Sir Peter MacCallum Department of Oncology - Theses
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ItemHow information technology improves the quality and efficiency of medical care and research( 2018)In 2007, the concept of rapid learning healthcare was proposed in the United States of America health system in a response to increasing healthcare costs. Its aim was to accelerate knowledge discovery through a systematic approach to integrating electronic medical records design with analysis infrastructure to rapidly and continuously assess health system performance. The delivery of healthcare is becoming increasingly performed and documented within the electronic domain, and large databases of healthcare-related information being created as a by-product. This has led to an unprecedented level of access to detailed and structured clinical data that could be used to accelerate research. In a rapid learning healthcare system, the high level of integration from electronic record to policy would ensure that each patient and each click of the mouse would drive innovation. The attraction of rapid learning was not to supplant the traditional clinical trial paradigm, but to augment its effectiveness with accelerated analysis of real-world outcomes. The rapid learning concept relied heavily on electronic medical records, administrative systems and disease registries as data sources to power analyses. Electronic health record penetrance in Australia has lagged that achieved in the USA, primarily because of financial assistance provided as part of the HITECH act in the USA. However, one exception is seen in oncology, where radiotherapy is exclusively prescribed electronically. Additionally, there has been a significant shift toward electronic chemotherapy prescribing due to the clinical risk associated with manual systems. Perhaps in oncology there is an opportunity to replicate the successes of data-driven health research achieved elsewhere. The objective of the work contained in this thesis is to develop practical methods to expand and discover the infrastructure required to implement rapid learning health care in the Australian oncology context. Ultimately, the aim is to increase the quality and efficiency of medical care and research by harnessing novel information technology (IT) methods. In addition to leveraging existing secondary databases for health services research and creating high impact linkages with state-level cancer registries, advanced IT methods could also be used to automate manual data extraction tasks in a timely and cost-effective fashion. The integration of these methods into routine clinical practice has enormous implications for tracking patient care quality, and accelerating research by utilising all data by-products of health care.
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ItemProfiling desmoid tumours and exploring new strategies to prevent and treat desmoid tumours in familial adenomatous polyposis using a novel mouse model( 2018)Desmoid tumour is a benign growth that causes morbidity and mortality from local enlargement. Desmoids are thought to result from dysfunction in WNT signalling. Trauma, including that from surgical intervention, is implicated in the pathogenesis of desmoid tumour, with desmoids often occurring at surgical sites. Patients with familial adenomatous polyposis (FAP) possess a germline mutation in the APC gene on chromosome 5, resulting in numerous colorectal adenomas that inevitably develop into colorectal carcinoma. Patients with FAP undergo prophylactic colectomy to manage risk of future carcinoma. The germline mutation in APC, combined with surgical trauma from prophylactic colectomy, place patients with FAP at a significant risk of future desmoid tumour development. Desmoid tumour is the largest cause of mortality for patients with FAP following prophylactic colectomy. There is controversy regarding the utility of laparoscopic prophylactic colectomy in FAP, with some series suggesting that laparoscopic surgery results in a higher risk of future desmoid tumour. Desmoid tumours in FAP patients occur in the mesentery and abdominal wall. Management options are limited due to the precarious location, often in close relationship to the mesenteric vasculature. Desmoid tumours in this cohort pose significant clinical management challenges, with high recurrence rates after surgical excision, and no consensus on best medical management. Since desmoid tumours are rare tumours, a pre-clinical model would facilitate research in this area. This research thesis describes the development of a novel murine model for abdominal desmoid tumour that occurs in FAP. The Apcmin/+:p53-/- mouse develops numerous abdominal wall desmoid tumours. This model has been validated with histopathology and immunohistochemistry, and has facilitated the development of desmoid tumour cell lines, and xenograft studies in this area. The impact of surgical approach on future desmoid risk was investigated using the Apcmin/+:p53-/- mouse. Mice were subjected to laparotomy or laparoscopy and were then observed until they reached ethical endpoints, at which time an assessment of desmoid tumour burden was made. In the Apcmin/+:p53-/- mouse model, surgical approach had no impact on survival or the number of macroscopically identifiable desmoid tumours. Furthermore, the use of humidification/warming device for open and laparoscopic surgery was trialed and found to have no impact on survival or desmoid tumour burden. This research has also investigated the genomic landscape of human abdominal and abdominal wall desmoid tumours through RNA sequencing and immunohistochemistry. This study has identified that abdominal desmoid tumours share genomic similarity to wild-type gastrointestinal stromal tumours (negative for CD117 and PDGFRα). Sequencing identified a number of pathways (Such as VEGF, EGF and mTOR) involved in desmoid tumour formation that could be targets for therapy.
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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.