-
BJU International Dec 2023To compare radiographic progression-free survival (rPFS), overall survival (OS), and treatment-emergent adverse events (TEAEs) among patients with metastatic... (Meta-Analysis)
Meta-Analysis Review
Poly(adenosine diphosphate-ribose) polymerase inhibitor combinations in first-line metastatic castrate-resistant prostate cancer setting: a systematic review and meta-analysis.
OBJECTIVES
To compare radiographic progression-free survival (rPFS), overall survival (OS), and treatment-emergent adverse events (TEAEs) among patients with metastatic castrate-resistant prostate cancer (mCRPC) receiving a combination of first-line poly(adenosine diphosphate-ribose) polymerase inhibitors (PARPi) plus androgen receptor axis-targeted agents (ARAT) vs placebo/ARAT.
MATERIALS AND METHODS
We conducted a systematic review/meta-analysis of all published Phase III randomised controlled trials using EMBASE, MEDLINE, and Cochrane (inception until 6 June 2023). Published full-text manuscripts and conference abstracts were inclusion eligible. Study selection/data extraction were independently performed by two authors. The Cochrane Risk-of-Bias 2 Tool was used, and certainty of evidence assessed using the Grading of Recommendations, Assessment, Development, and Evaluations framework. Pooled hazard ratios (HRs) and relative risks, with corresponding confidence intervals (CIs), were generated using random-effects models.
RESULTS
Three trials were identified: PROpel, MAGNITUDE, and TALAPRO-2. Compared to placebo/ARAT, the PARPi/ARAT combination was associated with a 35% rPFS improvement in the overall cohort (HR 0.65, 95% CI 0.56-0.76), with 68%, 45%, and 26% improvements in the BReast CAncer gene 1/gene 2 (BRCA1/2)-mutated (BRCA1/2m; P < 0.001), homologous recombination repair-mutated (HRRm; P < 0.001), and non-HRRm cohorts (P = 0.003), respectively. OS data maturity ranged from 31% to 48%, with overall cohort OS data unavailable from MAGNITUDE. The PROpel/TALAPRO-2 pooled analysis demonstrated a 16% OS improvement in the overall cohort (HR 0.84, 95 CI 0.72-0.98; P = 0.02). OS in the HRRm (HR 0.76, 95% CI 0.61-0.95) and the BRCA1/2m cohorts (HR 0.53, 95% CI 0.18-1.56) were improved, with a higher effect magnitude compared to the overall cohort. This combination was associated with a 45% relative risk increase in Grade ≥3 TEAEs, including 6.22-fold for Grade ≥3 anaemia (31.9% vs 4.9%).
CONCLUSIONS
The addition of PARPi to ARAT in the first-line mCRPC setting is associated with rPFS benefits across subgroups, with the greatest magnitude of benefit in BRCA1/2m patients. OS benefits remain inconsistent irrespective of HRRm status, with significant increases in Grade ≥3 TEAEs, particularly anaemia. Currently, we suggest this combined approach be selectively offered to HRRm patients, preferentially BRCA1/2m.
Topics: Male; Humans; BRCA1 Protein; Ribose; Prostatic Neoplasms, Castration-Resistant; BRCA2 Protein; Anemia; Adenosine Diphosphate
PubMed: 37461140
DOI: 10.1111/bju.16130 -
PloS One 2023Glaucoma is a leading cause of irreversible blindness worldwide. Retinal ganglion cells (RGC), the neurons that connect the eyes to the brain, specifically die in...
PURPOSE
Glaucoma is a leading cause of irreversible blindness worldwide. Retinal ganglion cells (RGC), the neurons that connect the eyes to the brain, specifically die in glaucoma, leading to blindness. Elevated intraocular pressure (IOP) is the only modifiable risk factor, however, many patients progress despite excellent IOP control. Thus, alternative treatment strategies to prevent glaucoma progression are an unmet need. Citicoline has demonstrated neuroprotective properties in central neurodegenerative diseases. However, conclusive evidence of the effect of citicoline on glaucoma progression is missing. This systematic review investigates first-time the therapeutic potential of citicoline in glaucoma patients.
