Anticancer drug-induced interstitial lung disease: a critical appraisal of clinical practice guidelines and consensus statements.

Anticancer drug-induced interstitial lung disease (DIILD) has received increasing clinical attention, and the quality of relevant guidance documents has become critical. Our purpose was to assess the quality of documents for anticancer DIILD and summarize the recommendations. Clinical practice guidelines (CPGs) and consensus statements with recommendations were searched in electronic databases, websites of guideline organizations, and professional societies. The quality of documents was assessed using the Appraisal of Guidelines for Research & Evaluation II (AGREE II) methodology, and the specific recommendations were aggregated and compared. A total of 11 documents were eligible, including 6 CPGs and 5 consensus statements, and the quality of AGREE II assessments differed greatly. The domains of scope and purpose and clarity of presentation received the highest median scores, while the stakeholder involvement domain received the lowest score. Recommendations were inconsistent between documents, particularly regarding the selection of steroid regimens. The methodological quality of the guidance documents needs to be enhanced, especially in the domain of stakeholder involvement. Inconsistencies exist in documents, and further discussions among multidisciplinary experts are needed. Particularly, differences in steroid regimens require attentions, and researches on the risks of adverse events and discovery of precise biomarkers are necessary.

Risk of Thromboembolic Events in Cancer Patients Treated with Immune Checkpoint Inhibitors: A Meta-analysis of Randomized Controlled Trials.

BACKGROUND: The association between immune checkpoint inhibitors (ICIs) and thromboembolic events (TEEs) remains controversial. OBJECTIVE: The goal of this study was to assess the risk of major TEEs associated with ICIs. METHODS: We explored ICI-related TEEs in randomized controlled trials available in ClinicalTrials.gov and electronic databases up to June 30, 2021. Meta-analysis was performed by using Peto odds ratios (ORs) with 95% confidence intervals (CIs). RESULTS: A total of 61 studies were included. Patients treated with ICIs had a similar risk of venous thromboembolism (VTE) but a significantly increased risk of arterial thromboembolism (ATE) (Peto OR: 1.58 [95% CI: 1.21-2.06]) compared with non-ICI regimens. Stratified by different regimens, only PD-L1 (programmed cell death ligand 1) inhibitors showed a significant increase in ATE (Peto OR: 2.07 [95% CI: 1.26-3.38]). The incidence of VTE was higher in PD-1/PD-L1 inhibitor and CTLA-4 (cytotoxic T lymphocyte antigen 4) inhibitor combination therapies compared with monotherapies (Peto OR: 2.23 [95% CI: 1.47-3.37]). Stratified by tumor, for pulmonary embolism (PE) and cerebral ATE, the statistically significant results were only seen in lung cancer patients (Peto OR: 1.42 [95% CI: 1.02-1.97]; Peto OR: 2.10 [1.07-4.12]), and for myocardial infarction, the statistically significant result was only seen in other tumor types (Peto OR: 2.66 [95% CI: 1.68-4.20], p < 0.0001). CONCLUSION: There was no significant increase in the overall risk of VTE in patients treated with ICIs; however, special attention should be given to the risk of VTE in PD-1/PD-L1 inhibitor and CTLA-4 inhibitor combination therapy and PE in lung cancer patients. PD-L1 inhibitors were associated with a significant increase in ATE.

Interstitial lung disease in patients treated with Cyclin-Dependent Kinase 4/6 inhibitors: A systematic review and meta-analysis of randomized controlled trials.

