Medicine (St Vincent's) - Theses
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ItemAdenocarcinoma of the lung: an exploration of the relationships between histopathology, molecular pathology and inflammatory markers and their relationship to patient outcomes( 2017)Lung cancer remains the most common cause of cancer related death worldwide, with nearly 1.4 million deaths in 2008 globally. Adenocarcinoma is the most common type of lung cancer, and its frequency compared to other histologic subtypes is increasing. The simplicity of the label “adenocarcinoma” hides its significant pathologic and clinical heterogeneity. This thesis explores a number of clinicopathologic correlates in lung adenocarcinoma specimens obtained from patients treated at St Vincent’s Hospital in Melbourne, Australia. In 2011 the International Association for the Study of Lung Cancer (IASLC), the American Thoracic Society (ATS) and the European Respiratory Society (ERS) proposed a new classification system for pulmonary adenocarcinoma. This was subsequently adopted in the 2015 edition of the World Health Organisation Classification of Tumours of the Lung, Pleura, Thymus and Heart. Multiple groups demonstrated that the new classification had prognostic significance following resection of pulmonary adenocarcinoma independent of stage. The impact of the classification in metastatic disease was not known. This thesis found that it was possible to identify the adenocarcinoma patterns of solid with mucin, papillary, micropapillary and acinar in each specimen taken from a metastatic site and semi-quantitatively assess each component. Further, the identification of a major pattern was not prognostic, but did predict for differences in survival time for patients treated with systemic therapy. The worst outcomes were observed for patients with tumours with a major solid pattern. The major solid pattern was also found to have infrequent occurrence of activating epidermal growth factor receptor (EGFR) mutations. As this is the first time that this novel finding has been reported. Validation from other groups is required. The presence of the IASLC/ATS/ERS classification as a robust new tool with clinical relevance has led to further research to define other clinicopathologic correlates. Oncogene driver mutations in genes such as EGFR and Kirsten RAS (KRAS) are critical in selection of therapy in advanced disease. This thesis examined relationships between adenocarcinoma subtype and mutation status for patients who had resected lung adenocarcinoma. Patients with solid predominant adenocarcinoma were significantly less likely to have EGFR mutations, while KRAS mutation was a frequent event in invasive mucinous adenocarcinoma. No other significant associations were found. The findings were consistent with those recently reported by other groups from centres located in predominantly Caucasian countries. EGFR inhibition and the discovery of EGFR mutations was the starting point for a major change in the approach to treatment of advanced lung adenocarcinoma, however resistant to treatment occurs. It had been suggested that upregulation of phosphorylated STAT3 (pSTAT3) via interleukin 6 (IL6) and Janus Kinase (JAK) may be linked to EGFR mutation status in the absence of treatment with EGFR tyrosine kinase inhibitors and therefore may offer a rational target to delay resistance to such therapies. In the patient cohort studied the presence of EGFR or KRAS mutation status did not enrich for activation of IL6, JAK1 or pSTAT3 as determined by immunohistochemistry. Further, there was no clinicopathologic or prognostic correlates of note found by the IL6, JAK1 or pSTAT3 activation state. The assessment of IL6, JAK1 and pSTAT3 in the same samples and by two methods to assess positivity was a unique feature of this study. In conclusion this contributes new knowledge on the relevance of pathologic subtyping in advanced lung adenocarcinoma. It confirms and consolidates recent reports oncogene mutation status and adenocarcinoma subtype following surgical resection. It examines the IL6 / JAK1 / pSTAT3 pathway in detail in resected pulmonary adenocarcinoma. Translational research that explores why adenocarcinoma subtypes have different outcomes by treatment may allow clinicians to direct therapies differently or unlock new pathways for targeting lung adenocarcinoma with therapeutic effect.
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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.