METHODS
The present study was conducted according to the PRISMA 2020 statement. PubMed, Web of Science, Google Scholar, and Embase were accessed in July 2023 to identify all clinical studies investigating the efficacy of citicoline on IOP, the mean deviation of the 24-2 visual field testing (MD 24-2), retinal nerve fibre layer (RNFL), and the pattern electroretinogram (PERG) P50-N95 amplitude in glaucoma patients. The risk of bias was assessed using the Review Manager 5.3 software (The Nordic Cochrane Collaboration, Copenhagen) and the Risk of Bias in Non-randomised Studies of Interventions (ROBINS-I) tool.
RESULTS
Ten studies were eligible for this systematic review, including 424 patients. The mean length of the follow-up was 12.1 ± 11.6 months. The overall risk of bias was low to moderate. The mean age of the patients was 56.7 years. There were no significant differences in the IOP, MD 24-2, RNFL, or PERG P50-N95 amplitude between patients receiving citicoline and the control group. There was no improvement from baseline to the last follow-up in IOP, MD 24-2, RNFL, or PERG P50-N95 amplitude.
CONCLUSION
There is a lack of sufficient evidence to support that citicoline slows the progression of glaucoma.
Topics: Humans; Middle Aged; Cytidine Diphosphate Choline; Glaucoma, Open-Angle; Intraocular Pressure; Glaucoma; Retinal Ganglion Cells; Blindness
PubMed: 37768938
DOI: 10.1371/journal.pone.0291836 -
Medicina (Kaunas, Lithuania) Dec 2023: To identify the most frequently reported predictive factors for the persistency of pregnancy-related pelvic girdle pain (PPGP) at 3-6 months after childbirth in women... (Meta-Analysis)
Meta-Analysis Review
: To identify the most frequently reported predictive factors for the persistency of pregnancy-related pelvic girdle pain (PPGP) at 3-6 months after childbirth in women with PPGP alone or PPGP in association with pregnancy-related lower back pain (PLBP). : Eligibility criteria: Two authors independently selected studies excluding PPGP determined by a specific, traumatic, gynecological/urological cause or isolated PLBP and studies that did not include the presence/absence of PPGP as the the primary outcome. We, instead, included studies with an initial assessment in pregnancy (within 1 month of delivery) and with a follow-up of at least 3 months after delivery. : The research was performed using the databases of Medline, Cochrane, Pedro, Scopus, Web of Science and Cinahl from December 2018 to January 2022, following the indications of the PRISMA statement 2021 and the MOOSE checklist. It includes observational cohort studies in which data were often collected through prospective questionnaires (all in English). : Two independent authors performed evaluations of the risk of bias (ROB) using the quality in prognostic studies (QUIPS) tool. : An in-depth qualitative analysis was conducted because, due to a high degree of heterogeneity in the data collection of the included studies and a lack of raw data suitable for quantitative analysis, it was not possible to carry out the originally planned meta-analyses for the subgroups. : The research process led to the inclusion of 10 articles which were evaluated using the QUIPS tool: 5 studies were evaluated as low ROB and 5 were evaluated as moderate ROB. High levels of pain in pregnancy, a large number of positive provocation tests, a history of lower back pain and lumbo-pelvic pain, high levels of disability in pregnancy, neurotic behavior and high levels of fear-avoidance belief were identified as strong predictors of long-term PPGP, while there was weak or contradictory evidence regarding predictions of emotional distress, catastrophizing and sleep disturbances. : The impossibility of carrying out the meta-analysis by subgroups suggests the need for further research with greater methodological rigor in the acquisition of measures based on an already existing PPGP core predictors/outcome sets.
