model was used in our study for all outcome synthesizing due to different clinical characteristics. Four RCTs with 1,486 patients were eligible for quantitative analysis. There was no statistically significant difference between intravitreal faricimab and anti-VEGF in BCVA [weighted mean difference (WMD) = 0.47; 95% CI: (- 0.17, 1.11)]. The intravitreal faricimab group showed numerically lower CST [WMD = - 5.96; 95% CI = (- 7.11, - 4.82)], total CNV area [WMD = - 0.49; 95% CI = (- 0.68, - 0.30)], and total lesion leakage [WMD = - 0.88; 95% CI = (- 1.08, - 0.69)] after intravitreal therapy compared with the intravitreal anti-VEGF group. There were no statistically significant differences between intravitreal faricimab and anti-VEGF in ocular adverse events (AEs) [pooled odds ratio (OR) = 1.10; 95% CI = (0.81, 1.49)] and serious adverse events (SAEs) [pooled OR = 0.84; 95% CI = (0.37, 1.90)]. The intravitreal bispecific anti-VEGF/angiopoietin 2 (Ang2) antibody faricimab with a extended injection interval was non-inferior to first-line anti-VEGF agents in BCVA. It was safe and had better anatomical recovery. Large, well-designed RCTs are needed to explore the potential benefit of extended faricimab for nAMD. This systematic review was registered in the International Prospective Register of Systematic Reviews (PROSPERO) database (CRD42022327450).

Sodium-glucose co-transporter 2 inhibitor therapy reduces the administration frequency of anti-vascular endothelial growth factor agents in patients with diabetic macular oedema with a history of anti-vascular endothelial growth factor agent use: A cohort study using the Japanese health insurance claims database.

AIM: We assessed the effectiveness of sodium-glucose co-transporter 2 inhibitors (SGLT2is) in reducing the administration frequency of anti-vascular endothelial growth factor (VEGF) agents in patients with diabetic macular oedema (DMO) using a health insurance claims database. MATERIALS AND METHODS: This retrospective cohort study analysed health insurance claims data covering 11 million Japanese patients between 2005 and 2019. We analysed the frequency and duration of intravitreal injection of anti-VEGF agents after initiating SGLT2is or other antidiabetic drugs. RESULTS: Among 2412 matched patients with DMO, the incidence rates of anti-VEGF agent injections were 230.1 per 1000 person-year in SGLT2i users and 228.4 times per 1000 person-year in non-users, respectively, and the risk ratio for events was unchanged in both groups. Sub-analysis of each baseline characteristic of the patients showed that SGLT2is were particularly effective in patients with a history of anti-VEGF agent use [p = .027, hazard ratio (HR): 0.44, 95% confidence interval (CI): 0.22-0.91]. SGLT2is reduced the risk for the first (p = .023, HR: 0.45, 95% CI: 0.22-0.91) and second (p = .021, HR: 0.39, 95% CI: 0.17-0.89) anti-VEGF agent injections. CONCLUSIONS: There was no difference in the risk ratio for the addition of anti-VEGF therapy between the two treatment groups. However, the use of SGLT2is reduced the frequency of anti-VEGF agent administration in patients with DMO requiring anti-VEGF therapy. Therefore, SGLT2i therapy may be a novel, non-invasive, low-cost adjunctive therapy for DMO requiring anti-VEGF therapy.

Morphology of immune-mediated hepatitis: A comparison between immune checkpoint inhibitor therapy and combined immune checkpoint inhibitor/anti-angiogenic therapy.