BACKGROUND: Cyclin-Dependent Kinase (CDK) 4/6 inhibitors have shown significant clinical activity in cancer patients. However, some concerns regarding rare adverse events (AEs) have occurred including interstitial lung disease (ILD)/pneumonitis, for which data are deficient. The aim of this study was to evaluate the overall incidence and risk of ILD/pneumonitis related to CDK4/6 inhibitors in randomized controlled trials (RCTs). METHODS: Electronic databases and ClinicalTrials.gov were searched from inception to October 1, 2021 for RCTs reporting the occurrence of LD/pneumonitis in cancer patients treated with CDK4/6 inhibitors. Peto odds ratios (Peto ORs) and 95% confidence intervals (CIs) were used to pool the study. RESULTS: 12 RCTs with a total of 16,060 patients were eligible. The overall incidence of all-grade ILD/pneumonitis was 1.6% (131/8407) in the treatment group compared with 0.7% (50/7349) in the control group. CDK4/6 inhibitors significantly increased the risk of all-grade ILD/pneumonitis with a pooled Peto OR of 2.12 (95% CI [1.57, 2.86], P < 0.00001) with no heterogeneity (I2 = 0%, χ2 P = 0.98). A higher incidence of grade 3 or higher ILD/pneumonitis was also observed in the treatment group (0.2%, 16/7087) compared with the control group (0.05%, 3/6617) with a Peto OR of 3.22 (95% CI [1.28, 8.09], P = 0.01) with no heterogeneity (I2 = 0%, χ2 P = 0.62). Two grade 5 pneumonitis were reported in the included studies. Subgroup analyses did not show any significant difference. CONCLUSIONS: The risk of all-grade and grade 3 or higher ILD/pneumonitis was higher in patients treated with CDK4/6 inhibitors compared to controls. The awareness for these rare AEs in the application of CDK4/6 inhibitors should be enhanced. Further studies are required to validate the mechanisms and the risk factors of ILD/pneumonitis with CDK4/6 inhibitors.

Efficacy and safety of PARP inhibitors in patients with BRCA-mutated advanced breast cancer: A meta-analysis and systematic review.

OBJECTIVE: This meta-analysis aimed to investigate the efficacy and safety of poly (adenosine diphosphate-ribose) polymerase (PARP) inhibitors in BRCA-mutated advanced breast cancer patients comprehensively. METHODS: We conducted a systematic literature research through PubMed, the Cochrane Central Register of Controlled Trials (CENTRAL), Embase, China National Knowledge Infrastructure (CNKI), wanfang, China Biology Medicine disc (CBMdisc), and ClinicalTrials.gov from inception to January 2021. Randomized controlled trials (RCTs) with available data comparing PARP inhibitors versus control therapy in BRCA-mutated advanced breast cancer were eligible for analysis. Statistical analyses were performed with Review Manager (RevMan) version 5.4 and R version 4.0.3. RESULTS: 1706 studies were retrieved in total, and 4 RCTs with 1540 patients were eligible for meta-analysis finally. The results showed that progression-free survival (PFS) and overall survival (OS) were significantly improved in germline BRCA-mutated breast cancer patients with PARP inhibitors (HR 0.64, 95% CI [0.56-0.74]; HR 0.86, 95% CI [0.74-0.99], respectively) with no significant heterogeneity across studies (I2 = 22%, χ2 p = 0.28; I2 = 0%, χ2 p = 0.70, respectively). There was no significant difference in the overall adverse events (AEs), grade≥3 AEs and AEs leading to treatment discontinuation between PARP inhibitor arms and control arms (RR 1.01, 95% CI [0.99-1.02]; RR 0.95, 95% CI [0.83-1.09]; RR 1.17, 95% CI [0.87-1.57], respectively). Based on the available data, PARP inhibitors provided comparable or better results than control arms in improving the quality of life in BRCA-mutated advanced breast cancer patients. CONCLUSIONS: PARP inhibitors prolonged PFS and OS among patients with BRCA-mutated advanced breast cancer with tolerable safety and improved quality of life.

Pericardial Toxicities Associated With Immune Checkpoint Inhibitors: A Pharmacovigilance Analysis of the FDA Adverse Event Reporting System (FAERS) Database.

Introdution: Immune checkpoint inhibitors (ICIs) have significantly improved clinical outcomes for a wide range of cancers but can also lead to serious or fatal immune-related adverse events (irAEs). Although ICI-related pericardial toxicities have been reported, the clinical features are not well characterized in real-world studies. Objective: To characterize the main features of ICI-related pericardial toxicities and identify factors associated with death. Methods: Data from January 1, 2011 to March 31, 2020 in the FDA Adverse Event Reporting System database were retrieved for disproportionality analysis. We used the reporting odds ratio and the information component (IC) to evaluate the association between ICIs and pericardial adverse events. Clinical characteristics of patients with ICI-associated pericardial toxicities were collected and compared between fatal and non-fatal groups. The time to onset following different ICI regimens was further investigated. Results: We identified a total of 705 ICI-associated pericardial toxicities which appeared to influence more men (53.90%) than women (36.03%), with a median age of 63 (interquartile range [IQR] 54-69) years. Patients with lung cancer accounted for the largest proportion (55.6%). ICI therapies were detected with pharmacovigilance signals of pericardial toxicities, corresponding to IC025 = 2.11 and ROR 4.87 [4.51-5.25]. Nevertheless, there was a lack of association between anti-CTLA-4 and pericardial toxicities. There was no difference in onset time among all ICI regimens. However, TTO of fatal cases (25 days (interquartile range [IQR] 6-70)) occurred statistically earlier than non-fatal cases (42 days (IQR 12-114), p = 0.003). Conclusion: ICI monotherapy (PD-1/PD-L1 therapy) and combination therapy can lead to pericardial toxicities that can result in serious outcomes and tend to occur early. Early recognition and management of ICI-related pericardial disorders should attract clinical attention. The findings require further clinical surveillance for the quantification.