Topics: Pregnancy; Humans; Female; Pelvic Girdle Pain; Low Back Pain; Prospective Studies; Pregnancy Complications; Surveys and Questionnaires
PubMed: 38138226
DOI: 10.3390/medicina59122123 -
Phytochemistry Jul 2024Cembranoids and labdanes are two important types of diterpenes in tobacco (Nicotiana genus) that are predominantly found in the leaf and flower glandular trichome... (Review)
Review
Cembranoids and labdanes are two important types of diterpenes in tobacco (Nicotiana genus) that are predominantly found in the leaf and flower glandular trichome secretions. This is the first systematic review of the biosynthesis, chemical structures, bioactivities, and utilisation values of cembranoid and labdane diterpenes in tobacco. A total of 131 natural cembranoid diterpenes have been reported in tobacco since 1962; these were summarised and classified according to their chemical structure characteristics as isopropyl cembranoids (1-88), seco-cembranoids (89-103), chain cembranoids (104-123), and polycyclic cembranoids (124-131). Forty natural labdane diterpenes reported since 1961 were also summarised and divided into epoxy side chain labdanes (132-150) and epoxy-free side chain labdanes (151-171). Tobacco cembranoid and labdane diterpenes are both formed via the methylerythritol 4-phosphate pathway and are synthesised from geranylgeranyl diphosphate. Their biosynthetic pathways and the four key enzymes (cembratrienol synthase, cytochrome P450 hydroxylase, copalyl diphosphate synthase, and Z-abienol cyclase) that affect their biosynthesis have been described in detail. A systematic summary of the bioactivity and utilisation values of the cembranoid and labdane diterpenes is also provided. The agricultural bioactivities associated with cembranoid and labdane diterpenes include antimicrobial and insecticidal activities as well as induced resistance, while the medical bioactivities include cytotoxic and neuroprotective activities. Further research into the cembranoid and labdane diterpenes will help to promote their development and utilisation as plant-derived pesticides and medicines.
Topics: Diterpenes; Trichomes; Nicotiana; Molecular Structure; Humans
PubMed: 38697243
DOI: 10.1016/j.phytochem.2024.114117 -
Expert Review of Anticancer Therapy 2024Poly(adenosine diphosphate [ADP]-ribose) polymerase inhibitors (PARPi) treatment for ovarian cancer (OC) are ever-changing. This study aimed to compare the efficacy and... (Comparative Study)
Comparative Study Meta-Analysis Review
Comparison of poly (ADP-ribose) polymerase inhibitors (PARPis) as maintenance therapy for newly-diagnosed and platinum-sensitive recurrent ovarian cancer with mutational status: a systematic review and network meta-analysis.
BACKGROUND
Poly(adenosine diphosphate [ADP]-ribose) polymerase inhibitors (PARPi) treatment for ovarian cancer (OC) are ever-changing. This study aimed to compare the efficacy and overall safety of available PARPi as maintenance therapy for BRCA mutation status in patients with newly diagnosed and platinum-sensitive recurrent (PSR) OC patients.
RESEARCH DESIGN AND METHODS
Relevant RCTs were systematically retrieved from PubMed and Embase until 31 May 2022. Progression-free survival (PFS) and overall survival (OS) based on mutation status and adverse events (AEs) regardless of mutation were efficacy and safety endpoints.
RESULTS
In newly diagnosed BRCAm-OC patients, olaparib (HR: 0.33; 95% confidence interval [CI]: 0.25, 0.43) and other PARPis [niraparib (HR: 0.40; 95% CI: 0.29, 0.55), rucaparib (HR: 0.40; 95% CI: 0.21, 0.76) and veliparib (HR: 0.44; 95% CI: 0.28, 0.69)] had a statistically significant effect on PFS versus placebo. In BRCAm-PSROC patients, Olaparib exhibited significant benefit (HR: 0.69; 95% CI: 0.54, 0.88) for OS compared to other PARPis. In BRCAwt-PSR OC patients, Olaparib showed a favorable OS benefit than other PARPis (HR: 0.84; 95% CI: 0.57,1.22). Overall, safety profile of all PARPis was acceptable.
CONCLUSION
All PARPis showed significant benefit, with olaparib showing greater benefit in newly diagnosed and PSR OC women.
REGISTRATION
CRD42021288932.
