Nina Groes-Kofoed

Effect of intraperitoneal ropivacaine during and after cytoreductive surgery on time-interval to adjuvant chemotherapy in advanced ovarian cancer: a randomised, double-blind phase III trial

In a previous phase II trial, intraperitoneal local anaesthetics shortened the time interval between surgery and adjuvant chemotherapy, an endpoint associated with improved survival in advanced ovarian cancer. Our objective was to test this in a phase III trial. A double-blind, phase III parallel superiority trial was conducted at two university hospitals in Sweden, within a public and centralised healthcare system. Women >18 yr with advanced ovarian cancer scheduled for cytoreductive surgery, an ASA physical status of 1-3 with no speech/language issues, were eligible. Participants were randomly assigned using a central computerised system to receive either ropivacaine 0.2% or saline 0.9% (placebo) intraperitoneally during and after surgery. The primary endpoint was time to return to intended oncologic therapy (RIOT), analysed using t-test and linear regression adjusted for centre. Of the 225 women randomised between August 2020 and December 2023 (ropivacaine n=113; placebo n=112), 175 were included in the modified intention-to-treat analysis (ropivacaine n=86; placebo n=89). Median age: ropivacaine group 64 yr (56-73 yr), placebo group: 66 yr (57-74 yr). The mean RIOT in the ropivacaine group was 26.5 days vs 25.8 days in the placebo group, with a mean difference of 0.7 days (-2.2 to 3.4 days; P=0.65). Per-protocol analysis of 166 women yielded similar results, mean difference of 0.5 days (-2.4 to 3.4 days; P=0.74) days. There were no differences in short-term recovery or postoperative morbidity. Intraperitoneal local anaesthetic did not shorten the time to RIOT among women undergoing surgery for advanced ovarian cancer in this trial. ClinicalTrials.gov (NCT04065009), European Union Clinical Trials Register (2019-003299-38/SE).

The trajectory of conditional, recurrence-free, and long-term survival in a complete 10-year cohort of patients with advanced ovarian cancer

Background: The prognosis in advanced ovarian cancer is generally poor since the majority experience recurrence. Nevertheless, there is a chance of cure and very long-term survival may be achieved. However, traditional survival metrics do not account for the dynamic changes in prognosis over time. Our objectives were to examine conditional, very long-term and recurrence-free survival, in addition risk-factors for recurrence. Methods: In this observational study, all patients diagnosed with advanced ovarian cancer between 2009 and 2018 in the Stockholm/Gotland region, Sweden, were identified in the Swedish Quality Registry of Gynecologic Cancer. Conditional and recurrence-free survival were estimated with the Kaplan Meier method. The association between predefined clinical factors and hazard of death was analysed with Cox regression yielding hazard ratio (HR) with 95% confidence interval (CI). Results: A total of 888 patients were analysed of which 87.0% (n = 740) experienced a recurrence and 8.5 % (n = 76) were alive > 10 years. The 5-year conditional survival increased from 33.0% (95% CI: 30–36) in patients who had survived 1 year to 57.0% (95% CI: 50–63) in patients who had already survived 5 years. The median recurrence-free survival was 18 months (95% CI: 16–19). Risk factors associated with recurrence included any residual tumour (> 10 mm; HR: 2.15; 95% CI: 1.65 to 2.80) and evidence of disease at end of first line treatment (HR: 2.40; 95% CI: 1.97 to 2.93; p < 0.001). Interpretation: Conditional survival improves significantly with time survived following an advanced ovarian cancer diagnosis. Most patients experience relapse within 1 year after completing first-line treatment, nevertheless long-term survival is possible.

Perioperative trajectories of acute-phase proteins and their association with major postoperative complications in advanced ovarian cancer

Acute-phase proteins (APPs) reflect systemic inflammation and nutritional status, yet their perioperative trajectories and clinical utility as biomarkers of outcome in advanced ovarian cancer (aEOC) remain unclear. We aimed to characterise perioperative APP fluctuations and assess their associations with postoperative complications. This observational study included patients undergoing cytoreductive surgery for aEOC across two prospective studies (n = 274). Serial serum albumin, transthyretin, C-reactive protein (CRP), fibrinogen, and procalcitonin were measured preoperatively and on postoperative days (PoD) 1, 3, and 5. Associations between APP levels and major postoperative complications, classified by Clavien-Dindo (CD ≥ III), were examined using multivariable logistic regression. Length of stay (LOS) was evaluated for biomarkers showing significant associations. Predictive thresholds were derived by ROC analysis. Positive APPs peaked postoperatively (CRP and fibrinogen on PoD 3; procalcitonin on PoD 1), while negative APPs reached nadirs on PoD 3. Neither preoperative albumin (>35 g/L) nor transthyretin (>0.2 g/L) predicted major postoperative complications. In contrast, elevated CRP measured on PoD 3 was associated with both major postoperative complications, OR 2.78 (95% CI 1.45-5.48) and prolonged LOS (>7 days) OR 3.0 (95% CI 1.67-5.47), with optimal cut-offs of ≥287 mg/L and ≥322 mg/L respectively (AUC 0.80). Preoperative APPs were not associated with postoperative outcomes in this cohort. CRP measured on postoperative day 3 was the most informative biomarker associated with major postoperative complications and prolonged hospital stay after cytoreductive surgery for advanced ovarian cancer and may support postoperative surveillance and recovery assessment when interpreted alongside clinical findings.

The IPLA-OVCA Trial, Intra-Peritoneal Local Anaesthetics in Ovarian Cancer

Surgery and chemotherapy combined constitute first line treatment in women with advanced ovarian cancer. The aim of surgery apart from staging is cytoreduction, i.e. surgical resection of tumour. Radical resection of all tumour visible by the naked eye followed by adjuvant chemotherapy is associated with best chance of prolonged survival. However, because of tumour dissemination in the peritoneal cavity, radical surgery is often very extensive with surgery in all quadrants of the abdomen and multi-organ resection with substantial risk of postoperative severe complications and subsequent delay in administration of adjuvant chemotherapy. Longer time-interval between surgery to start of adjuvant chemotherapy has been associated with decrease in survival. Surgery presents opportunities not only for eradicating tumours but, paradoxically, also for proliferation and invasion of residual cancer cells. It increases the shedding of malignant cells into the blood and lymphatic circulations, inhibits their apoptosis and potentiates their invasion capacity. Additionally, the immune system, the inflammatory system and the neuroendocrine system react to surgery with important changes, which have been proven to promote progression of cancer. Several anaesthesia-related factors play an important role in perioperative tumorigenesis such as inhalational anaesthetics, opiate analgesics, local anaesthetics and regional anaesthesia, all of which may impact short-term morbidity and long-term mortality. A previous randomized placebo-controlled pilot study suggests that women who receive local anesthetics intraperitoneally preoperatively have a significantly decreased time-interval to initiation of adjuvant chemotherapy. In a prospective, randomised, multi-centre study, we plan to further assess if intraperitoneal local anaesthetics administered perioperatively during 72 h leads to early start of chemotherapy compared to placebo in patients undergoing cytoreductive surgery for FIGO stage III-IV ovarian cancer.