Intra-Peritoneal Local Anaesthetics in Ovarian Cancer

Introduction:

Ovarian cancer accounts for 2.5 percent of cancers in women. In Sweden, a total of 694 new cases of ovarian and fallopian tube cancers were reported in 2012. During the period 2005-2009, the relative 1-year survival for all ovarian cancers was 81.8% but 5-year survival was only 44% (1). The low survival can be due to the aggressiveness of epithelial ovarian cancer and because it is often diagnosed late. Today, patients with widespread malignant intra-abdominal ovarian cancers (Stage III-IV) are operated by cyto-reductive surgery (CRS) followed by early chemotherapy, which has been shown to improve patient survival (2). However, CRS is often accompanied by a severe inflammatory and immuno-compromised perioperative course associated with early morbidity, delayed rehabilitation and, sometimes, prolonged start of chemotherapy. Early start of chemotherapy has been a major factor in improving long-term outcomes (3), and therefore perioperative factors such as choice of anaesthesia and analgesia and fluid replacement may be important. Tumorigenesis and the perioperative environment: Surgery, perioperative stress and anaesthesia may all modulate the immuno-surveillance mechanisms and compromise host defences that normally maintain a balance between immunity & tumorigenesis (4,5). There is increasing evidence that surgery itself may promote the recurrence and metastases of cancer, which depends largely on the tumour's ability to metastasise, combined with the host immunity and inflammatory response (6). Natural killer (NK) cells act as a primary defence against perioperative cancer metastases (6). Negative effects of anaesthetics and analgesics on NK-cell activity may promote pro-inflammatory effects and may also activate cancer cell survival pathways. Additionally, concentrations of tumour-related anti-angiogenic factors are decreased while angiogenic factors such as vascular endothelial growth factor (VEGF) are increased (7). Hypoxia inducing factor (HIF-1) is a transcriptional factor that has also been shown to play an important role for tumour survival (8). Hypoxia in solid tumours leads to activation of HIF-1, which in turn increases cancer cell survival (9). Similarly, hyperoxia may, paradoxically, lead to activation of HIF-1 and potentially worsen long-term survival. Inhalational anaesthetics but not propofol have been shown to affect VEGF as well as transforming growth factor-beta (TGF-β) in patients undergoing breast surgery that may affect long-term survival (7). VEGF and TGF-β play a significant role in establishing tumour blood supply and cell proliferation. Other factors such as surgical stress, blood transfusions, hypothermia, hyperglycaemia, and postoperative pain may also affect immunity and the tumour microenvironment. Even after complete excision of the tumour, circulating tumour cells released during the surgical procedure may eventually lead to recurrence or metastases as they escape the immune surveillance (10). Role of anaesthetics and analgesics in cancer metastases: Preventing a major systemic inflammatory response and preserving immuno-surveillance in the perioperative period are fundamental in promoting improved postoperative outcome in cancer surgery. The severity of injury correlates with the magnitude of inflammation. In vitro studies have shown that amide local anaesthetics have cytotoxic activity, which could prove to be beneficial in preventing cancer recurrence (11). These potential cytotoxic effects of LA may effectively reduce postoperative morbidity and promote early start of chemotherapy (manuscript). Anaesthetic drugs, specifically inhalation anaesthetics, impair numerous immune functions, including those of neutrophils, macrophages, dendritic cells, T-cell, and natural killer (NK) cells. Upregulation of hypoxia-inducible-factors (HIF) in tumour cells by volatile anaesthetics may contribute to a tumour's recurrence by stimulating cytoprotective or pro-tumorigenic behaviour in residual cells. However, propofol may not depress the immune function (12) and does not upregulate synthesis of HIF (13). Opioid analgesics inhibit both cellular and humoral immune function, increase angiogenesis, and promote breast tumour growth in rodents. Opioids interfere with immune function by depressing NK cell activity (14). The use of epidural anaesthesia and analgesia thus prevents the stress response to surgery, reduces the need for opiates and may prolong survival (15). Fluid dynamics and early recovery: Fluid optimization remains a challenge because of several factors: preoperative fluid shifts and accumulation of ascitic fluid, low preoperative albumin from malnutrition, as well as perioperative fluid and blood loss. Both hypo- and hypervolemia have been shown to have adverse effects and may delay recovery and start of chemotherapy and a large prospective, randomised study concluded that hypovolemia may even lead to renal insufficiency (16).

The main objectives of the prospective, randomised, double-blind study is to assess:

1. Time to start of chemotherapy postoperatively

2. Overall survival at 3 and 5-years in patients undergoing CRS for ovarian cancer. We will also record postoperative complications as defined by the Clavien-Dindo classification (CDC) and postoperative morbidity score (POMS) during the hospital stay in patients randomised to intraperitoneal local anaesthetics or placebo during 72 h postoperatively. We will measure plasma levels of certain biomarkers such as VEGF, TGF-β and HIF1a, pre- and post-operatively to assess the effect of local anaesthetics. We will also assess patient-assessed quality of recovery and quality of life at fixed time points during the study.