Synthetic Lethality Beyond BRCA: A Phase I Study of Rucaparib and Irinotecan in Metastatic Solid Tumors With Homologous Recombination-Deficiency Mutations Beyond BRCA1/2.

PURPOSE: Combining poly ADP-ribose polymerase (PARP) and topoisomerase I inhibitors has demonstrated synergistic effects in in vivo models. This phase I trial evaluated rucaparib and irinotecan in metastatic solid tumors with homologous recombination deficiency. METHODS: This study enrolled patients in three cohorts to determine the tolerability and preliminary efficacy of (1) rucaparib 400 mg PO twice a day (days 1-7, 15-21) and irinotecan 65 mg/m2 intravenously once every 2 weeks; (2) rucaparib 400 mg PO twice a day (D1-7, 15-21) and irinotecan 100 mg/m2 once every 2 weeks; and (3) rucaparib 400 mg per os twice a day (D1-7) and irinotecan 100 mg/m2 once every 3 weeks. RESULTS: Twenty patients were enrolled: 95% with previous platinum, 40% with previous irinotecan, and 20% with previous PARP inhibitor. The maximally tolerated was determined as rucaparib 400 mg twice a day days 1-7 and irinotecan 100 mg/m2 once every 3 weeks. Four dose-limiting toxicities (all grade 3-4 neutropenia) occurred during dose escalation with only neutropenia as other grade 3-4 toxicities (25%; grade 3 [n = 3], grade 4 [n = 2]). Treatment-related grade 1-2 adverse events included neutropenia (45%), diarrhea (45%), nausea (40%), and fatigue (30%). Of 17 patients with evaluable disease, six patients (35%) derived clinical benefit (n = 2 with PR, n = 4 with stable disease for over 6 months). Three patients remained on study >1 year: two with ATM mutations (small bowel carcinoma and pancreatic neuroendocrine tumor) and one patient with a PALB2 mutation (primary peritoneal cancer). CONCLUSION: Pulse dosing of rucaparib and once every 3 weeks irinotecan was well tolerated for up to 18 months with durable responses in BRCA-, PALB2-, and ATM-mutated cancers despite progression on previous platinum.

Evidence-based prescribing of opioids after laparotomy: A quality-improvement initiative in gynecologic oncology.

Introduction: Across specialties, surgeons over-prescribe opioids to patients after surgery. We aimed to develop and implement an evidence-based calculator to inform post-discharge opioid prescription size for gynecologic oncology patients after laparotomy. Methods: In 2021, open surgical gynecologic oncology patients were called 2-4 weeks after surgery to ask about their home opioid use. This data was used to develop a calculator for post-discharge opioid prescription size using two factors: 1) age of the patient, 2) oral morphine equivalents (OME) used by patients the day before hospital discharge. The calculator was implemented on the inpatient service from 8/21/22 and patients were contacted 2-4 weeks after surgery to again assess their opioid use at home. Results: Data from 95 surveys were used to develop the opioid prescription size calculator and are compared to 95 post-intervention surveys. There was no difference pre- to post-intervention in demographic data, surgical procedure, or immediate postoperative recovery. The median opioid prescription size decreased from 150 to 37.5 OME (p < 0.01) and self-reported use of opioids at home decreased from 22.5 to 7.5 OME (p = 0.05). The refill rate did not differ (12.6 % pre- and 11.6 % post-intervention, p = 0.82). The surplus of opioids our patients reported having at home decreased from 1264 doses of 5 mg oxycodone tabs in the pre-intervention cohort, to 490 doses in the post-intervention cohort, a 61 % reduction. Conclusions: An evidence-based approach for prescribing opioids to patients after laparotomy decreased the surplus of opioids we introduced into our patients' communities without impacting refill rates.

Exploring the relationship between language, postoperative pain, and opioid use.

