Medical Education - Research Publications

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    Evaluation of Managing Cancer and Living Meaningfully (CALM) in people with advanced non-small cell lung cancer treated with immunotherapies or targeted therapies: protocol for a single-arm, mixed-methods pilot study
    Lynch, FA ; Rodin, G ; Jefford, M ; Duffy, M ; Lai-Kwon, J ; Heynemann, S ; Mileshkin, L ; Briggs, L ; Burke, J ; Leigh, L ; Spelman, T ; Ftanou, M (BMJ PUBLISHING GROUP, 2023-07)
    INTRODUCTION: People with advanced non-small cell lung cancer (NSCLC) treated with immunotherapies (IT) or targeted therapies (TT) may have improved outcomes in a subset of people who respond, raising unique psychological concerns requiring specific attention. These include the need for people with prolonged survival to reframe their life plans and tolerate uncertainty related to treatment duration and prognosis. A brief intervention for people with advanced cancer, Managing Cancer and Living Meaningfully (CALM), could help people treated with IT or TT address these concerns. However, CALM has not been specifically evaluated in this population. This study aims to evaluate the acceptability and feasibility of CALM in people with advanced NSCLC treated with IT or TT and obtain preliminary evidence regarding its effectiveness in this population. METHODS AND ANALYSIS: Twenty people with advanced NSCLC treated with IT or TT will be recruited from Peter MacCallum Cancer Centre, Melbourne, Australia. Participants will complete three to six sessions of CALM delivered over 3-6 months. A prospective, single-arm, mixed-methods pilot study will be conducted. Participants will complete outcome measures at baseline, post-intervention, 3 months and 6 months, including Patient Health Questionnaire, Death and Dying Distress Scale, Functional Assessment of Cancer Therapy General and Clinician Evaluation Questionnaire. The acceptability of CALM will be assessed using patient experiences surveys and qualitative interviews. Feasibility will be assessed by analysis of recruitment rates, treatment adherence and intervention delivery time. ETHICS AND DISSEMINATION: Ethics approval has been granted by the Peter MacCallum Cancer Centre Human Research Ethics Committee (HREC/82047/PMCC). Participants with cancer will complete a signed consent form prior to participation, and carers and therapists will complete verbal consent. Results will be made available to funders, broader clinicians and researchers through conference presentations and publications. If CALM is found to be acceptable in this cohort, this will inform a potential phase 3 trial.
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    Multiomic analysis of homologous recombination-deficient end-stage high-grade serous ovarian cancer
    Burdett, NL ; Willis, MO ; Alsop, K ; Hunt, AL ; Pandey, A ; Hamilton, PT ; Abulez, T ; Liu, X ; Hoang, T ; Craig, S ; Fereday, S ; Hendley, J ; Garsed, DW ; Milne, K ; Kalaria, S ; Marshall, A ; Hood, BL ; Wilson, KN ; Conrads, KA ; Pishas, K ; Ananda, S ; Scott, CL ; Antill, Y ; McNally, O ; Mileshkin, L ; Hamilton, A ; Au-Yeung, G ; Devereux, L ; Thorne, H ; Bild, A ; Bateman, NW ; Maxwell, GL ; Chang, JT ; Conrads, TPP ; Nelson, BH ; Bowtell, DDL ; Christie, ELL (NATURE PORTFOLIO, 2023-03)
    High-grade serous ovarian cancer (HGSC) is frequently characterized by homologous recombination (HR) DNA repair deficiency and, while most such tumors are sensitive to initial treatment, acquired resistance is common. We undertook a multiomics approach to interrogate molecular diversity in end-stage disease, using multiple autopsy samples collected from 15 women with HR-deficient HGSC. Patients had polyclonal disease, and several resistance mechanisms were identified within most patients, including reversion mutations and HR restoration by other means. We also observed frequent whole-genome duplication and global changes in immune composition with evidence of immune escape. This analysis highlights diverse evolutionary changes within HGSC that evade therapy and ultimately overwhelm individual patients.