Topics: Female; Humans; Adenosine Diphosphate; Carcinoma, Ovarian Epithelial; Neoplasm Recurrence, Local; Network Meta-Analysis; Ovarian Neoplasms; Poly(ADP-ribose) Polymerase Inhibitors; Poly(ADP-ribose) Polymerases; Ribose
PubMed: 38174379
DOI: 10.1080/14737140.2023.2298832 -
American Journal of Clinical Oncology Jun 2024Breast cancer is the second leading cause of women's cancer deaths after lung cancer. Risk factors such as environment, lifestyle, and genetics contribute to its...
Efficacy and Safety of BRCA-targeted Therapy (Polyadenosine Diphosphate-ribose Polymerase Inhibitors) in Treatment of BRCA-mutated Breast Cancer: A Systematic Review and Meta-analysis.
Breast cancer is the second leading cause of women's cancer deaths after lung cancer. Risk factors such as environment, lifestyle, and genetics contribute to its development, including mutation in the breast cancer (BRCA) gene. Polyadenosine diphosphate-ribose polymerase inhibitors (PARPi) target these mutations, benefiting patients with advanced cancers. This review summarizes PARPi' safety and efficacy in the treatment of BRCA-mutated breast cancer. PubMed, The Cochrane Library for Clinical Trials, and Science Direct, were searched for articles from inception to April 2024. Eligible articles were analyzed, and data were extracted for meta-analysis using RevMan 5.4 software with a random-effect model. Out of 430 articles identified from online databases, only 6 randomized control trials including 3610 patients were included in the analysis. PARPi therapy improved progression-free survival (hazard ratio: 0.64; 95% CI: 0.56, 0.73; P< 0.00001) and overall survival (hazard ratio: 0.84; 95% CI: 0.73, 0.98 P = 0.02), according to the analysis. In our safety analysis, the risk of adverse events was not statistically different between PARPi versus chemotherapy (relative risk [RR]: 1.08; 95% CI: 0.44, 2.68; P = 0.86), and combined PARPi and standard chemotherapy (RR: 1.00; 95% CI: 0.93, 1.07; P = 0.80). The only statistically significant difference was observed in anemia, where PARPi increased the risk of developing anemia compared with standard chemotherapy (RR: 6.17; 95% CI: 2.44, 15.58; P = 0.0001). In BRCA-mutated breast cancer, PARPi treatment shows better overall survival and progression-free survival compared with standard chemotherapy or placebo. Furthermore, PARPi, either alone or in combination therapy, does not increase the risk of adverse events in these patients, as per the meta-analysis.
PubMed: 38899756
DOI: 10.1097/COC.0000000000001120 -
AIDS Education and Prevention :... Oct 2023Prevalence of human immunodeficiency virus (HIV) is higher in transgender populations. Pre-exposure prophylaxis (PrEP) intervention is successful in reducing HIV...
Prevalence of human immunodeficiency virus (HIV) is higher in transgender populations. Pre-exposure prophylaxis (PrEP) intervention is successful in reducing HIV acquisition. We aimed to investigate the adherence to oral PrEP by HIV-negative transgender women (TW). We followed the and the PRISMA Statement. We searched in WoS, OVID, Scopus, MEDLINE, and the Cochrane Central Register of Controlled Trials databases. Participation and adherence to the intervention were low for TW compared to cisgender men who have sex with men (cMSM), and it was measured mostly by self-report (72.7%) or tenofovir-diphosphate/emtricitabine triphosphate dried blood spot (45.5%). Awareness should increase and the effect of oral PrEP on gender-affirming hormone therapy should be explained to TW at the beginning of the trials. One limitation is that our sample size was dominated by two Thai studies with TW sex workers. Future studies should evaluate adherence to new PrEP modalities.
Topics: Male; Humans; Female; HIV Infections; Tenofovir; Homosexuality, Male; Pre-Exposure Prophylaxis; Transgender Persons; Sexual and Gender Minorities; Anti-HIV Agents; Medication Adherence
PubMed: 37843906
DOI: 10.1521/aeap.2023.35.5.362 -
Ontario Health Technology Assessment... 2023Ovarian cancer affects the cells of the ovaries, and epithelial cancer is the most common type of malignant ovarian cancer. The homologous recombination repair pathway...
