Local anaesthetics, fluid balance and perioperative outcomes in surgery for advanced ovarian cancer

The majority of women with ovarian cancer are diagnosed at an advanced stage with extensive dissemination of tumour to the mesothelial lining of the abdomen, the peritoneum. Moreover, large amounts of ascites are often prevalent. Best chance of prolonged survival comprises the combination of cytoreductive surgery (CRS) and adjuvant chemotherapy. The aim of CRS is to resect all visible tumour to achieve complete macroscopic resection, which often necessitates high complexity surgery with risk of substantial fluid shifts and risk of postoperative complications that prolongs (or inhibits) the time-interval to adjuvant chemotherapy. A prolonged time interval to adjuvant chemotherapy has been associated with inferior survival. Local anaesthetics have anti-inflammatory properties and when applied at site of injury in the abdomen, phase II and III trials have demonstrated an improved postoperative recovery after abdominal surgery and reduced time-interval to adjuvant chemotherapy during CRS.

Previous observational studies suggests that scheduling of surgery earlier on the week may be associated with improved outcomes and for ovarian cancer the ability to achieve complete macroscopic resection is increased.

In the IPLA-OVCA trial, a Swedish multicenter randomised double-blind, placebo-controlled trial, women with advanced epithelial ovarian cancer (aEOC) were randomised to receive Ropivacaine (local anaesthetics) or Saline (placebo) intraperitoneally during and for 72 hours postoperative. Participating hospitals were Karolinska University hospital and Skåne University hospital, Lund. Primary endpoint was time (days), 173 women were included in the intention-to-treat (ITT) and 166 women in the Per Protocol (PP) analyses. There were no differences between groups in mean time between surgery and start of chemotherapy in the ITT (0.4 days (95% CI: -2.4 to 3.2; p=0.77) or the PP analyses, 0.5 days (95% CI: -2.4 to 3.4; p=0.77). Moreover, there was no difference in postoperative opioid consumption, self-reported pain or postoperative complications.

In a register-based cohort study, we investigated the association between weekday of CRS in aEOC and overall survival in 524 women subjected to surgery in the Region of Stockholm-Gotland, Sweden. In the adjusted analysis, a 28% increase in the risk of death (HR 1.28, 95% CI 1.04–1.58, p = 0.02) was evident when surgery was performed later in the week (Wednesday-Thursday) as compared to early week (Monday-Tuesday).

Two observational case-series examined the association between fluid balance and major postoperative complications. The first with retrospective design and the other with prospective design and predefined fluid balance categories. Multivariate regression models adjusted for potential confounders in both studies. In the retrospective study of 184 women, a net positive fluid balance of >3000mL in the first 48 perioperative hours increased the risk of major postoperative complications (OR 4.85, 95% CI 1.23–19.2, p=0.02). Similarly, in the prospective study with 162 women included a threshold fluid balance greater than 1750mL was also associated with increased risk of postoperative complication (OR 3.40, 95% CI 1.06-10.9; p=0.04).

In this thesis we demonstrate that the addition of intraperitoneal local anaesthetics during and after CRS in aEOC, does not reduce the time-interval to adjuvant chemotherapy. We also suggest that CRS may best be performed early in the week and in addition, to reduce risk of major postoperative complications we suggest that the aim of perioperative fluid balance should be below 1750 mL (excluding initial ascites) or less than 2700 mL (including initial ascites).

List of scientific papers

I. Perioperative fluid balance and major postoperative complications in surgery for advanced epithelial ovarian cancer. Emma Hasselgren, Daniel Hertzberg, Tina Camderman, Håkan Björne, Sahar Salehi. Gynecol Oncol. 2021 May;161(2)402-407.
https://doi.org/10.1016/j.ygyno.2021.02.034

II. Surgery performed later in the week is associated with inferior survival in advanced ovarian cancer. Nina Groes-Kofoed*, Emma Hasselgren*, Håkan Björne, Hemming Johansson, Henrik Falconer, Sahar Salehi. Acta Oncol. 2021 Nov;60(11):1513-1519. *Shared first authorship.
https://doi.org/10.1080/0284186X.2021.1970221

III. Effect of intra-peritoneal local anaesthetics during and after cytoreductive surgery in advanced ovarian cancer: A randomised double-blind phase III trial. Emma Hasselgren, Nina Groes-Kofoed, Henrik Falconer, Håkan Björne, Diana Zach, Daniel Hunde, Hemming Johansson, Mihaela Asp, Päivi Kannisto, Anil Gupta, Sahar Salehi. [Manuscript]

IV. Prospective assessment of the association between perioperative fluid balance and postoperative complications after surgery for advanced ovarian cancer. Emma Hasselgren, Nina Groes-Kofoed, Henrik Falconer, Håkan Björne, Diana Zach, Daniel Hunde, Hemming Johansson, Mihaela Asp, Karin Thorlacius, Päivi Kannisto, Sahar Salehi. [Submitted]