Ferric derisomaltose and Outcomes in the Recovery of Gynecologic oncology: ERAS (Enhanced Recovery After Surgery) (FORGE) - a protocol for a pilot randomised double-blinded parallel-group placebo-controlled study of the feasibility and efficacy of intravenous ferric derisomaltose to correct preoperative iron-deficiency anaemia in patients undergoing gynaecological oncology surgery.

INTRODUCTION: Iron-deficiency anaemia is common in gynaecological oncology patients. Blood transfusions are immunosuppressive and carry immediate and long-term risks. Oral iron replacement remains the standard of care but requires prolonged treatment courses associated with gastrointestinal side effects, poor compliance and variable absorption in cancer patients. Intravenous iron has been shown to decrease the need for allogeneic blood transfusion in gynaecological oncology patients undergoing chemotherapy, but the efficacy of this treatment in the preoperative period is unknown. The goal of this pilot study is to determine the effect of intravenous ferric derisomaltose on preoperative haemoglobin in patients undergoing surgery for gynaecological malignancy. METHODS AND ANALYSIS: We will conduct a pilot single-centre, parallel-arm randomised controlled trial of intravenous ferric derisomaltose versus placebo among consenting patients with iron-deficiency anaemia having elective major surgery on the gynaecological oncology service. Patients, clinicians and outcome assessors will be blinded. The intervention consists of a single infusion of 500-1000 mg of intravenous ferric derisomaltose administered a minimum of 21 days prior to the planned operation. The primary outcome is mean preoperative haemoglobin concentration measured 0-3 days prior to surgery in patients receiving intravenous ferric derisomaltose compared with those receiving placebo. Secondary outcomes include the following: change in haemoglobin concentration, postoperative haemoglobin concentration, perioperative blood transfusion rates, patient-reported quality of life scores (Quality of Recovery 15, Modified Short Form 36 v1, EuroQol 5-dimension 5-level and Functional Assessment of Cancer Therapy - Anaemia), surgical site infection, complication rates, length of hospital stay and readmission rate. Analyses will follow intention-to-treat principles for all randomised participants. All patients will be followed up to 60 days following surgery. ETHICS AND DISSEMINATION: Ethical approval has been granted by Health Research Ethics Board of Alberta (Project ID: HREBA.CC-22-0187) and Health Canada (HC6-024-c264013). Results will be disseminated through presentation at scientific conferences, peer-reviewed publication and social and traditional media. TRIAL REGISTRATION NUMBER: NCT05407987.

Effect of transversus abdominis plane block on postoperative outcomes in gynecologic oncology patients managed on an Enhanced Recovery After Surgery pathway.

OBJECTIVES: To characterize the effect of transversus abdominis plane (TAP) blocks on post-operative outcomes in patients undergoing laparotomy for gynecologic malignancy. METHODS: This retrospective cohort study assessed patients undergoing laparotomy in 2016-2017 and 2020 in Alberta, Canada. The primary outcome was opioid consumption in oral morphine milligram equivalent (MME). Secondary outcomes included maximum pain scores, length of stay, and patient-controlled analgesia (PCA) use. Outcomes were compared using t-test with subgroup analysis by NSAID use. Multivariate regression modelling was performed for potential confounders. RESULTS: Data was collected on 956 patients; 828 received a TAP block, 128 did not. Opioid use in the first 24 h was lower in the TAP block group (35.9 mg MME vs 44.5 mg MME, p = 0.0294), without any increase in pain scores, this did not remain significant after regression analysis. Patients with TAP blocks had significant reduced mean length of stay (3.2 days vs. 5.0 days, p < 0.0001), and PCA use (19.9% vs. 56.25%, p < 0.0001). On subgroup analysis of patients that did not receive NSAIDs (n = 160), mean opioid use was decreased in those patients with TAP blocks compared to those without TAP blocks in the first 24 h (36.1 mg vs. 61.2 mg, p = 0.0017), and at 24 to 48 h (16.3 mg vs. 51.0 mg, p < 0.0001). CONCLUSIONS: Surgeon-administered TAP blocks were associated with decreased length of stay and post-operative opioid use in patients not receiving scheduled NSAIDs. This decrease in opioid use was not associated with any increase in average or maximum pain scores.

Thoracic epidural analgesia as part of an enhanced recovery program in gynecologic oncology: a prospective cohort study.