Thromboembolic events associated with immune checkpoint inhibitors: A real-world study of data from the food and drug administration adverse event reporting system (FAERS) database.

BACKGROUND: Although there have been a few studies reporting thromboembolic events (TEEs) in patients treated with immune checkpoint inhibitors (ICIs), the detailed profile of the TEEs and the prothrombotic effects of ICIs remain mostly unknown. METHODS: Data from January 2004 to December 2019 in the FAERS database were retrieved. We investigated the clinical characteristics of the TEEs and conducted disproportionality analysis by using reporting odds ratios (ROR) to compare ICIs with the full database and other anti-cancer agents. RESULTS: We identified 1855 reports of TEEs associated with ICIs. Affected patients tended to be male (59.68%) and older than 65 (47.12%). The case-fatality rate of the reported TEEs was high (38%). The median time to onset (TTO) of all cases was 42 (interquartile range [IQR] 15-96) days and the median TTO of fatal cases (31 [IQR 13-73] days) was significantly shorter than non-fatal cases (50 [IQR 20-108] days, p = 0.000002). ICIs showed increased risks of VTE (ROR 2.81, 95% CI 2.69-2.95) and ATE (ROR 1.44, 95% CI 1.37-1.52) compared with the full database. Compared with protein kinase inhibitors, ICIs showed an increased risk of VTE (ROR 1.23, 95% CI 1.17-1.29), but only anti-PD-L1 showed an increased risk of cerebral ATE (ROR 1.38, 95% CI 1.08-1.76). Compared with chemotherapy, ICIs showed an increased risk of PE (ROR 1.14, 95% CI 1.07-1.21). CONCLUSIONS: Our study suggested ICIs tend to increase risks of VTE and ATE. The poor clinical outcome and early onset of these events should attract clinical attention.

Effect of polymorphisms of MTHFR in controlled ovarian stimulation: a systematic review and meta-analysis.

OBJECTIVE: Although several studies have reported a potential impact of methylenetetrahydrofolate reductase (MTHFR) polymorphisms on controlled ovarian stimulation (COS), the results remain controversial. The aim of the systematic review and meta-analysis was to evaluate the effect of MTHFR polymorphism on COS outcomes. METHODS: PubMed, Web of Science, Embase, and Cochrane Central Register of Controlled Trials databases were searched up to December 2, 2020. COS clinical outcomes based on gene polymorphisms were included. Two reviewers independently extracted the data. The primary outcome was the number of oocytes retrieved. The secondary outcomes were the number of metaphase II (MII) oocytes, stimulation duration, basal follicle-stimulating hormone (FSH) level, FSH dosage, positive pregnancy test, ongoing pregnancy rate, clinical pregnancy rate, miscarriage rate, and live birth rate. Meta-analysis was performed using a fixed-effect model or random-effect model with Review Man 5.3.5. Mean difference (MD) with 95% confidence intervals (95%CIs) was calculated for continuous outcomes. The quality assessment of included studies was evaluated by using the Newcastle-Ottawa Scale. RESULTS: Eleven studies were included in the systematic review, and seven studies with 2015 participants were included in the meta-analysis. Basal FSH level was significantly lower in CC homozygotes than TT homozygotes (four studies, 867 participants, MD - 0.54, 95%CI - 0.85 to - 0.23, P = 0.0006; I2 = 0%) of MTHFR (rs1801133). FSH dose was significantly fewer in CC homozygotes compared with CT heterogeneous (three studies, 949 participants, MD - 75.78, 95%CI - 135.23 to - 16.33, P = 0.01; I2 = 32%) or CT/TT model (three studies, 1097 participants, MD - 80.18, 95%CI - 135.54 to - 24.81, P = 0.005; I2 = 42%). Differences in the oocytes retrieved and stimulation duration were insignificant. Gene variants on MTHFR (rs1801133) and MTHFR (rs1801131) were reported in ongoing pregnancy rate, clinical pregnancy rate, and live birth rate. CONCLUSION: Studies to date indicate that polymorphisms of MTHFR could influence basal FSH level and FSH dose. The results could be useful to promote clinical practice on COS protocols. Further studies are needed to evaluate the clinical relevance of the multigene combination on COS.