BACKGROUND: The combination of immune checkpoint inhibitors (ICIs) with anti-angiogenic drugs has shown promising anticancer effects. However, ICIs can trigger immune-mediated hepatitis (IMH). We aimed to clarify whether the combined use of anti-angiogenic drugs and ICIs would increase the severity of IMH. METHODS: One hundred IMH patients (ICI monotherapy vs. ICI plus anti-angiogenic therapy 30 vs. 70) were retrospectively enrolled. Clinicopathological parameters were compared between the two groups. RESULTS: IMH mainly showed variable degrees of panlobular hepatitis (84 %), while some cases presented mixed cholangio-hepatitic (14 %) or cholangitic (2 %) pattern. The incidence of moderate-severe injury was not significantly different between the two groups (combination vs. monotherapy 38.6 % vs. 20.0 %, p = 0.109). Specifically, the rates of marked lobular injury and portal inflammation were higher in the combination group than in the monotherapy cohort (p < 0.005), while the frequencies of interface hepatitis, bile duct injury, histiocytosis aggregates, and endothelialitis were comparable between the two groups (p > 0.05). Compared to mild IMH cases, severe IMH cases showed higher immunostaining expression levels of PD-L1 (60.7 % vs. 19.4 %, p < 0.0001). Treatments and outcomes of IMH were not significantly different between the two groups (p > 0.05). CONCLUSIONS: Compared to ICI monotherapy, the administration of anti-angiogenic drugs in combination with ICIs was not associated with increased hepatotoxicity.

Renal Implications of Long-Term Systemic Bevacizumab for Recurrent Respiratory Papillomatosis.

BACKGROUND: Bevacizumab is a vascular endothelial growth factor (VEGF) inhibitor that is used off-label for select cases of recurrent respiratory papillomatosis (RRP) that are severe, involve the distal airway or lung parenchyma, and refractory to other forms of adjuvant therapy. However, there is limited safety data for the use of bevacizumab in children and VEGF inhibitors are reported to have a range of adverse renal effects, including hypertension, proteinuria, and thrombotic microangiopathy (TMA). CASE-DIAGNOSIS/TREATMENT: This report describes a case of severe juvenile-onset RRP that had an exceptionally high operative burden that was refractory to several adjuvant treatment strategies (including intralesional cidofovir and subcutaneous pegylated interferon). Bevacizumab treatment resulted in a dramatic and sustained improvement in disease control over a 5-year period. However, after 3 years of treatment, the patient developed hypertension and proteinuria and was found to have evidence of a glomerular TMA on kidney biopsy. These complications were successfully managed with a reduction in bevacizumab frequency and angiotensin-converting enzyme inhibitor initiation. CONCLUSIONS: Clinicians caring for children treated with VEGF inhibitors should be aware of the potential renal complications and their management.

Intralesional cidofovir vs. bevacizumab for recurrent respiratory papillomatosis: a systematic review and indirect meta-analysis.

BACKGROUND: Specific HPV types cause recurrent respiratory papillomatosis (R.R.P.). When administered intralesionally, cidofovir, an antiviral agent, has shown favorable outcomes in reducing papilloma. Bevacizumab, an angiogenesis inhibitor, has demonstrated improved R.R.P. However, both treatments lack FDA approval for R.R.P. Our study aims to evaluate the efficacy and safety of intralesional Cidofovir and Bevacizumab for R.R.P. and compare the two interventions. METHODS: We searched five electronic databases to find relevant studies. After the screening, data were extracted from the included studies. Pooled ratios with 95% confidence intervals (CIs) were used for categorical outcomes, and mean difference (MD) was used for continuous outcomes. Statistical heterogeneity was evaluated using the chi-squared test for I2 statistics. The Cochrane Risk of Bias assessment tool was used to assess the methodological quality of randomized controlled trials (RCTs), while the National Institutes of Health's tool was used for observational studies. Analysis was done by Review Manager software. RESULTS: In our comprehensive meta-analysis of 35 articles involving 836 patients, cidofovir demonstrated an overall remission ratio of (0.90 [95% CI: 0.83, 0.98], p = 0.01), while bevacizumab (0.92 [95% CI: 0.79, 1.07]), p = 0.3). The complete remission ratio for cidofovir was (0.66 [95% CI: 0.57, 0.75], p > 0.0001), while bevacizumab was (0.29 [95% CI: 0.12, 0.71], p = 0.07). In partial remission, Bevacizumab showed a higher ratio than Cidofovir 0.74 [0.55, 0.99] vs. 0.40 [0.30, 0.54]. Bevacizumab had a pooled ratio of 0.07 [95% CI: 0.02, 0.30] in terms of no remission, indicating better outcomes compared to Cidofovir with a ratio of 0.28 [95% CI: 0.16, 0.51]. Additionally, Cidofovir showed a favorable decrease in the Derkay Severity Score (DSS) with a mean difference (MD) of 1.98 [95% CI: 1.44, 2.52]. CONCLUSION: Cidofovir had a higher impact on complete remission compared to Bevacizumab. Both showed partial remission, with Bevacizumab having a higher ratio. Moreover, Cidofovir showed a significant decrease in DSS. Bevacizumab had lower rates of no remission and recurrence and fewer adverse events compared to Cidofovir. However, the difference between the two treatments was not significant, except for partial remission.

