Sir Peter MacCallum Department of Oncology - Theses
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ItemPrediction and prognosis in anal cancer: developing models to improve patient outcome( 2017)Anal squamous cell carcinoma is a human papilloma virus–related disease for which definitive treatment comprises chemoradiotherapy that has not changed substantially for forty years. Few advances in treatment have been made since then, especially for those patients who develop disease relapse and for whom no surgical options exist. Predicting responses in patients for whom conventional treatment will fail remains elusive and is a significant clinical problem. As anal cancer is reasonably described as a rare cancer, innovative approaches are required to address this pressing clinical issue as large clinical trials are exceptionally challenging and are unlikely to be undertaken. This thesis describes a range of research strategies to identify potential avenues to predict and improve patient responses to existing and novel therapies. It comprises a combination of clinical and translational research. Using our institutional database I have assessed the utility of post-treatment imaging with FDG-PET as it may serve as a means of early detection of poor response to treatment. I found that a complete metabolic response on post-treatment PET scan was predictive of overall survival and disease-free survival. The database, which spans a thirty year period, was also interrogated to explore patterns of treatment failure, subsequent salvage treatment and outcomes. I found that multiple treatment modalities have been utilised to treat patients with persistent or recurrent disease, with satisfactory survival benefit in carefully selected patients. I also evaluated the literature that investigated the molecular biology of anal cancer finding that no clinically valuable biomarkers have emerged. Some suggestions have been reported that regulators of apoptosis, including survivin, and agents targeting the PI3K/AKT pathway, might offer opportunities for targeted therapy. Additionally, antibody therapy targeting epidermal growth factor receptor may prove efficacious although the safety profile in combination with standard chemoradiotherapy has proven to be suboptimal. In the laboratory, next generation RNA sequencing was utilised in eleven anal SCC patient samples. Through stratification of the tumours into clinically relevant groups and Bioinformatic analysis, eight genes with differential expression were chosen for further validation. One of these genes was identified as a novel target which could ultimately lead to expanding therapeutic options in anal cancer management. Due to a lack of pre-clinical models, including cell lines and mouse models for testing new therapies, I developed a new anal cancer model based upon patient-derived tumour xenografts. I used this model in a pilot experiment to assess the novel drug target identified by RNA-seq. The outcomes were promising with stand-alone efficacy of the novel drug observed with statistical significance, while also validating the feasibility of using xenografts for anal SCC. This thesis builds upon the clinical experience of decades of management of patients with anal cancer identifying both clinical and laboratory approaches to advance assessment and identify novel treatment possibilities for this group of patients.
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ItemA health and economic impact analysis of robotic surgery for the treatment of localised prostate cancer in the Victorian public health system( 2017)Background: The rising prevalence of prostate cancer in Australia will increasingly contribute significant morbidity, mortality and economic burden on society. Radical prostatectomy is the mainstay of treatment for localised prostate cancer, and robotic prostatectomy the dominant surgical approach to management in the United States and Europe. Large systematic reviews have demonstrated some perioperative and functional benefits of robotic over open and laparoscopic approaches, however no differences in oncological outcomes have been demonstrated to date. The cost of the robot is undoubtedly greater than open and laparoscopic approaches however studies have shown a significant cost offset due to reduced length of stay and other improved clinical outcomes. We aim to perform a comprehensive health and economic impact analysis of robotic surgery for the treatment of localised prostate cancer in the Victorian public health system since the introduction of the da Vinci surgical robot to Peter MacCallum Cancer Centre (Peter Mac) in July 2010. Methods: To compare patterns of care and perioperative outcomes of robotic prostatectomy to other approaches, we utilised a large dataset from the Victorian Admitted Episodes Dataset (VAED) including all prostatectomy patients performed in the Victorian public sector since the installation of the da Vinci robot. Additionally the RARP series of perioperative, complication, oncological, functional and quality of life (QOL) outcomes at Peter Mac was compared to local, national and international literature. We then created an economic model to evaluate the incremental cost of robotic-assisted radical prostatectomy (RARP) versus open radical prostatectomy (ORP) and laparoscopic radical prostatectomy (LRP), incorporating the cost-offset from differences in length of stay and blood transfusion rate. The economic model constructs estimates of the diagnosis-related group (DRG) costs of ORP and LRP, adds the gross cost of the surgical robot (capital, consumables, maintenance and repairs), and manipulates these DRG costs to obtain a DRG cost per day, which can be used to estimate the cost-offset associated with RARP in comparison with ORP and LRP. Economic modelling was performed around a base-case scenario assuming a 7-year robot lifespan and 124 RARPs performed per financial year. One and two-way sensitivity analyses were performed for the four-arm da Vinci S HD, Si and Si dual console surgical systems. Results: The robotic surgical approach has become the dominant technique to radical prostatectomy for localised prostate cancer in the Victorian health system over ORP and LRP. The introduction of a surgical robot to the Victorian public system has resulted in centralisation of prostatectomy to Peter Mac with huge institutional growth since its instillation. Length of hospital stay and blood transfusion rates are significantly improved with the robotic approach. Positive surgical margin rates with RARP are improved compared to prior Victorian data consisting of primarily an ORP cohort. Complication and oncological outcomes of RARP are comparable between surgical approaches and to large international RARP series. Definitive comparison of RARP functional and QOL outcomes between approaches was difficult without a comparative cohort however compared favourably with previous literature. Improvements in length of stay and blood transfusion rates offset most of the additional cost of the robot in the base case scenario where 124 robotic cases are performed per year. RARP can become cost-equivalent with ORP where ~140 cases are performed in the base-case scenario. Increasing the surgical volume, lifespan of the robot and reducing the cost of the consumables can ameliorate cost. Conclusions: The da Vinci surgical robot has been safely introduced into the Victorian public health system at Peter Mac. The addition of the robot has significantly altered the way we treat patients with localised prostate cancer in Victoria. The robotic approach confers some clinical advantages compared to laparoscopic and open prostatectomy consistent with international literature, and the reduction in length of stay offsets much of the increased cost of the robotic procedure.