Risk of pneumonitis in cancer patients treated with PARP inhibitors: A meta-analysis of randomized controlled trials and a pharmacovigilance study of the FAERS database.

OBJECTIVE/BACKGROUND: We aimed to evaluate the risk of PARP inhibitors (PARPis) causing pneumonitis in randomized controlled trials (RCTs) and in the real-world practice. METHODS: First, a systematic review based on meta-analysis was conducted. RCTs with available data reporting pneumonitis events for PARPis were eligible for analysis. Second, we conducted a disproportionality analysis based on data from the FDA Adverse Event Reporting System (FAERS) database to characterize the main features of PARPi-related pneumonitis. RESULTS: 16 trials with 5771 patients were included in our meta-analysis. Compared with control arms, PARPis showed a significant increase in the risk of pneumonitis events (Peto OR 2.68 [95% CI 1.31-5.47], p = 0.007) with no heterogeneity (I2 = 0%, χ2p = 0.70). The incidence of pneumonitis across treatment arms was 0.79% (28/3551). In the FAERS database, we identified 84 cases of PARPi-pneumonitis with a fatality rate of 16% (13/79). The median time to event onset was 81 (interquartile range [IQR] 27-131) days and 87% of the adverse events occurred within 6 months. CONCLUSION: PARPis increased the risk of pneumonitis that can result in serious outcomes and tend to occur early. Early recognition and management of PARPi-pneumonitis is of vital importance in clinical practice. The mechanisms and risk factors should be studied further to improve clinical understanding and innovative treatment strategies for these diseases.

The Association Between the Risk of Hypertensive Disorders of Pregnancy and Folic Acid: A Systematic Review and Meta-Analysis.

PURPOSE: Although folic acid (FA) supplementation has been shown to reduce general cardiovascular risks, its impact on hypertensive disorders of pregnancy (HDP) is unclear. We performed a systematic review and meta-analysis to clarify the association between FA and the risk of HDP (pre-eclampsia (PE) and gestational hypertension (GH)). METHODS: PubMed, EmBase, and Cochrane Library were searched up to June 18, 2020, stratified by type of disease, initiation time of FA, form of FA and pre-conception Body Mass Index (BMI). The quality assessment of included studies was evaluated using Newcastle-Ottawa Scale (NOS) for cohort studies and Cochrane Collaboration's Risk of Bias Assessment Tool for randomized controlled trials (RCTs). Between-study heterogeneity was quantified using Cochran's Q-statistic and I2 statistics. Sensitivity analysis was performed by excluding the studies one by one, and publication bias was analyzed using funnel plots. RESULTS: Twenty studies with 359041 patients were identified for inclusion in the meta-analysis which included 3 RCTs and 17 cohort studies. Pooled estimates showed RR of 0.83 (95%CI 0.74-0.93, P=0.0008) for association between low dose FA (LD-FA) and the risk of PE, but LD-FA was not associated with GH (RR 1.05, 95% CI 0.97-1.13, P=0.20). In addition, the results of subgroup analysis showed that post-conception LD-FA had a 31% decreased risk of PE (RR 0.69, 95% CI 0.59-0.80, P<0.00001), and LD-FA in patients with pre-conception BMI<25 kg/m2 had a 32% decreased risk of PE (RR 0.68, 95% CI 0.56-0.81, P<0.0001) Conclusions: LD-FA significantly decreased the risk of PE but not GH, and post-conception LD-FA and pre-conception BMI<25 kg/m2 were considered as protective factors to reduce the risk of PE.