Surgery (Austin & Northern Health)

Millions of surgeries are undertaken every year worldwide. Mechanical ventilation is an essential component of many of these.Despite the essential nature of its use the ideal approach to mechanical ventilation is currently not known. Data from the critical care literature primarily in patients with acute respiratory distress syndrome suggest that low tidal volume ventilation is associated with significant improvement in outcomes.Whether this confers benefit in operative patients is unknown. This thesis sought to identify how Australian anaesthetists set the ventilator and administer oxygen during surgery. The impact of intra-operative low tidal volume ventilation, 6mL per kilogram versus conventional tidal volume strategy, 10mL per kilogram on a variety of postoperative outcomes was also studied. We found that in 2014 Australian anaesthetists set a conventional tidal volume of 10mL per kilogram lean body mass and administered high inspired fractions of oxygen during surgery.In a randomised controlled trial we found that low tidal volume ventilation did not reduce postoperative pulmonary or non pulmonary complications relative to a conventional ventilation strategy. This thesis suggests that a physiologic tidal volume of 6mL per kilogram is appropriate during major surgery given the absence of benefit of a supra-physiologic tidal volume.

Nephrectomy is one of multiple treatment modalities available for managing renal cancer. As more effective systemic therapies emerge, the optimal approach to treat renal cancer needs re-evaluation. While surgery is the gold standard for curative management of localised renal cell carcinoma, the role in metastatic disease is more complex. In 2001, two seminal clinical trials from the United States and Europe established the role for cytoreductive nephrectomy in the cytokine era. Then, in 2018, the CARMENA trial reported non-inferiority for upfront sunitinib compared with nephrectomy followed by sunitinib. At the time of the trial’s publication, immune checkpoint blockade rather than sunitinib was the standard of care for metastatic renal cell carcinoma, further obfuscating the role for surgery. In this thesis, I aimed to analyse how a cytoreductive nephrectomy alters the natural history of metastatic renal cell carcinoma. First, I reviewed the literature relating to the natural history of renal cell carcinoma and the information gaps about the role of the cytoreductive nephrectomy in the evolving multimodal setting. I addressed this question by focusing on five components that were not evaluated in the aforementioned prospective trial: 1. Do cytoreductive nephrectomy outcomes vary depending on the metastatic picture? 2. Do cytoreductive nephrectomy outcomes vary depending on the histology? 3. Why are some patients not selected for a cytoreductive nephrectomy? 4. What role do anaesthesia and kidney disease have on nephrectomy outcomes? 5. What are the biologic effects of a cytoreductive nephrectomy? Studies of renal cell carcinoma often quantify disease burden by the size of the primary tumour and the location of metastases. My research team identified that the primary tumour size was independently prognostic in cytoreductive nephrectomy. However, a more nuanced approach was needed to assess the overall burden and distribution of disease. Therefore, in collaboration with the radiology department we used semi-automated segmentation analysis to measure the 3-dimensional burden of both the primary tumour and metastases in patients undergoing cytoreductive nephrectomy. We determined that primary tumour volume resected was prognostic whereas the proportion resected and the residual volume of disease were of equivocal significance. Due to the heterogeneity of renal cell carcinomas, patients with non-clear cell histology were not assessed in the cytoreductive clinical trials. Therefore, we compiled the largest single-institution series of non-clear cell cytoreductive nephrectomies. In conjunction with genitourinary pathologists, a comprehensive review of histological subtypes enabled us to identify clinicopathological characteristics with prognostic implications: tumours with papillary features were associated with favourable outcomes and tumours displaying sarcomatoid dedifferentiation were associated with adverse outcomes. We further evaluated sarcomatoid features by exploring outcomes across treatment eras, noting that while survival continues to improve, the combination of non-clear cell histology and sarcomatoid dedifferentiation represents a very aggressive phenotype with distinct metastatic patterns and very poor survival outcomes. A recurrent limitation of these retrospective studies was that I was looking at populations selected for surgery. To address this selection bias, I used a ground-based theory to develop a framework of oncological and patient-fitness factors outlining why some patients were not selected for surgery. The specific reason for not operating on a patient carried prognostic implications and is potentially generalisable to other cancers. In altering the disease course of renal cancer, a nephrectomy may also alter renal function. Indeed, one factor for reduced case selection was poor renal function. Therefore, we evaluated the impact of a nephrectomy for patients with chronic kidney disease. Patients with grade 3A chronic kidney disease were able to maintain their renal function postoperatively. Conversely, patients with grade 3B or worse chronic kidney disease slowly declined after surgery, although all groups had very low rates of dialysis. While many studies explored how newer surgical approaches can improve perioperative and oncological outcomes, few had looked at the role of anaesthetic techniques. Onco-anaesthesia is a nascent field and no clinical paper to date had researched the role of intraoperative opioids on outcomes following renal cell carcinoma surgery. We identified that increased intraoperative opioids were associated with adverse oncological outcomes. This finding highlights the importance of assessing both surgical and anaesthetic techniques in future clinical trials. The natural history of metastatic renal cell carcinoma ranges from indolent to rapidly progressive disease. To determine whether a cytoreductive nephrectomy alters this trajectory, we assessed validated biomarkers prior to and following surgery. We identified significant changes in these biomarkers with corresponding changes in survival outcomes. The novel finding of this study was to demonstrate variable responses to cytoreductive nephrectomy at the biomarker level. By characterising these distinct phenotypes, we provide a basis for a prospective trial aiming to refine case selection. This thesis covers cytoreductive nephrectomy in an historical context, provides granularity about tumour burden, explores rarer tumour phenotypes, evaluates case selection, analyses perioperative factors, and characterises the biological effects of surgery. Further work can continue to be undertaken to refine surgical selection and the integration of cytoreductive nephrectomy with emerging systemic therapies.

Surgery (Austin & Northern Health) - Theses

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