Hyperthermic intraperitoneal chemotherapy (HIPEC) for the management of primary advanced and recurrent ovarian cancer: a systematic review and meta-analysis of randomized trials.

INTRODUCTION: Ovarian cancer is the most lethal gynecologic malignancy. Although treatment with hyperthermic intraperitoneal chemotherapy (HIPEC) has shown promising results, its role remains elusive. The aim of this study was to assess the comprehensive randomized evidence for the use versus non-use of HIPEC in primary and recurrent ovarian cancer. MATERIALS AND METHODS: The Medline, Embase and Cochrane databases, as well as the European Society for Medical Oncology (ESMO) and American Society of Clinical Oncology (ASCO) conference abstracts of the last 5 years, were scrutinized in January 2022 for randomized, controlled trials that studied the use of HIPEC in ovarian cancer. Overall survival (OS), disease-free survival (DFS) and progression-free survival, as well as post-operative morbidity were the outcomes of interest. This study was reported in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) reporting guideline. RESULTS: Six randomized, controlled trials that randomized 737 patients were included in our analysis; of these, four studies (519 patients) were in primary and two (218 patients) in recurrent settings. In primary ovarian cancer, the combination of HIPEC with interval cytoreductive surgery (CRS) and neoadjuvant chemotherapy significantly improved the 5-year OS [393 patients, risk ratio (RR) = 0.77; 95% confidence interval (CI) 0.67-0.90; P value = 0.001] and DFS (hazard ratio = 0.60; 95% CI 0.41-0.87; P value = 0.008) compared with standard treatment alone. In the absence of neoadjuvant chemotherapy, the use of HIPEC + CRS was not associated with any survival advantage (126 patients, 4-year OS, RR = 0.93; 95% CI 0.57-1.53; P value = 0.781), but the sample size was smaller in this subset. Use of HIPEC in recurrent ovarian cancer did not provide any survival advantage (5-year OS: 218 patients, RR = 0.85; 95% CI 0.45-1.62; P value = 0.626). The risk for grade ≥3 adverse events was similar between HIPEC and no HIPEC (RR = 1.08; 95% CI 0.98-1.18; P value = 0.109). CONCLUSIONS: In primary ovarian cancer the combination of HIPEC with interval CRS and neoadjuvant chemotherapy is a safe option that significantly improved 5-year OS and DFS. Its use in other settings should continue to be considered investigational.

Candidate genetic variants and antidepressant-related fall risk in middle-aged and older adults.

BACKGROUND: Antidepressant use has been associated with increased fall risk. Antidepressant-related adverse drug reactions (e.g. orthostatic hypotension) depend partly on genetic variation. We hypothesized that candidate genetic polymorphisms are associated with fall risk in older antidepressant users. METHODS: The association between antidepressant use and falls was cross-sectionally investigated in a cohort of Dutch older adults by logistic regression analyses. In case of significant interaction product term of antidepressant use and candidate polymorphism, the association between the variant genotype and fall risk was assessed within antidepressant users and the association between antidepressant use and fall risk was investigated stratified per genotype. Secondly, a look-up of the candidate genes was performed in an existing genome-wide association study on drug-related falls in antidepressant users within the UK Biobank. In antidepressant users, genetic associations for our candidate polymorphisms for fall history were investigated. RESULTS: In antidepressant users(n = 566), for rs28371725 (CYP2D6*41) fall risk was decreased in TC/variant allele carriers compared to CC/non-variant allele carriers (OR = 0.45, 95% CI 0.26-0.80). Concerning rs1057910 (CYP2C9*3), fall risk was increased in CA/variant allele carriers compared to AA/non-variant allele carriers (OR = 1.95, 95% CI 1.17-3.27). Regarding, rs1045642 (ABCB1), fall risk was increased in AG/variant allele carriers compared to GG/non-variant allele carriers (OR = 1.69, 95% CI 1.07-2.69). Concerning the ABCB1-haplotype (rs1045642/rs1128503), fall risk was increased in AA-AA/variant allele carriers compared to GG-GG/non-variant allele carriers (OR = 1.86, 95% CI 1.05-3.29). In the UK Biobank, in antidepressant users(n = 34,000) T/variant-allele of rs28371725 (CYP2D*41) was associated with increased fall risk (OR = 1.06, 95% CI 1.01-1.12). G/non-variant-allele of rs4244285 (CY2C19*2) was associated with decreased risk (OR = 0.96, 95% CI 0.92-1.00). CONCLUSION: This is the first study showing that certain genetic variants modify antidepressant-related fall risk. The results were not always consistent across the studies and should be validated in a study with a prospective design. However, pharmacogenetics might have value in antidepressant (de)prescribing in falls prevention.