Evaluation der Prognose bei dünnen malignen Melanomen (0.8-1.0mm Tumordicke) anhand eines Datensatzes der Universitätshautklinik Tübingen 2000-2010

Das maligne Melanom steigt in der Inzidenz weiter an, so dass die Anzahl zu versorgender Patienten seit Jahren weiter zunimmt. Hierbei nimmt die Nachsorge einen großen Stellenwert ein, um Zweitmelanome in möglichst frühen Stadien – bei noch geringer Tumordicke – sowie deren Rezidive frühzeitig zu erkennen, um einen Progress zu verhindern. Die achte Version der AJCC führte eine neue Stadieneinteilung für Melanome ein. In der vorliegenden Dissertation wurde untersucht, ob sich durch die neue Klassifizierung Änderungen für das Nachsorgeschema bei Melanomen mit einer Tumordicke von bis zu 1 mm erforderlich machen. Hierzu wurden in der vorliegenden Arbeit anhand eines Datensatzes des Zentralregisters der Deutschen Dermatologischen Gesellschaft und ebenso der Universitätshautklinik Tübingen prognostische Faktoren und Verläufe bei dünnen Melanomen untersucht. Die Einschlusskriterien setzten sich zusammen aus invasiven, kutanen malignen Melanomen der Tumordicke ≤2.0mm, Erstdiagnose zwischen 2000-2010 mit der T-Subklassifikation T1a/T1b oder T2a und einer Nachsorgezeit (Follow-up Time) von >3 Monaten. So ergab sich ein Kollektiv aus 12.132 Patienten. Der Datensatz wurde stratifiziert nach Tumordicke, die gemäß der aktuellen Tumordickeneinteilung der AJCC klassifiziert wurde: Die drei Subgruppen <0.8mm (n=7324), 0.8-1.0mm (n=1879) und 1.01-2.0mm (n=2929) wurden hinsichtlich des Rezidivverhaltens, der Rezidivhäufigkeit, des Rezidivfreien Überlebens und des Melanomspezifischen Überlebens analysiert. Außerdem wurden Patientencharakteristika, Prognosefaktoren und Häufigkeitsverteilungen innerhalb des Kollektivs nach Tumordickeneinteilung bestimmt. Die Analysen erfolgten mittels IBM SPSS Statistics (Version 27). Statistische Methoden wie die Kaplan-Meier-Überlebensanalyse, Bestimmung der Hazard Raten und Cox-Regressionsanalysen wurden angewandt. In der vorliegenden Studie zeigten sich Tumordicke und Ulzeration als signifikante, unabhängige prognostische Faktoren mit einem relativen Risiko von 2.1 für die Tumordicke und 3.0 für die Ulzeration in der Cox-Regressionsanalyse. Mit steigender Tumordicke ergibt sich ein Anstieg der Rezidive von 3.7% bei <0.8mm, über 9.8% bei 0.8-1.0mm, bis 15.8% bei 1.01-2.0mm. Die mediane rezidivfreie Zeit beträgt 32 Monate. In allen drei Gruppen zeigen sich lokoregionäre Metastasen als häufigste Rezidivart mit 2.7% bei <0.8mm, 7.2% bei 0.8-1.0mm und 9.9% bei 1.01-2.0mm. Eine Fernmetastasierung konnte in allen drei Gruppen seltener beobachtet werden. Das Melanomspezifische Überleben liegt in den drei Gruppen nach Tumordicke (<0.8mm, 0.8-1.0mm, 1.01-2.0mm) bis zum 5-Jahres-Zeitpunkt bei über 94%. Beim 10-Jahres-Überleben zeigt die Gruppe mit 0.8-1.0mm eine Wahrscheinlichkeit von 89.8% und die Gruppe mit 1.01-2.0mm eine Wahrscheinlichkeit von 88.1%. Das Rezidivfreie Überleben (1-10-Jahres-Überleben) liegt bei der Gruppe mit <0.8mm zwischen 91.5%-99.4%, für die Gruppe mit 0.8-1.0mm bei 81.9%-98.1% und für die Gruppe mit 1.01-2.0mm bei 74.0%-97.0%. Hazard Raten für das Auftreten von Rezidiven zeigten bei Melanomen einer Tumordicke von 1.04mm zeigen ein vergleichbar hohes Risiko unter Berücksichtigung der Hazard Raten über 1:40 im 3- und 8-Jahresabstand mit ebenso vergleichbaren Überlebensdaten (RFS, MSS). Die Veränderungen durch die Anpassung der T-Klassifikation in der aktuellen AJCC Definition mit den Tumordicken <0.8mm, 0.8-1.0mm und 1.01-2.0mm und Änderung der Zusammensetzung in den Tumorstadien IA und IB, ergaben keine Hinweise, dass eine Änderung der Nachsorge in diesen Tumorstadien angepasst werden müsste