Homologous Recombination Deficiency Testing to Inform Patient Decisions About Niraparib Maintenance Therapy for High-Grade Serous or Endometrioid Epithelial Ovarian Cancer: A Health Technology Assessment.
BACKGROUND
Ovarian cancer affects the cells of the ovaries, and epithelial cancer is the most common type of malignant ovarian cancer. The homologous recombination repair pathway enables error-free repair of DNA double-strand breaks. Damage of key genes associated with this pathway leads to homologous recombination deficiency (HRD), which results in unrepaired DNA and can lead to cancer. Tumours with HRD are believed to be sensitive to treatment with poly-adenosine diphosphate (ADP)-ribose polymerase (PARP) inhibitors, such as niraparib. We conducted a health technology assessment to evaluate the clinical utility and cost-effectiveness of HRD testing to inform patient decisions about the use of niraparib maintenance therapy for patients with high-grade serous or endometrioid epithelial ovarian cancer. We also evaluated the efficacy and safety of niraparib maintenance therapy in patients with HRD or homologous recombination proficiency (HRP), the cost-effectiveness of HRD testing, the budget impact of publicly funding HRD testing, and patient preferences and values.
METHODS
We performed a systematic literature search of the clinical evidence. We assessed the risk of bias of each included study using the Cochrane risk-of-bias tool for randomized trials version 2, and the quality of the body of evidence according to the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) Working Group criteria. We performed a systematic economic literature search and conducted a cost-utility analysis with a 5-year time horizon from a public payer perspective. We also analyzed the budget impact of publicly funding HRD testing in people with ovarian cancer in Ontario. We performed a literature search for quantitative evidence of patient and provider preferences with respect to HRD testing and maintenance therapy with PARP inhibitors. To contextualize the potential value of HRD testing, we spoke with people with ovarian cancer.
RESULTS
The clinical evidence review included two studies in high-grade epithelial ovarian cancer (one in patients with newly diagnosed advanced cases and one in patients with recurrent cancer). The studies evaluated niraparib maintenance therapy compared with no maintenance therapy and used HRD testing to group patients according to HRD status. Compared to placebo, niraparib maintenance therapy improved progression-free survival in patients with newly diagnosed and recurrent ovarian cancer, and in tumours with HRD or HRP (GRADE: High), but the studies did not compare the results between the HRD and HRP groups. The frequency of adverse events was higher in the niraparib group. We identified no studies that evaluated the clinical utility of HRD testing.We conducted a primary economic evaluation to evaluate the cost-effectiveness of HRD testing for people with newly diagnosed ovarian cancer in an Ontario setting. Our analysis used a 5-year time horizon. HRD testing (for all eligible people or only for people with wild type) resulted in a lower proportion of patients receiving niraparib maintenance therapy, leading to lower costs and fewer quality-adjusted life-years (QALYs). The average total cost per patient was $131,375 for no HRD testing, $126,867 for HRD testing only in people with wild type, and $127,746 for HRD testing in all eligible people. The average total QALYs per patient were 2.087 for no HRD testing, 1.971 for HRD testing only in people with wild type, and 1.971 for HRD testing in all eligible people. Our budget impact analysis suggested that assuming a high uptake rate, publicly funding HRD testing for people with newly diagnosed ovarian cancer would lead to a total saving of $9.00 million (if HRD testing were funded for all) to $12.67 million (if HRD testing were funded for people with wild type) over the next 5 years. Publicly funding HRD testing for people with recurrent cancer would lead to a total saving of $16.31 million (if HRD testing were funded for all) to $21.67 million (if HRD testing were funded for people with wild type) over the next 5 years.We identified no studies that evaluated quantitative preferences for HRD testing. Based on two studies that evaluated patients and oncologists' preferences for maintenance therapy with a PARP inhibitor in the recurrent setting, a decrease in moderate to severe adverse events was more important for patients than an improvement in progression-free survival; however, improvement in progression-free survival was more important for oncologists. Both patients and oncologists accepted some trade-offs between efficacy and safety. The people with ovarian cancer we spoke with demonstrated a shared value for access to information, prevention of cancer recurrence, and overall survival with minimal adverse effects. This was consistent with findings from another survey in patients with ovarian cancer and at least one episode of recurrence, which suggest that patients prioritize treatment benefit over some treatment adverse events in the context of niraparib maintenance therapy. Interviewees also emphasized the importance of the patient-doctor partnership, access to local health care services, and patient education.