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    Modified study designs to expand treatment options in personalised oncology: a multistakeholder view
    Le Tourneau, C ; Andre, F ; Helland, A ; Mileshkin, L ; Minnaard, W ; Schiel, A ; Tasken, K ; Thomas, DM ; Veronese, ML ; Duran-Pacheco, G ; Leyens, L ; Rufibach, K ; Thomas, M ; Kraemer, A (ELSEVIER SCI LTD, 2023-11)
    Personalised oncology, whereby patients are given therapies based on their molecular tumour profile, is rapidly becoming an essential part of optimal clinical care, at least partly facilitated by recent advances in next-generation sequencing-based technology using liquid- and tissue-based biopsies. Consequently, clinical trials have shifted in approach, from traditional studies evaluating cytotoxic chemotherapy in largely histology-based populations to modified, biomarker-driven studies (e.g. basket, umbrella, platform) of molecularly guided therapies and cancer immunotherapies in selected patient subsets. Such modified study designs may assess, within the same trial structure, multiple cancer types and treatments, and should incorporate a multistakeholder perspective. This is key to generating complementary, fit-for-purpose and timely evidence for molecularly guided therapies that can be used as proof-of-concept to inform further study designs, lead to approval by regulatory authorities and be used as confirmation of clinical benefit for health technology assessment bodies. In general, the future of cancer clinical trials requires a framework for the application of innovative technologies and dynamic design methodologies, in order to efficiently transform scientific discoveries into clinical utility. Next-generation, modified studies that involve the joint efforts of all key stakeholders will offer individualised strategies that ultimately contribute to globalised knowledge and collective learning. In this review, we outline the background and purpose of such modified study designs and detail key aspects from a multistakeholder perspective. We also provide methodological considerations for designing the studies and highlight how insights from already-ongoing studies may address current challenges and opportunities in the era of personalised oncology.
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    Palliative care facilitates the preparedness of caregivers for thoracic cancer patients
    Zomerdijk, N ; Panozzo, S ; Mileshkin, L ; Yoong, J ; Nowak, AK ; Stockler, MR ; Philip, J (WILEY, 2022-11)
    OBJECTIVE: Palliative care improves outcomes for patients with thoracic cancer; however, limited evidence exists for the benefits of this approach for caregivers. This study aimed to advance understanding of the experiences of palliative care described by bereaved caregivers. METHODS: Fifteen adult caregivers completed semi-structured interviews following prior participation in a randomised controlled trial of early referral to palliative care versus discretionary referral to palliative care. Interviews explored caregiver experiences of palliative care delivery. Interview transcripts were thematically analysed. RESULTS: Four related themes about the experiences of palliative care were identified, each of which required sufficient time between palliative care first contact and death: 'relationship building'; 'clear communication and information'; 'access to practical support'; and 'access to psychosocial support'. The core category underpinning these themes was palliative care facilitates caregiver preparedness. Caregivers noted that palliative care played a critical role in preparing them for the future and described a sense of practical and emotional 'relief' associated with the support services made available to them. CONCLUSION: Our findings emphasise that palliative care can have a positive impact on caregivers' preparedness for providing the care needed by thoracic cancer patients and that this can improve the experiences of both caregivers and patients.
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    A comparison of DNA sequencing and gene expression profiling to assist tissue of origin diagnosis in cancer of unknown primary
    Posner, A ; Prall, OW ; Sivakumaran, T ; Etemadamoghadam, D ; Thio, N ; Pattison, A ; Balachander, S ; Fisher, K ; Webb, S ; Wood, C ; DeFazio, A ; Wilcken, N ; Gao, B ; Karapetis, CS ; Singh, M ; Collins, IM ; Richardson, G ; Steer, C ; Warren, M ; Karanth, N ; Wright, G ; Williams, S ; George, J ; Hicks, RJ ; Boussioutas, A ; Gill, AJ ; Solomon, BJ ; Xu, H ; Fellowes, A ; Fox, SB ; Schofield, P ; Bowtell, D ; Mileshkin, L ; Tothill, RW (WILEY, 2023-01)