Smoking and short-term response to intravitreal anti-Vascular Endothelial Growth Factor injections in neovascular age-related macular degeneration.

PURPOSE: To evaluate the role of smoking status on the response to three monthly intravitreal anti-Vascular Endothelial Growth Factor (anti-VEGF) injections in treatment-naive neovascular AMD (nAMD) patients. METHODS: We conducted a single-center, retrospective, case-control cohort study in Belgium. RESULTS: Intravitreal treatment (IVT) was performed in 147 eyes of 131 patients, including 92 females (70%). Mean age at the time of the first IVT was 79±9 years. Seventeen patients (13%) were actively smoking at the time of the anti-VEGF IVT. On average, active smokers were 11 years younger than non-smokers when starting IVT treatment. They also showed more frequent subretinal fluid than non-smokers (94% vs. 65%). Mann-Whitney analyses comparing change in central macular thickness and change in logarithm of the minimum angle of resolution visual acuity between active smokers and non-smokers showed no significant difference in treatment response between both groups. Likewise, no significant difference was found when comparing treatment response between patients with less than 10 pack-years (PY) (including never-smokers) and patients with over 10 PY. In a binary logistic regression model, male patients responded worse to anti-VEGF IVT than their female counterparts, with an odds ratio (OR) of 0.27 for good response. This was the only statistically significant predictor of treatment response. CONCLUSION: Our study failed to demonstrate an effect of smoking on the short-term treatment response to anti-VEGF in nAMD.

Efficacy and safety of neoadjuvant chemotherapy containing anti-angiogenic drugs, immunotherapy, or PARP inhibitors for ovarian cancer.

Ovarian cancer is the most lethal gynecologic malignancy. The standard treatment involves chemotherapy with platinum-paclitaxel following cytoreductive surgery. For patients battling widespread and aggressive tumor spread, neoadjuvant chemotherapy (NACT) followed by interval debulking surgery emerges as an encouraging alternative. However, the effectiveness of this strategy is often limited by advanced-stage diagnosis and high likelihood of recurrence. The high mortality rate necessitates the exploration of targeted therapies. Present results signal promising efficacy and acceptable toxicities of anti-angiogenic drugs, immunotherapy, or PARP inhibitors used in chemotherapy. However, the potential integration of these drugs into NACT raises questions about response rates, surgical outcomes, and adverse events. This review delves into the findings from all published articles and ongoing studies, aiming to summarize the clinical use of anti-angiogenic drugs, immunotherapy, or PARP inhibitors in NACT, highlight the positive and negative aspects, and outline future perspectives.

Cardiovascular Toxicity of Angiogenesis Inhibitors Among Patients With Cancer in Taiwan: A Nested Case-Control Study.