CONCLUSIONS
In patients with newly diagnosed (advanced) or recurrent high-grade serous or endometrioid ovarian cancer, niraparib maintenance therapy improved progression-free survival compared with no maintenance therapy in tumours with HRD or HRP (GRADE: High). Because we identified no studies on the clinical utility of HRD testing, we cannot comment on how it would affect patient decisions and clinical outcomes.Over a 5-year time horizon, HRD testing for people with wild type could save $4,509 per person and lead to a loss of 0.116 QALY. The findings of our economic analyses are dependent on assumptions about the use of niraparib following HRD testing. We estimate that publicly funding HRD testing would lead to a total saving of $9 million to $12.67 million for newly diagnosed cancer, and a total saving of $16.31 million to $21.67 million for recurrent cancer over 5 years, assuming the use of niraparib maintenance therapy would be reduced following HRD testing.Patients prioritized decreasing the risk of moderate to severe adverse events of maintenance therapy with PARP inhibitors over improving progression-free survival, and oncologists prioritized improving progression-free survival over decreasing the risk of moderate to severe adverse events. However, both patients and oncologists were open to accepting certain trade-offs between treatment efficacy and toxicity. The people we interviewed, who had lived experience with ovarian cancer and genetic testing, valued the potential clinical benefits of HRD testing for themselves and their family members. They emphasized patient education as an important consideration for public funding in Ontario.
Topics: Humans; Female; Carcinoma, Ovarian Epithelial; Technology Assessment, Biomedical; Poly(ADP-ribose) Polymerase Inhibitors; Carcinoma, Endometrioid; Ovarian Neoplasms
PubMed: 37637244
DOI: No ID Found -
World Journal of Oncology Dec 2023The emergence of olaparib, a poly (adenosine diphosphate (ADP)-ribose) polymerase (PARP) inhibitor to treat metastatic castration-resistant prostate cancer (mCRPC),...
BACKGROUND
The emergence of olaparib, a poly (adenosine diphosphate (ADP)-ribose) polymerase (PARP) inhibitor to treat metastatic castration-resistant prostate cancer (mCRPC), created a measurable clinical question on whether the agent positively influences the treatment outcomes and acceptable safety factors. The objective was to elaborate on the efficacy and safety of olaparib-added regimens in treating mCRPC patients as compared to the established guideline.
METHODS
The literature search was performed on several scientific databases, e.g., PubMed, Cochrane, and ScienceDirect, by applying the Boolean Term method. Statistical and risk of bias (RoB) analyses were calculated through RevMan 5.4.1. to investigate our outcomes, i.e., progression-free survival (PFS) and overall survival (OS) with the reported adverse effects (AEs). These outcomes were presented in hazard ratio (HR) and risk ratio (RR).
RESULTS
Three trials consisting of 1,325 individuals with comparable baseline characteristics were investigated. The meta-analysis showed that introducing olaparib into the regimens significantly improved the PFS (HR 0.59 (0.48 - 0.73); P < 0.05), which disclosed even better outcomes among mutated homologous recombinant repair (HRR) and ataxia-telangiectasia mutated (ATM) gene (HR 0.43 (0.30 - 0.62); P < 0.05) in 95% confidence interval (CI). Furthermore, similar outcomes were observed in OS analysis (HR 0.81 (0.67 - 0.99); P < 0.05), despite olaparib group disclosed higher AEs rate with insignificant difference in mortality rate.
CONCLUSION
The efficacy and safety of olaparib-added regimens in mCRPC patients need to be explored more extensively in trials because they are beneficial, particularly among -mutated individuals.
PubMed: 38022404
DOI: 10.14740/wjon1685