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    Healthcare Costs Before and After Diagnosis of Cancer of Unknown Primary Versus Ovarian Cancer in Australia
    Gordon, LG ; Wood, C ; Tothill, RW ; Webb, PM ; Schofield, P ; Mileshkin, L (SPRINGER INT PUBL AG, 2023-01)
    BACKGROUND: Little is known about the healthcare resource usage and costs for patients with cancer of unknown primary (CUP). OBJECTIVE: The aim of this study was to describe and quantify healthcare resource use and costs in Australia, 6 months prior to and after a diagnosis of CUP, and compare to those of women with ovarian cancer. METHODS: Individual-level data combining baseline surveys, clinical records and Medicare Benefits Schedule (MBS) claim records were analysed for 149 patients with CUP and 480 patients with ovarian cancer from two prospective cohort studies. MBS data were aggregated for the period 6 months prior to diagnosis date and 6 months after diagnosis. Data included doctor consultations, pathology, diagnostics, therapeutic procedures, imaging, allied health and medicines. Generalised linear models were used to evaluate the cost differences between CUP and ovarian cancer using gamma family and log link functions. Models were adjusted for age, employment, marital status, surgery, chemotherapy and number of comorbidities. RESULTS: The mean healthcare costs in the 6 months prior to diagnosis of CUP were Australian (AU) $3903 versus AU$1327 for ovarian cancer (adjusted cost ratio 2.94, 95% confidence interval [CI] 2.08-4.15). Mean healthcare costs 6 months post-diagnosis were higher for patients with CUP versus ovarian cancer (AU$20,339 vs AU$13,819, adjusted cost ratio 1.47, 95% CI 1.13-1.92). Higher costs for patients with CUP were driven by imaging (AU$1937 vs AU$1387), procedures (AU$5403 vs AU$2702) and prescribed medicines for all conditions (AU$10,111 vs AU$6717). CONCLUSIONS: Pre-diagnosis costs for patients with CUP are nearly triple those for ovarian cancer. Six months after diagnosis, healthcare costs for CUP remained higher than for ovarian cancer due to imaging, procedures and medicines.
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    Results of PD-L1 Analysis of Women Treated with Durvalumab in Advanced Endometrial Carcinoma (PHAEDRA)
    Smith, D ; Robledo, KP ; Yip, S ; Cummins, MM ; Kok, P-S ; Lee, YC ; Friedlander, M ; Baron-Hay, S ; Shannon, C ; Coward, J ; Beale, P ; Goss, G ; Meniawy, T ; Lombard, J ; Spurdle, AB ; Andrews, J ; Stockler, MR ; Mileshkin, L ; Antill, Y (MDPI, 2023-01)
    Women with advanced endometrial carcinoma (EC) with mismatch repair (MMR) deficiency have improved outcomes when treated with immune checkpoint inhibitors; however, additional biomarkers are needed to identify women most likely to respond. Scores for programmed death ligand 1 (PD-L1), immunohistochemical staining of tumor (TC+), immune cells (IC+) and presence of tumor-associated immune cells (ICP) on MMR deficient (n = 34) and proficient (n = 33) EC from women treated with durvalumab in the PHAEDRA trial (ANZGOG1601/CTC0144) (trial registration number ACTRN12617000106336, prospectively registered 19 January 2017) are reported and correlated with outcome. Receiver operating characteristic (ROC) analyses and area under the ROC curve were used to determine optimal cutpoints. Performance was compared with median cutpoints and two algorithms; a novel algorithm derived from optimal cutpoints (TC+ ≥ 1 or ICP ≥ 10 or IC+ ≥ 35) and the Ventana urothelial carcinoma (UC) algorithm (either TC+ ≥ 25, ICP > 1 and IC+ ≥ 25 or ICP = 1 and IC+ = 100). The cutpoint ICP ≥ 10 had highest sensitivity (53%) and specificity (82%), being prognostic for progression-free survival (PFS) (p = 0.01), while the optimal cutpoints algorithm was associated with overall survival (p = 0.02); these results were not significant after adjusting for MMR status. The optimal cutpoints algorithm identified non-responders (p = 0.02) with high sensitivity (88%) and negative predictive value (92%), remaining significant after adjustment for MMR. Although MMR status had the strongest association with response, further work to determine the significance of ICP ≥ 10 and the novel optimal cutpoint algorithm is needed.