BACKGROUND: Racial and ethnic disparities in pain management are well documented. Differences in pain assessment and management by language have not been studied in the postoperative setting in gynecologic surgery. OBJECTIVE: This study aimed to investigate the association between language and immediate postoperative pain management by comparing pain assessments and perioperative opioid use in non-English speakers and English speakers. STUDY DESIGN: This was a retrospective cohort study comparing perioperative outcomes between non-English-speaking patients and English-speaking patients who had undergone a gynecologic oncology open surgery between July 2012 and December 2020. The primary language was extracted from the electronic medical record. Opioid use is expressed in oral morphine equivalents. Proportions are compared using chi-square tests, and mean values are compared using 2-sample t tests. Although interpreter services are widely available in our institution, the use of interpreters for any given inpatient-provider interaction is not documented. RESULTS: Between 2012 and 2020, 1203 gynecologic oncology patients underwent open surgery, of whom 181 (15.1%) were non-English speakers and 1018 (84.9%) were English speakers. There was no difference between the 2 cohorts concerning body mass index, surgical risk score, or preoperative opioid use. Compared with the English-speaking group, the non-English-speaking group was younger (57 vs 54 years old, respectively; P<.01) and had lower rates of depression (26% vs 14%, respectively; P<.01) and chronic pain (13% vs 6%, respectively; P<.01). Although non-English-speaking patients had higher rates of hysterectomy than English-speaking patients (80% vs 72%, respectively; P=.03), there was no difference in the rates of bowel resections, adnexal surgeries, lengths of surgery, intraoperative oral morphine equivalents administered, blood loss, use of opioid-sparing modalities, lengths of hospital stay, or intensive care unit admissions. In the postoperative period, compared with English-speaking patients, non-English-speaking patients received fewer oral morphine equivalents per day (31.7 vs 43.9 oral morphine equivalents, respectively; P<.01) and had their pain assessed less frequently (7.7 vs 8.8 checks per day, respectively; P<.01) postoperatively. English-speaking patients received a median of 19.5 more units of oral morphine equivalents daily in the hospital and 205.1 more units of oral morphine equivalents at the time of discharge (P=.02 and P=.04, respectively) than non-English-speaking patients. When controlling for differences between groups and several factors that may influence oral morphine equivalent use, English-speaking patients received a median of 15.9 more units of oral morphine equivalents daily in the hospital cohort and similar oral morphine equivalents at the time of discharge compared with non-English-speaking patients. CONCLUSION: Patients who do not speak English may be at risk of undertreated pain in the immediate postoperative setting. Language barrier, frequency of pain assessments, and provider bias may perpetuate disparity in pain management. Based on this study's findings, we advocate for the use of regular verbal pain assessments with language-concordant staff or medical interpreters for all postoperative patients.

Roadmap to safety: a single center study of evidence-informed approach to placenta accreta spectrum.

Objective: To assess the impact of an evidence-informed protocol for management of placenta accreta spectrum (PAS). Methods: This was a retrospective cohort study of patients who underwent cesarean hysterectomy (c-hyst) for suspected PAS from 2012 to 2022 at a single tertiary care center. Perioperative outcomes were compared pre- and post-implementation of a standardized Multidisciplinary Approach to the Placenta Service (MAPS) protocol, which incorporates evidence-informed perioperative interventions including preoperative imaging and group case review. Intraoperatively, the MAPS protocol includes placement of ureteral stents, possible placental mapping with ultrasound, and uterine artery embolization by interventional radiology. Patients suspected to have PAS on prenatal imaging who underwent c-hyst were included in the analysis. Primary outcomes were intraoperative complications and postoperative complications. Secondary outcomes were blood loss, need for ICU, and length of stay. Proportions were compared using Fisher's exact test, and continuous variables were compared used t-tests and Mood's Median test. Results: There were no differences in baseline demographics between the pre- (n = 38) and post-MAPS (n = 34) groups. The pre-MAPS group had more placenta previa (95% pre- vs. 74% post-MAPS, p = 0.013) and prior cesarean sections (2 prior pre- vs. 1 prior post-MAPS, p = 0.012). The post-MAPS group had more severe pathology (PAS Grade 3 8% pre- vs. 47% post-MAPS, p = 0.001). There were fewer intraoperative complications (39% pre- vs.3% post-MAPS, p < 0.001), postoperative complications (32% pre- vs.12% post-MAPS, p = 0.043), hemorrhages >1l (95% pre- vs.65% post-MAPS, p = 0.001), ICU admissions (59% pre- vs.35% post-MAPS, p = 0.04) and shorter hospital stays (10 days pre- vs.7 days post-MAPS, p = 0.02) in the post-MAPS compared to pre-MAPS patients. Neonatal length of stay was 8 days longer in the post-MAPS group (9 days pre- vs. 17 days post-MAPS, p = 0.03). Subgroup analyses demonstrated that ureteral stent placement and uterine artery embolization (UAE) may be important steps to reduce complications and ICU admissions. When comparing just those who underwent UAE, patients in the post-MAPS group experienced fewer hemorrhages greater five liters (EBL >5l 43% pre- vs.4% post-MAPS, p = 0.007). Conclusion: An evidence-informed approach to management of PAS was associated with decreased complication rate, EBL >1l, ICU admission and length of hospitalization, particularly for patients with severe pathology.