Estimating current and future demands for stereotactic ablative body radiotherapy (SABR) in the Australian lung cancer population

Stereotactic ablative body radiotherapy (SABR) is the current standard of care for inoperable early-stage non-small cell lung carcinoma (NSCLC). It is a curative treatment option that offers excellent survival rates through non-invasive out-patient visits. SABR can be offered to frail, elderly patients and those with comorbidities or poor performance status, who may be ineligible for surgery or radical radiotherapy and would otherwise be referred to palliative treatments or (sometimes) left untreated. While strong evidence from randomised trials have supported SABR use for peripherally located tumours (>2cm from the proximal bronchial tree (PBT), treatment of central tumours with SABR remains controversial due to increased risks of severe toxicities. Determining the total demand for lung SABR, also known as the optimal rate of utilisation, is an important step in ensuring adequate and efficient provision of radiotherapy services. Once established, it can used as a benchmark against which actual SABR utilisation rates can be compared and any shortfalls in service provision identified. This optimal SABR utilisation rate can be calculated using an evidence-based approach involving first identifying all indications/clinical situations for which lung SABR is a guideline-recommended treatment, then obtaining data on the proportion of each indication within the lung cancer population. This, however, has so far been hindered by lack of published data on the proportions of peripheral versus centrally located lung tumours. The difficulty in determining the distribution of central and peripheral tumours is related to how these tumours are distinguished in clinical practice; based on clinicians’ manual delineations (i.e. contours) of the PBT. Manual contouring is a well-known source of uncertainty caused by inter- and intra-observer variabilities. Such uncertainties preclude relying on retrospective records of patients (assessed by multiple clinicians) to establish reliable estimates of the proportions of central and peripheral tumours. To overcome this, a novel, fully automatic tool for PBT contouring and measuring distance to the tumour was developed as part of this thesis. The tool relies on an intensity-based algorithm that detects bronchus airways based on pre-determined Hounsfield Unit thresholds. Manual PBT contours generated by different clinicians were used to assess inter-observer variabilities11 and to assess the accuracy of automatically generated contours. Results from this investigation have validated the tool’s ability to generate contours within the accuracy experts-generated ones without the need for manual intervention. Subsequently, this tool was applied on a retrospective dataset (N=234) of Stage I and II NSCLC patients treated with radiotherapy at Liverpool and Macarthur Cancer Therapy Centre in Sydney, Australia. This allowed for patients’ tumour centrality to be assessed efficiently and, more importantly, with less influence from observer variabilities. The tool successfully generated PBT contours and measured the minimum distance to the tumour for all patients within the obtained dataset. Patients were then stratified based on the tumour proximity to the PBT, allowing the distribution of peripheral and central tumours to be determined. Previous studies reporting this distribution have relied on manual PBT contours, which are largely affected by observer variabilities as shown in this work. To calculate the total demand for lung SABR, epidemiological data on the proportions of all clinical attributes where SABR is recommended (including the proportion of peripheral versus central tumours) were incorporated into an evidence-based optimal utilisation model developed as part of this work. Based on most recent evidence and guidelines, it was estimated that a total of 6% of all new patients diagnosed with lung cancer in Australia will require SABR at least once during the course of their illness. In those with early-stage NSCLC, this rate was estimated to be at 24%. This is the first report of evidence-based optimal rates of lung SABR utilisation. The utilisation model can be easily modified and updated with new data to ensure accurate and up-to-date estimates of lung SABR demands within the population. Finally, this work also provided an investigation into the potential impact of upcoming technologies on future demands for lung SABR. Magnetic resonance imaging (MRI) guidance, for example, promises to significantly improve treatment accuracy and transform how radiotherapy is delivered. A planning study was conducted to simulate the dosimetric gains expected by such technologies, in particular, the potential reductions in planning safety margins. Results from this study indicated the potential for such technologies to extend SABR treatments to a substantial proportion of patients currently deemed too high-risk to receive it. As such, it is expected that the demand for lung SABR may increase in the near future as such technologies become more widely availabl

