Efficacy and safety of tivozanib in recurrent, platinum-resistant ovarian, fallopian tube or primary peritoneal cancer, an NCCN phase II trial.

OBJECTIVE: Tivozanib is a potent selective pan-vascular endothelial growth factor receptor tyrosine kinase inhibitor with a long half-life. This study assessed its activity in patients with recurrent, platinum-resistant ovarian, fallopian tube or primary peritoneal cancer (OC). METHODS: This open-label phase II study used a Simon's two-stage design. Eligible patients had recurrent, platinum-resistant OC and measurable or detectable disease. There was no limit on the number of prior regimens. Treatment consisted of tivozanib 1.5 mg orally once daily for 21 days in a 28-day cycle. The primary endpoint was objective response rate (ORR). Secondary endpoints were progression-free survival (PFS), overall survival (OS), and toxicity assessment. RESULTS: Thirty-one patients were enrolled, and 30 were treated. The median age was 59.5 years, and median number of prior regimens was 4 (range 1-9). Twenty-four patients were evaluable for response, and four (16.7%) achieved a partial response (PR; ORR = 16.7%). An additional fourteen (58.3%) patients had stable disease (SD). The clinical benefit rate (PR + SD) was 75.0%, and the median duration of objective response was 5.7 months. For all patients on trial, the median PFS was 4.1 months (95% confidence interval (CI): 1.7-5.8) and OS 8.6 months (95% CI: 5.4-12.5). There were no treatment-related deaths. Serious adverse events occurred in 13.3% of patients and included small intestinal perforation or obstruction and stroke. Grade 3-4 adverse events occurred in 60% of patients, including hypertension (26.7%) and fatigue (10%). CONCLUSIONS: Tivozanib is effective in patients with recurrent OC, with moderate toxicity and no treatment-related deaths, supporting its further development.

Effect of continuous post-operative lidocaine infusion in an enhanced recovery program on opioid use following gynecologic oncology surgery.

OBJECTIVE: To determine the effectiveness of implementing an Enhanced Recovery After Surgery (ERAS) program, including continuous intraoperative and postoperative intravenous (IV) lidocaine infusion, on perioperative opioid use. METHODS: This was a single-institution retrospective pre- post- cohort study. Consecutive patients undergoing planned laparotomy for known or potential gynecologic malignancy were identified after implementation of an ERAS program and compared to a historical cohort. Opioid use was calculated as morphine milligram equivalents (MMEs). Cohorts were compared using bivariate tests. RESULTS: A total of 215 patients were included in the final analysis, 101 patients received surgery before ERAS implementation and 114 received surgery after. A reduction in total opioid use was observed in ERAS patients compared with historical controls (MME 26.5 [9.6-60.8] versus 194.5 [123.8-266.8], p<0.001). Length of stay (LOS) was reduced by 25% in the ERAS cohort (median 3 days, range 2-26, versus 4 days, range 2-18; p<0.001). Within the ERAS cohort, 64.9% received IV lidocaine for the planned 48 hours, and 5.6% had the infusion discontinued early. Within the ERAS cohort, patients who received IV lidocaine infusion used less opioids compared to those who did not (median 16.9, range 5.6-55.1, versus 46.2, range 23.2-76.1; p<0.002). CONCLUSION: An ERAS program including a continuous IV lidocaine infusion as the opioid-sparing analgesic strategy was noted to be safe and effective, leading to decreased opioid consumption and LOS compared with a historic cohort. Additionally, lidocaine infusion was noted to decrease opioid consumption even among patients already receiving other ERAS interventions.

Identification of metabolic pathways contributing to ER+ breast cancer disparities using a machine-learning pipeline.

African American (AA) women in the United States have a 40% higher breast cancer mortality rate than Non-Hispanic White (NHW) women. The survival disparity is particularly striking among (estrogen receptor positive) ER+ breast cancer cases. The purpose of this study is to examine whether there are racial differences in metabolic pathways typically activated in patients with ER+ breast cancer. We collected pretreatment plasma from AA and NHW ER+ breast cancer cases (AA n = 48, NHW n = 54) and cancer-free controls (AA n = 100, NHW n = 48) to conduct an untargeted metabolomics analysis using gas chromatography mass spectrometry (GC-MS) to identify metabolites that may be altered in the different racial groups. Unpaired t-test combined with multiple feature selection and prediction models were employed to identify race-specific altered metabolic signatures. This was followed by the identification of altered metabolic pathways with a focus in AA patients with breast cancer. The clinical relevance of the identified pathways was further examined in PanCancer Atlas breast cancer data set from The Cancer Genome Atlas Program (TCGA). We identified differential metabolic signatures between NHW and AA patients. In AA patients, we observed decreased circulating levels of amino acids compared to healthy controls, while fatty acids were significantly higher in NHW patients. By mapping these metabolites to potential epigenetic regulatory mechanisms, this study identified significant associations with regulators of metabolism such as methionine adenosyltransferase 1A (MAT1A), DNA Methyltransferases and Histone methyltransferases for AA individuals, and Fatty acid Synthase (FASN) and Monoacylglycerol lipase (MGL) for NHW individuals. Specific gene Negative Elongation Factor Complex E (NELFE) with histone methyltransferase activity, was associated with poor survival exclusively for AA individuals. We employed a comprehensive and novel approach that integrates multiple machine learning and statistical methods, coupled with human functional pathway analyses. The metabolic profile of plasma samples identified may help elucidate underlying molecular drivers of disproportionately aggressive ER+ tumor biology in AA women. It may ultimately lead to the identification of novel therapeutic targets. To our knowledge, this is a novel finding that describes a link between metabolic alterations and epigenetic regulation in AA breast cancer and underscores the need for detailed investigations into the biological underpinnings of breast cancer health disparities.