Medicine (RMH) - Theses
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ItemThe effect of patient factors and clinician choices on management of colorectal cancer and other malignancies( 2011)Cancer is one of the leading causes of morbidity and mortality world-wide, and colorectal cancer is one of the most common malignancies in the developed world. Being able to predict the most appropriate strategies for diagnosis, treatment and monitoring for any malignancy, both in the adjuvant and metastatic disease settings, is crucial as more management options come into play. In particular, the choices surrounding chemotherapy dosing can depend on many factors, and increasing interest is developing regarding optimization and individualization of treatment strategies for cancer based on these factors. Modern oncology is currently focused on biomarker-based research and translation to care. Although this thesis does not incorporate any pre-clinical biomarker-based research, patient variables (such as age and comorbidities) can be regarded as a type of clinical ‘biomarker’ – for example, age is a very strong prognostic factor for a number of malignancies, perhaps even more important than particular laboratory-based biomarkers in many circumstances. This research will focus on key aspects of patient care, from surgery to chemotherapy, radiation therapy and disease monitoring, which may be potentially regarded as ‘biomarkers’ - stratifying patients into those who may benefit the most, and least, from various treatment modalities and strategies. This body of work focuses primarily on colorectal cancer. The thesis provides a comprehensive ‘snapshot’ of current management strategies in Australia for colorectal cancer – from diagnosis through to surgical and oncological management – and each paper compares the findings with what is currently regarded as ‘gold-standard’ practice. It is well known that patients on clinical trials are mostly younger and fitter than those seen in routine practice, and treating physicians cannot always apply the findings from randomized controlled studies to the individual cancer patient. It is useful to understand in parallel with the evidence gained from clinical trials, its applicability and modifications employed in routine practice and as such, this research has been largely conducted using a prospectively collected comprehensive cancer database; together with surveys of Australian oncologists and review of available literature. Many issues requiring treatment decisions for colorectal cancer are also applicable to many malignancies, and the thesis also includes some papers which relate to cancer management in general – in particular, the impact of patient age and comorbidity on treatment decisions, and the effect of liver dysfunction on chemotherapy choices for cancer patients.
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ItemMolecular prognostic and predictive biomarkers in colorectal cancer( 2012)Increasing knowledge of the underlying signalling pathways and molecular defects involved in colorectal cancer (CRC) growth/progression has led to the development of several novel target-based therapeutics along with the discovery of various prognostic and predictive biomarkers. The mitogen-activated protein kinase (MAPK) signalling pathway plays a critical role in colorectal cancer progression. Mutations in BRAF, a principal effector of Ras in this signaling cascade, are found in 10% of CRC. The low frequency of this mutation makes it a challenging target for drug development, unless subsets of patients with higher rates of BRAFV600E can be defined. This thesis first investigates the potential of enriching a CRC patient population for BRAFV600E mutations based on clinical features and KRAS status. The mutational concordance between primary-metastasis pairs, and the impact of BRAFV600E and other molecular changes on patient outcome were also evaluated. This was achieved by analyzing primary CRC from 525 patients evenly matched for age, gender and tumour location, and 81 primary-metastasis pairs. BRAFV600E, KRAS, PIK3CA, NRAS mutations, microsatellite instability (MSI) and loss of heterozygosity (LOH) were determined and correlated with clinical features and patient outcomes. The prevalence of BRAFV600E was found to be considerably higher in older females with KRAS wild-type right-sided colon cancers (50%) compared to the unselected cohort (10%). BRAFV600E was associated with inferior overall survival in metastatic CRC and is independent of MSI status. The previous study suggested that BRAF mutant cancers represent a discrete subset of metastatic CRC defined by poorer survival, right-side tumour location and association with MSI. Whether BRAF mutant CRC is further defined by a distinct pattern of metastatic spread was investigated by using prospective clinical data and molecular analyses from 2 major centers (Royal Melbourne Hospital and The University of Texas MD Anderson Cancer Center). Patients with known BRAF mutation status were analysed for clinical characteristics, survival, and metastatic sites. A distinct pattern of metastatic spread was observed in BRAF mutant tumours, namely higher rates of peritoneal metastases (46% vs 24%, P=0.001), distant lymph node metastases (53% vs 38%, P=0.008), and lower rates of lung metastases (35% vs 49%, P=0.049). To further develop the concept of cancer gene mutations as predictors of site of relapse, CRC metastases from different sites were then examined for oncogene mutation profiles. One-hundred CRC metastases were screened for mutations in 19 oncogenes, and further 61 metastases and 87 matched primary cancers were analysed for genes with identified mutations. Mutation prevalence was compared between metastases from liver, lung and brain. Differential mutations between metastasis sites were evaluated as predictors for site of relapse in patients from the VICTOR trial. KRAS mutation prevalence differed between metastasis sites, being more common in lung (62.0%) and brain (56.5%) than in liver metastases (32.3%; P=0.003). Mutation status was highly concordant between primary cancer and metastasis from the same individual. KRAS mutation was found to be predictive of lung relapse but not liver relapse in patients from the VICTOR trial.
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ItemThe management of colorectal cancer in Australia: heterogeneity of care and the need for increased data collection( 2011)Australia has one of the highest world-wide incidence rates of colorectal cancer, affecting one person in 20. It is the second most commonly diagnosed invasive malignancy. Each year, approximately 14,200 cases are diagnosed representing 13.1% of all incident cancer diagnoses. Of those diagnosed, about 50% will ultimately die from metastatic disease. After lung cancer, it is the second leading cause of cancer death in our country, resulting in around 80 deaths each week. Multiple factors impact on peoples’ outcomes, with stage at diagnosis being the most significant factor. Despite the commonness of this condition in our community, there are a number of areas where data are lacking, resulting in treatment uncertainty. These areas include the medical management (chemotherapy dosing, selection of appropriate candidates for adjuvant and metastatic therapy) and staging and surveillance strategies (optimal imaging modalities) for those diagnosed with this condition. The publications comprising this thesis examine these various aspects of colorectal cancer management in Australia. A recurrent finding arising from the research is the distinct heterogeneity of care, with no adopted standard. This emphasises the need for ongoing data collection in this area and proposed methods to address this issue are discussed in the later part of the thesis. The thesis comprises of four chapters, each focussing on a specific area of colorectal cancer management in Australia. A review of the current literature and discussion of the common themes precedes each set of associated publications. (Part Thesis Overview and Introduction only)