BACKGROUND: Research on the cardiovascular toxicity of angiogenesis inhibitors among patients with cancer in Taiwan is lacking. This observational study explored the risk of major adverse cardiovascular events (MACEs) associated with angiogenesis inhibitors in Taiwan. METHODS AND RESULTS: We conducted a nested case-control study using the TCR (Taiwan Cancer Registry) linked with the Taiwan National Insurance Claim Database. We matched every case with 4 controls using risk-set sampling by index date, age, sex, cancer type, and cancer diagnosis date. Conditional logistic regression was used to evaluate the risks of MACEs and different cardiovascular events using propensity score adjustment or matching. Sensitivity analyses were used to evaluate the risks matched by cancer stages or exposure within 1 year. Among a cohort of 284 292 after the exclusion of prevalent cases, the incidences of MACEs among the overall cohort and those exposed to angiogenesis inhibitors were 22.5 and 32.5 events per 1000 person-years, respectively. We matched 17 817 cases with 70 740 controls, with a mean age of 74.9 years, and 56.8% of patients were men. After propensity score adjustment, angiogenesis inhibitors were associated with increased risks of MACEs (odds ratio, 4.56; 95% CI, 1.78-11.59). Significantly increased risks were noted for heart failure hospitalization, myocardial infarction, cerebrovascular accident, and venous thromboembolism, but not for new-onset atrial fibrillation. Similar results were observed after matching by cancer stage or restriction of 1-year exposure. CONCLUSIONS: Angiogenesis inhibitors were associated with increased risks of MACEs among patients with various malignancies in Taiwan but were not associated with new-onset atrial fibrillation.

Baseline characteristics associated with the incidence of intraocular inflammation after the intravitreous injection of brolucizumab.

PURPOSE: To investigate baseline characteristics associated with the incidence of intraocular inflammation (IOI) after the intravitreal injection of brolucizumab (IVBr) for the treatment of neovascular age-related macular degeneration (nAMD). METHODS: This retrospective study included 66 eyes of 62 consecutive patients with nAMD who received IVBr (18 eyes were treatment naïve and 48 eyes had switched from other anti-vascular endothelial growth factor [VEGF] therapy). Baseline clinical characteristics were compared in non-IOI and IOI groups. RESULTS: Although a dry macula was achieved at a high rate even 6 months after IVBr, IOI occurred in 8 of 66 eyes (12.1%; all had switched therapy) during the study period. Baseline characteristics including age, sex, nAMD type, lens status, visual acuity, central macular thickness, and a history of diabetes did not differ between the groups. The number of previous anti-VEGF injections before IVBr was greater in the IOI group (P = 0.004), and the ratio of patients with a laser flare-cell photometry (LFCP) value over 15 photon count per millisecond (pc/ms) was higher in the IOI group (P = 0.017). Multivariate logistic regression analysis showed that a greater number of previous anti-VEGF injections (odds ratio [OR]: 1.12, P = 0.006; area under the curve: 0.82, cut-off score: 14.0) and an LFCP value over 15 pc/ms (OR: 81.6, P = 0.031) were significantly associated with the incidence of IOI after IVBr. CONCLUSION: A number of previous anti-VEGF injections greater than 14 and an LFCP value more than 15 pc/ms might be useful predictors of the incidence of IOI after IVBr in eyes with nAMD.

Efficacy and safety profile of combining antiangiogenic agents with chemotherapy in patients with advanced malignant pleural mesothelioma: A systematic review and meta-analysis of randomized controlled trials.