OBJECTIVE: To evaluate the safety and the effectiveness of thoracic epidural analgesia as part of the enhanced recovery after surgery (ERAS) multimodal analgesic protocol in patients with gynecologic oncology who have undergone laparotomy for suspected or confirmed malignancy. METHODS: We conducted a prospective cohort study, following an enhanced recovery after surgery pathway, among patients who had undergone laparotomy for confirmed or suspected gynecological malignancy between January 2020 and September 2021. All patients who underwent laparotomy at the gynecologic oncology department for the aforementioned reason during that time were considered eligible. Patients (n=217) were divided into two groups: epidural (n=118) and non-epidural (n=99) group. Both groups were treated with the standard ERAS departmental analgesic protocol. The primary outcomes were length of hospital stay, complications, and readmission rates. RESULTS: Data from 217 patients (epidural group, n=118 vs non-epidural group, n=99) with median age of 61 years (IQR 53-68) were analyzed. The most common type of cancer was of ovarian origin (85/217, 39.2%, p=0.055) and median (Aletti) surgical complexity score was 3 (p=0.42). No differences were observed in the patients' demographics, clinical, and surgical characteristics. Primarily, median length of stay was 4 days in both groups with statistically significant lower IQR in the epidural group (3-5 vs 4-5, p=0.021). Complication rates were more common in the non-epidural group (38/99, 38.3% vs 36/118, 30.5%, p<0.001) with similar rates of grade III (p=0.51) and IV (0%) complications and readmission rates (p=0.51) between the two groups. Secondarily, the epidural group showed lower pain scores (p<0.001) on the day of surgery and in the first post-operative day (p<0.001), higher mobilization rates on the day of surgery (94.1% vs 57.6%, p<0.001), faster removal of urinary catheter (p<0.001), shorter time to flatus (p<0.001), and less nausea on the day of surgery (p<0.001). CONCLUSION: In this study we showed that thoracic epidural analgesia, when used as part of an ERAS protocol, is safe and offers more favorable pain relief along with a number of additional benefits, improving the peri-operative experience of patients with gynecologic cancer.

Outcomes of Enhanced Recovery after Surgery (ERAS) in Gynecologic Oncology: A Review.

Enhanced Recovery After Surgery (ERAS) is a global surgical quality improvement program that started in colorectal surgery and has now expanded to numerous specialties, including gynecologic oncology. ERAS guidelines comprise multidisciplinary, evidence-based recommendations in the preoperative, intraoperative, and postoperative period; these interventions broadly encompass patient education, anesthetic choice, multimodal pain control, avoidance of unnecessary drains, maintenance of nutrition, and prevention of emesis. Implementation of ERAS has been shown to be associated with improved clinical outcomes (length of hospital stay, complications, readmissions) and cost. Marx and colleagues first demonstrated the feasibility of ERAS in gynecologic oncology in 2003; since then, over 30 comparative studies and 4 guidelines have been published encompassing major gynecologic surgery, cytoreductive surgery, and vulvar/vaginal surgery. Implementation of ERAS in gynecologic oncology has been demonstrated to provide improvements in length of stay, complications, cost, opioid use, and patient satisfaction. Increased compliance with ERAS guidelines has been associated with greater improvement in outcomes.

Aplicación del programa ERAS® como una política de salud pública en el sistema de salud de Alberta, Canadá / ERAS® as a public health policy: Implementation in the Alberta Health System

RESUMEN El protocolo de recuperación optimizada Enhanced Recovery After Surgery (ERAS®) se puso en marcha a partir de 2013 en el sistema de salud de Alberta, un sistema estatal de cobertura médica totalmente financiado con fondos provinciales. Su aplicación en cirugía colorrectal en múltiples centros provincia les disminuyó la incidencia de complicaciones en un 12% y redujo la estancia hospitalaria en un día. Posteriormente, la introducción del programa en ginecología oncológica redujo las complicaciones postoperatorias en un 17% y la duración de la estancia en 2 días en los procedimientos quirúrgicos complejos. Se estima que la ejecución del programa produjo un ahorro neto de 7,22 millones de dóla res canadienses (CAD) en 5 años para la provincia, con un rendimiento de la inversión de 1,05 a 7,31 dólares por cada dólar invertido en el proyecto. La participación de los pacientes permitió que el pro grama tuviera éxito, y el apoyo, la educación y la atenuación del estrés de los pacientes se identificaron como los componentes principales del éxito. El conocimiento y la motivación de los profesionales sani tarios fueron esenciales para garantizar el cumplimiento continuo de las recomendaciones del progra ma ERAS. La educación de los profesionales sanitarios y la demostración de la mejora de los resultados de los pacientes mediante supervisiones es una forma de garantizar que los profesionales sanitarios sigan motivados. Es esencial contar con líderes en el sistema de salud para proporcionar un mensaje coherente y apoyar las iniciativas. El liderazgo también es importante entre los médicos y coordina dores de enfermería para garantizar el cumplimiento y la integración adecuada de la recuperación optimizada en la práctica diaria. La aplicación del programa ERAS en un sistema de salud unificado ha mejorado los resultados de los pacientes y ahorrado recursos. Se está investigando la posibilidad de ampliar el programa a los hospitales comunitarios y a todos los ámbitos quirúrgicos.