Outcomes of English Colorectal Cancer Care: Observation, Quantification and Comparison of Outcomes

Colorectal cancer is the fourth most common cancer in England, but English colorectal cancer outcomes have traditionally lagged behind those of similar income level countries. Reasons behind these poor outcomes are multi-factorial but include high numbers of elderly patients presenting with advanced disease and a stubbornly high rate of emergency admissions. Recent years have seen significant changes in the National Health Service’s approach to cancer treatment, alongside the development of population-level databases. This study uses population-level data, obtained through the National Cancer Data Repository to investigate how short-term outcomes of colorectal cancer patients within the English NHS between 1998 and 2010 have changed. Further, it seeks to evaluate the impact of the NHS Bowel Cancer Screening Program and novel technologies such as laparoscopic surgery and endoluminal stents on those outcomes. Risks factors for emergency colorectal cancer admission such as older age and increased co-morbidity remain although short-term mortality rates (30 and 90-day) appear to be falling. Length of stay for colorectal cancer patients fell markedly over the study period, aided by the introduction of laparoscopic surgery, whilst those who engaged in the screening program were seen to have a greater likelihood of presenting electively and with early stage disease. Endoluminal stents have a clear, but as yet undefined role to play in the management of the colorectal cancer patient, but do appear to offer certain advantages to selected patients. Population-level data allows evaluation of interventions in healthcare and comparison of international outcomes. English colorectal cancer outcomes improved over the study period reported here, but are still not at the level of our European and international neighbours. There remains much work to do to improve these outcomes; it is likely that population-level data will play a pivotal role in this

“Unknown” prostate cancer stage at diagnosis in a population-based cancer registry: impact on epidemiological studies and use of multiple imputation

Routinely collected population-based cancer registry stage data are crucial to inform health service planning and to monitor variations in cancer outcomes. However, incomplete stage information is a major concern due to potential biases this introduces. This thesis examined the reasons why a large proportion of prostate cancer cases are recorded as “unknown” stage in the New South Wales (NSW) Cancer Registry (NSWCR) and validated the multiple imputation (MI) method for dealing with “unknown” stage data. NSW is the most populous state in Australia, with almost one third of the total national population. The NSWCR is the only population-based cancer registry in Australia that has collected stage information since its inception in 1972. The usefulness of long-term historical cancer registry stage data when examining cancer outcomes is illustrated in Chapter 2, with an investigation of geographical variation in long-term survival over time. The research reported in Chapter 3 shows that prostate cancer cases with “unknown” stage differ from those with a known stage, as survival and risk of disease progression for cases with “unknown” stage was intermediate between those for cases with localised and regional disease. Several possible reasons that could contribute to why “unknown” stage is recorded in the NSWCR are identified in Chapter 4. The publication included in Chapter 5 shows that MI appears to be valid for “unknown” stage when the MI is implemented according to the practical guidelines recommended in the literature. The application of MI to the NSWCR “unknown” stage data reported in Chapter 6 shows that the imputed stage data appear to be reliable. These findings provide important insights into prostate cancer cases with “unknown” stage recorded in the NSWCR, and an understanding of the potential biases in epidemiological studies that use these data. The validated MI method to handle “unknown” stage will help to increase the utility of the cancer registry data