OBJECTIVES: Several prospective trials had been reported on chemotherapy with or without antiangiogenic agents in patients with advanced malignant pleural mesothelioma (MPM), with diverse results. We performed this systematic review and meta-analysis to evaluate the efficacy and safety of the combination regimen. METHODS: We systematically identified trials in several databases, including MEDLINE, EMBASE, Cochrane Central Register of Controlled Trials, ASCO Abstracts and ESMO Abstracts. All the randomized controlled trials (RCTs) about chemotherapy combined with antiangiogenic agents in advanced MPM were identified. Overall survival (OS) was the primary outcome, while progression-free survival (PFS), overall response rate (ORR) and serious toxicities were the secondary outcomes. Review Manager 5.3 was used to perform the statistical analyses. Stata 12.0 was used to assess the publication bias of egger's test. RESULTS: 5 randomized controlled trials containing 1250 patients were finally included in this analysis. Statistical analyses showed that the addition of antiangiogenic agents to chemotherapy could prolong OS [HR 0.79 (0.71-0.89), p<0.0001] and PFS [HR 0.75 (0.68-0.84), p<0.00001] in advanced MPM, especially in the epithelioid subgroup, with a tolerable toxicity profile. No significant difference was found in the analysis of ORR [HR 1.13 (0.95-1.35), p = 0.18]. Heterogeneity was found in the analyses of PFS and ORR, which might be caused by the limitation in uniform evaluation of tumor response. CONCLUSIONS: The combination of antiangiogenic agents with chemotherapy showed superior over chemotherapy alone in patients with advanced MPM. More prospective trials should be warranted to identify patients who would most likely benefit from the combination regimen.

Efficacy and Safety of Brolucizumab for Diabetic Macular Edema: The KINGFISHER Randomized Clinical Trial.

Importance: Despite the effectiveness of existing anti-vascular endothelial growth factor (VEGF) therapies, a need remains for further treatment options to improve response rates and/or reduce injection or monitoring frequency in patients with diabetic macular edema (DME). Objective: To evaluate the efficacy and safety of brolucizumab vs aflibercept dosed every 4 weeks in participants with DME. Design, Participants, and Setting: This 52-week, double-masked, phase 3 randomized clinical trial included treatment-naive adults and adults who had previously received anti-VEGF therapy. Data were collected from September 2019 to March 2020, and data were analyzed from April 2020 to February 2021. Intervention: Brolucizumab, 6 mg, intravitreal injection every 4 weeks or aflibercept, 2 mg, intravitreal injection every 4 weeks. Main Outcomes and Measures: Participants were randomized 2:1 to brolucizumab, 6 mg, or aflibercept, 2 mg. The primary end point was change from baseline in best-corrected visual acuity at week 52. Secondary end points were the proportion of participants with a 2-step improvement or greater from baseline in Diabetic Retinopathy Severity Scale score, the proportion of eyes with absence of both subretinal fluid and intraretinal fluid, change from baseline in central subfield thickness, and safety at week 52. Results: A total of 517 participants were randomized to brolucizumab (n = 346) or aflibercept (n = 171); 299 (57.8%) were male, and the mean (SD) age was 60.7 (10.2) years. Brolucizumab was noninferior to aflibercept in best-corrected visual acuity (Early Treatment Diabetic Retinopathy Study letter score) change from baseline at week 52 (brolucizumab, 12.2-letter improvement; aflibercept, 11.0-letter improvement; difference, 1.1; 95% CI, -0.6 to 2.9; noninferiority margin, 4; P < .001). Brolucizumab was superior to aflibercept for the proportion of eyes without subretinal and intraretinal fluid (brolucizumab, 144 of 346 [41.6%]; aflibercept, 38 of 171 [22.2%]; difference, 20.0%; 95% CI, 12.5to 28.6; P < .001) and mean central subfield thickness change from baseline at week 52 (brolucizumab, -237.8 µm; aflibercept, -196.5 µm; difference, -41.4; 95% CI, -58.9 to -23.8; P < .001). Incidence of intraocular inflammation was 4.0% (14 of 346) in the brolucizumab arm and 2.9% (5 of 171) in the aflibercept arm, incidence of retinal vasculitis was 0.9% (3 of 346) and 0.6% (1 of 171), respectively, and incidence of retinal vascular occlusion was 0.3% (1 of 346) and 0.6% (1 of 171). One participant in the brolucizumab arm had retinal artery occlusion. Conclusions and Relevance: In these study participants with DME, no clinically meaningful differences in visual outcomes were noted between the brolucizumab and aflibercept arms; some superior anatomic improvements were noted in the brolucizumab arm. No new safety concerns were identified. Trial Registration: ClinicalTrials.gov Identifier: NCT03917472.