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    CCNE1 Amplification as a Therapeutic Target
    Au-Yeung, G ; Mileshkin, L ; Bowtell, DDL (LIPPINCOTT WILLIAMS & WILKINS, 2023-03-20)
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    Women with gynaecological cancer awaiting radiotherapy: Self-reported wellbeing, general psychological distress, symptom distress, sexual function, and supportive care needs
    Gough, K ; Bergin, RJ ; Drosdowsky, A ; Aranda, S ; Mileshkin, L ; Jackson, M ; Kinnane, N ; Bernshaw, D ; Juraskova, I ; White, K ; Mohamed, M ; Schofield, P (ACADEMIC PRESS INC ELSEVIER SCIENCE, 2022-10)
    OBJECTIVE: To better serve women with gynaecological cancers, we need a sound understanding of their health, wellbeing and needs. This study sought to explore these issues in a sample of Australian women before commencing curative radiotherapy. METHODS: We undertook a secondary analysis of baseline data from a supportive care trial (n = 311). Descriptive statistics were used to summarise responses to measures of wellbeing, general psychological distress, symptom distress, sexual function and vaginal changes, and supportive care needs. Pre-specified regression models were used to examine sources of variation in wellbeing and sexual function. RESULTS: Women reported lower emotional, functional and physical wellbeing than population norms (all p < 0.001). The prevalence of general psychological distress was 31% (95% CI 26-36%). Distress caused by physical symptoms was typically low. Health system and information needs comprised eight of the top ten moderate-to-high supportive care needs. Most women reported no change in interest for physical contact or sex compared to pre-diagnosis, but some sexually active women (16-24%) reported smaller vaginal size, increased dryness, and more pain on intercourse. General psychological distress was a robust marker of poorer wellbeing and sexual function. CONCLUSIONS: Before radiotherapy, a substantial minority of women with gynaecological cancers experience general psychological distress, reduced wellbeing and moderate-to-high health system and information needs. A model of comprehensive care incorporating assessment of unmet needs, general psychological distress, and sexual issues is recommended. Healthcare providers may require training to elicit and respond to a constellation of interrelated issues and access relevant services for women requiring additional support.
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    Immune and genomic biomarkers of immunotherapy response in cancer of unknown primary
    Posner, A ; Sivakumaran, T ; Pattison, A ; Etemadmoghadam, D ; Thio, N ; Wood, C ; Fisher, K ; Webb, S ; DeFazio, A ; Wilcken, N ; Gao, B ; Karapetis, CS ; Singh, M ; Collins, IM ; Richardson, G ; Steer, C ; Warren, M ; Karanth, N ; Fellowes, A ; Fox, SB ; Hicks, RJ ; Schofield, P ; Bowtell, D ; Prall, OWJ ; Tothill, RW ; Mileshkin, L (BMJ PUBLISHING GROUP, 2023-01)
    BACKGROUND: Cancer of unknown primary (CUP) is a heterogeneous group of metastatic cancers where a primary tissue of origin (TOO) is uncertain. Most patients with CUP have limited treatment options and poor survival outcomes. Immune checkpoint inhibitors (ICIs) can be efficacious in some patients with CUP, but the optimal predictive biomarkers are unknown. We therefore assessed immune and genomic biomarkers as well as predicted TOO in patients with CUP, including a subset treated with ICIs. METHODS: Patients with CUP were subject to gene-expression profiling (GEP) and DNA panel sequencing. Immune and stromal-related gene expression was explored by NanoString, including genes associated with immunotherapy response (IR) in other solid malignancies. ICI responsive cancer types were assigned based on Food and Drug Administration-approved indications, and either detection of a latent primary tumor or the TOO was suspected based on genomics informed pathology review. Tumor mutation burden (TMB) and gene mutations were also assessed. RESULTS: A total of 219 patients with CUP were included, 215 assessed for TOO in a previous study, with the majority (163) receiving both RNA and DNA tests. Of GEP profiled cases, 33% (59/175) had a high IR gene-expression score. Of the DNA sequenced cases, 16% (32/203) had high TMB (>10 mutations/Mb), including two with mismatch repair deficiency. Low correlation was observed between TMB and an IR score (R=0.26, p<0.001). Among 110 CUPs with a latent primary or suspected TOO, 47% (52/110) belonged to ICI-responsive cancer types. More than half of the CUPs had at least one feature that may predict ICI response (high IR score, high TMB, ICI-responsive cancer type). Among patients with CUP treated with ICIs, 8/28 (29%) responded (2 complete responses and 6 partial responses). Among non-responders, 9 had stable and 11 had progressive disease. All responders had a high IR score (7/8) and/or high TMB (3/8), while most (5/8) belonged to ICI-responsive cancer types. These features were detected at a lower frequency in non-responders and mostly in patients with stable disease. CONCLUSIONS: A significant fraction of CUP tumors had genomic features previously associated with ICI response. High IR score was the most sensitive predictive feature of ICI response, warranting evaluation in a larger patient series.