Cancer survival in New South Wales (NSW) and the impact of distance from and access to cancer surgical services: a data linkage study

Cancer survival is poorer in rural NSW but specialist cancer surgical services are predominately located in the Sydney region. The aim of this thesis is to examine whether increasing distance from cancer surgical services affects access to those services and ultimately cancer survival. The method used was population based data linkage for patients diagnosed between 2000 and 2008 (data obtained from the NSW Central Cancer Registry database and linked to hospitalisations) and followed to the end of 2008. Distance was measured in kilometres from a person’s home to their hospital of surgery (bladder cancer) or the closest specialist hospital (ovarian and lung cancer) by using geographical coordinates. Associations were modelled using logistic regression and the hazard of death using Cox regression and the survival time parametric method (stpm2). The hazard of death decreased with distance for people with bladder cancer who had a cystectomy. People with ovarian and lung cancer who lived further from specialist surgical hospitals were much more likely to attend general hospitals, have advanced or unknown stage cancer at diagnosis and have limited or no surgery. Understanding the factors that impede referral to specialist surgical hospitals particularly those who live remotely is essential for optimal cancer survival

Treatment and survival from breast cancer: The experience of patients at South Australian teaching hospitals between 1977 and 2003

Rationale: Treatment guidelines recommend a more conservative surgical approach than mastectomy for early stage breast cancer and a stronger emphasis on adjuvant therapy. Registry data at South Australian teaching hospitals have been used to monitor survivals and treatment in relation to these guidelines. Aims and objectives: To use registry data to: (1) investigate trends in survival and treatment; and (2) compare treatment with guidelines. Methods: Registry data from three teaching hospitals were used to analyse trends in primary courses of treatment of breast cancers during 1977–2003 (n = 4671), using univariate analyses and multiple logistic regression. Disease-specific survivals were analysed using Kaplan–Meier product limit estimates and multivariable Cox proportional hazards regression. Results: The 5-year survival was 79.9%, but with a secular increase, reaching 83.6% in 1997–2003. The relative risk of death (95% confidence limits) was 0.74 (0.62, 0.88) for 1997–2003, compared with previous diagnoses, after adjusting for tumour node metastasis stage, grade, age and place of residence. Treatment changes included an increase in conservative surgery (as opposed to mastectomy) from 51.7% in 1977–1990 to 76.8% in 1997–2003 for stage I (P < 0.001) and from 31.1% to 52.2% across these periods for stage II (P < 0.001). Adjuvant radiotherapy also became more common (P < 0.001), with 20.6% of patients receiving this treatment in 1977–1990 compared with 60.7% in 1997–2003. Radiotherapy generally was more prevalent when conservative surgery was provided, although also relatively common in mastectomy patients when tumour diameters exceeded 50 mm or when there were four or more involved nodes. The proportion of patients receiving chemotherapy increased (P < 0.001), from 19.6% in 1977–1990 to 36.9% in 1997–2003, and the proportion having hormone therapy also increased (P < 0.001), from 34.3% to 59.4% between these periods. Conclusions: Survivals appear to be increasing and treatment trends are broadly consistent with guideline directions, and the earlier research on which these recommendations were based.Colin Luke, Grantley Gill, Stephen Birrell, Vlad Humeniuk, Martin Borg, Christos Karapetis, Bogda Koczwara, Ian Olver, Michael Penniment, Ken Pittman, Tim Price, David Walsh, Eng Kiat (Eric) Yeoh and David Rode