ABSTRACT Enhanced Recovery After Surgery (ERAS®) was implemented across Alberta Health Services, a single payer publicly funded provincial health system starting in 2013. Implementation across multiple provincial sites in colorectal surgery reduced postoperative complications by 12% and median length of stay by one day. Subsequent implementation in gynecologic oncology reduced postoperative complications by 17% and length of stay by 2 days in high complexity surgery. Implementation has had an estimated net savings in the province of $7.22 million Canadian dollars (CAD) over 5 years with a return on investment of $1.05 to $7.31 for every dollar invested in the project. Patient involvement enabled success of the program, with support, education, and mitigation of patient stress identified as key components for success. Provider knowledge and motivation were essential to ensure ongoing compliance with ERAS guidelines. Provider education, and demonstration of improvement in patient outcomes using audit is one method to ensure continued motivation from care providers. System-level leadership is essential to provide consistent messaging and support for initiatives, while provider-level leadership in the form of physician champions and nurse coordinators ensures compliance and appropriate integration of ERAS into daily practice. Implementation of ERAS across a unified health care system has improved patient outcomes while saving resources. Further research into expansion of the program to community hospitals and all surgical domains is underway.

Treatment Tolerance and Side Effects of Intraperitoneal Carboplatin and Dose-Dense Intravenous Paclitaxel in Ovarian Cancer.

OBJECTIVE: To describe the frequency of clinically significant side effects associated with adjuvant intraperitoneal (IP) carboplatin and intravenous (IV) dose-dense paclitaxel chemotherapy for epithelial ovarian cancer (EOC). METHODS: Patients with stage II to IV EOC who underwent upfront cytoreductive surgery followed by adjuvant IP carboplatin (AUC 6) every 3 weeks with IV paclitaxel weekly at 80 mg/m2 were included. Side effects and the resulting changes in treatment are presented using univariate analysis and compared to major phase III RCTs. RESULTS: Between March 2013 and October 2015, 49 patients comprising 289 cycles of chemotherapy were included in the analysis; 43 patients (87.8%) completed six cycles of chemotherapy and 38 (77.6%) completed six cycles of IP carboplatin. Treatment was discontinued early due to neuropathy (5/49) and disease progression (1/49). Carboplatin IV was substituted due to port access (3/49) and poor postoperative performance status (3/49). Neutropenia occurred in 16 patients (32.7%). Fourteen patients (28.6%) required red blood cell transfusion. Thrombocytopenia affected nine patients (18.4%). Infection delaying treatment occurred in five patients (10.4%). Gastrointestinal and renal toxicity occurred in four (8.1%) and one patient (2.0%), respectively. Four patients experienced a taxane reaction. No patients experienced ototoxicity, fistula formation, chemotherapy leakage, or severe abdominal pain. CONCLUSION: Carboplatin IP and weekly IV paclitaxel was well-tolerated with a side-effect profile similar to or better than previously published traditional treatment regimens.

Negative modulation of invariant natural killer T cell responses to glycolipid antigens by p38 MAP kinase.

Invariant natural killer T (iNKT) cells are CD1d-restricted, glycolipid-reactive lymphocytes with potent immunoregulatory characteristics. Although recent years have witnessed intensified interest in iNKT cells, little is known about intracellular signaling pathways that control iNKT cell responses, including those mediated by mitogen-activated protein kinases (MAPKs). We employed selective inhibitors of ERK1/2, JNK and p38 to examine the importance of these MAPKs in iNKT cell responses to the prototype glycolipid antigen alpha-galactosylceramide (alpha GC). Activation of DN32.D3 iNKT cells in the presence of PD98059 led to decreased interleukin (IL)-2 production, indicating a role for ERK in mouse iNKT cell responses. In contrast, addition of the JNK inhibitor SP600125 to cultures did not significantly affect cytokine production, suggesting that JNK is not critically needed for iNKT cell responses. Interestingly, selective inhibition of p38 by either SB203580 or SK&F 86002 resulted in augmented IL-2 production by DN32.D3 cells after stimulation with alpha GC. This was also evident when iNKT cells were stimulated with an anti-CD3 monoclonal antibody thus bypassing the requirement for CD1d-mediated antigen presentation, indicating that p38 inhibition affects signal transduction downstream of iNKT cells' T cell receptors. Primary splenic iNKT cells similarly exhibited enhanced cytokine response to alpha GC when cultured in the presence of p38 inhibitors. Importantly, in vivo administration of SB203580 resulted in higher IL-4 and interferon-gamma secretion in alpha GC-treated mice. These results demonstrate that MAPKs play distinct signaling roles in iNKT cells and that both in vitro and in vivo iNKT cell responses to glycolipid antigens can be negatively modulated by p38.