Adelaide Cancer Center
Adelaide Cancer Center
Eatock M.M.,Belfast City Hospital |
Tebbutt N.C.,Northern Health |
Bampton C.L.,Adelaide Cancer Center |
Strickland A.H.,Monash Medical Centr |
And 9 more authors.
Annals of Oncology | Year: 2013
Background: We evaluated AMG 386, an investigational peptibody that neutralizes the interaction between angiopoietins-1 and -2 and the Tie2 receptor, combined with cisplatin/capecitabine (CX) as first-line treatment for metastatic gastro-oesophageal cancer. Patients and Methods: Patients with metastatic gastric, gastro-oesophageal junction, or distal oesophageal adenocarcinoma were randomized 1:1:1 to CX (cisplatin 80 mg/m2 IV Q3W; capecitabine 1000 mg/m2 P.O. BID for 14 days Q3W) plus intravenous AMG 386 10 mg/kg QW (Arm A) or 3 mg/kg QW (Arm B), or placebo QW (Arm C). The primary end point was estimated progression-free survival (PFS). Results: A total of 171 patients were enrolled. Median estimated PFS in Arms A, B, and C was 4.2, 4.9, and 5.2 months, respectively (hazard ratio for Arms A+B combined versus Arm C, 0.98; 95% CI 0.67-1.43; P = 0.92). Objective response rates were 27% (Arm A), 43% (Arm B), and 35% (Arm C). Incidence of grade ≥3 adverse events was 80% in Arm A, 84% in Arm B, and 75% in Arm C. There was no evidence of pharmacokinetic interactions. Conclusions: In this study, PFS and ORR were estimated to be similar with AMG 386 plus CX and placebo plus CX treatment. Compared with placebo, toxicity of AMG 386 plus CX was greater but manageable. Previous presentation: The results ofthis study have not been previously published or submitted for publication elsewhere. The results were presented in part at the Gastrointestinal Cancers Symposium, San Francisco, CA, January 20-22, 2011. © The Author 2012. Published by Oxford University Press on behalf of the European Society for Medical Oncology.
PubMed | Cedars Sinai Comprehensive Cancer Center, Adelaide Cancer Center, Monash University, Alfred Hospital and Boreal Genomics
Type: | Journal: Leukemia | Year: 2016
Mutational characterisation in multiple myeloma (MM) currently relies on bone marrow (BM) biopsy, which fails to capture the putative spatial and genetic heterogeneity of this multifocal disease. Analysis of plasma (PL)-derived circulating free tumour DNA (ctDNA) as an adjunct to BM biopsy, for mutational characterisation and tracking disease progression, was evaluated. Paired BM MM cell DNA and ctDNA from 33 relapsed/refractory (RR) and 15 newly diagnosed (ND) patients were analysed for KRAS, NRAS, BRAF and TP53 mutations using the OnTarget Mutation Detection (OMD) platform. OMD detected 128 mutations (PL=31, BM=59, both=38) indicating the presence of PL mutations (54%). A higher frequency of PL-only mutations was detected in RR patients than ND (27.2% vs 6.6%, respectively), authenticating the existence of spatial and genetic heterogeneity in advanced disease. Activating RAS mutations were more highly prevalent than previously described with 69% harboring at least one RAS mutation. Sequential ctDNA quantitation with droplet digital PCR through longitudinal PL tracking of specific clones in seven patients demonstrated changes in fractional abundance of certain clones reflective of the disease status. We conclude that ctDNA analysis as an adjunct to BM biopsy represents a noninvasive and holistic strategy for improved mutational characterisation and therapeutic monitoring of MM.Leukemia advance online publication, 3 January 2017; doi:10.1038/leu.2016.366.
Vermorken J.B.,University of Antwerp |
Stohlmacher-Williams J.,Universitatsklinikum Carl Gustav Carus |
Davidenko I.,Krasnodar City Oncology Center |
Licitra L.,Fondazione IRCCS Instituto Nazionale Tumori |
And 14 more authors.
The Lancet Oncology | Year: 2013
Background: Previous trials have shown that anti-EGFR monoclonal antibodies can improve clinical outcomes of patients with recurrent or metastatic squamous-cell carcinoma of the head and neck (SCCHN). We assessed the efficacy and safety of panitumumab combined with cisplatin and fluorouracil as first-line treatment for these patients. Methods: This open-label phase 3 randomised trial was done at 126 sites in 26 countries. Eligible patients were aged at least 18 years; had histologically or cytologically confirmed SCCHN; had distant metastatic or locoregionally recurrent disease, or both, that was deemed to be incurable by surgery or radiotherapy; had an Eastern Cooperative Oncology Group performance status of 1 or less; and had adequate haematological, renal, hepatic, and cardiac function. Patients were randomly assigned according to a computer-generated randomisation sequence (1:1; stratified by previous treatment, primary tumour site, and performance status) to one of two groups. Patients in both groups received up to six 3-week cycles of intravenous cisplatin (100 mg/m2 on day 1 of each cycle) and fluorouracil (1000 mg/m2 on days 1-4 of each cycle); those in the experimental group also received intravenous panitumumab (9 mg/kg on day 1 of each cycle). Patients in the experimental group could choose to continue maintenance panitumumab every 3 weeks. The primary endpoint was overall survival and was analysed by intention to treat. In a prospectively defined retrospective analysis, we assessed tumour human papillomavirus (HPV) status as a potential predictive biomarker of outcomes with a validated p16-INK4A (henceforth, p16) immunohistochemical assay. Patients and investigators were aware of group assignment; study statisticians were masked until primary analysis; and the central laboratory assessing p16 status was masked to identification of patients and treatment. This trial is registered with ClinicalTrials.gov, number NCT00460265. Findings: Between May 15, 2007, and March 10, 2009, we randomly assigned 657 patients: 327 to the panitumumab group and 330 to the control group. Median overall survival was 11·1 months (95% CI 9·8-12·2) in the panitumumab group and 9·0 months (8·1-11·2) in the control group (hazard ratio [HR] 0·873, 95% CI 0·729-1·046; p=0·1403). Median progression-free survival was 5·8 months (95% CI 5·6-6·6) in the panitumumab group and 4·6 months (4·1-5·4) in the control group (HR 0·780, 95% CI 0·659-0·922; p=0·0036). Several grade 3 or 4 adverse events were more frequent in the panitumumab group than in the control group: skin or eye toxicity (62 [19%] of 325 included in safety analyses vs six [2%] of 325), diarrhoea (15 [5%] vs four [1%]), hypomagnesaemia (40 [12%] vs 12 [4%]), hypokalaemia (33 [10%] vs 23 [7%]), and dehydration (16 [5%] vs seven [2%]). Treatment-related deaths occurred in 14 patients (4%) in the panitumumab group and eight (2%) in the control group. Five (2%) of the fatal adverse events in the panitumumab group were attributed to the experimental agent. We had appropriate samples to assess p16 status for 443 (67%) patients, of whom 99 (22%) were p16 positive. Median overall survival in patients with p16-negative tumours was longer in the panitumumab group than in the control group (11·7 months [95% CI 9·7-13·7] vs 8·6 months [6·9-11·1]; HR 0·73 [95% CI 0·58-0·93]; p=0·0115), but this difference was not shown for p16-positive patients (11·0 months [7·3-12·9] vs 12·6 months [7·7-17·4]; 1·00 [0·62-1·61]; p=0·998). In the control group, p16-positive patients had numerically, but not statistically, longer overall survival than did p16-negative patients (HR 0·70 [95% CI 0·47-1·04]). Interpretation: Although the addition of panitumumab to chemotherapy did not improve overall survival in an unselected population of patients with recurrent or metastatic SCCHN, it improved progression-free survival and had an acceptable toxicity profile. p16 status could be a prognostic and predictive marker in patients treated with panitumumab and chemotherapy. Prospective assessment will be necessary to validate our biomarker findings. Funding: Amgen Inc. © 2013 Elsevier Ltd.
Parente P.,Box Hill Hospital |
Parente P.,Monash University |
Parnis F.,Adelaide Cancer Center |
Gurney H.,Westmead Hospital
Asia-Pacific Journal of Clinical Oncology | Year: 2014
Prior to 2010, docetaxel was the standard option for chemotherapy in men with metastatic castration-resistant prostate cancer (mCRPC). Today, the picture is vastly different: several additional therapies have each demonstrated a survival benefit such that we now have chemotherapy (cabazitaxel), androgen suppressive agents (abiraterone acetate and enzalutamide), a cellular vaccine (sipuleucel-T) and radium-233 (for symptomatic bone metastases). With several other agents in the pipeline for late-stage disease, the future looks promising for mCRPC. As the available data are not able to inform as to the optimum sequencing of therapy, this remains a challenge. This paper draws on insights from published and ongoing clinical studies to provide a practical patient-focused approach to maximize the benefits of the current therapeutic armamentarium. Preliminary sequencing suggestions are made based on clinical trial criteria. But until more data become available, clinical gestalt, experience, cost and individual patient preferences will continue to drive choices. © 2014 Wiley Publishing Asia Pty Ltd.
Burge M.,Royal Brisbane and Womens Hospital |
Francesconi A.B.,Royal Brisbane and Womens Hospital |
Kotasek D.,Adelaide Cancer Center |
Fida R.,Cytopia Research Pty Ltd |
And 4 more authors.
Investigational New Drugs | Year: 2013
Summary: Purpose CYT997 is a novel microtubule inhibitor and vascular disrupting agent. This phase I trial examined the safety, tolerability, pharmacokinetics and vascular-disrupting effects of orally-administered CYT997. Experimental design We performed a phase I accelerated dose-escalation study of CYT997 given orally once every 2 to 3 weeks in patients with advanced solid tumours. Vascular disruption was assessed by measurement of plasma von Willebrand factor (vWF) levels and dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI). Results A total of 56 doses were administered to 21 patients over 8 dose levels (15-164 mg/m2). Grade 3 fatigue and grade 3 hypoxia were dose limiting. Oral bioavailability was observed with approximate linear pharmacokinetics over the 11-fold dose range. At doses of 84 mg/m 2 and above, plasma vWF levels increased above baseline and DCE-MRI scans showed reductions in tumour Ktrans in some patients. Conclusions CYT997 is orally bioavailable. The 118 mg/m2 dose level should be used to guide dosing in future studies. © 2012 Springer Science+Business Media, LLC.
Parente P.,Box Hill Hospital |
Parente P.,Monash University |
Parnis F.,Adelaide Cancer Center |
Gurney H.,Westmead Hospital
Asia-Pacific Journal of Clinical Oncology | Year: 2011
Since the establishment of docetaxel as first-line chemotherapy for metastatic castration-resistant prostate cancer significant advancements have been made in the management of this disease. Clinical trials have investigated agents for use prior to docetaxel, in combination with docetaxel and agents for second-line treatment for patients who have progressed despite docetaxel. In addition, several new agents have been developed and clinically investigated in the fields of hormonal, cytotoxic, targeted and immune therapy, providing options either side of first-line chemotherapy. As a result of this considerable research activity, three new therapies; cabazitaxel, sipuleucel-T and abiraterone acetate, have each demonstrated improvement in overall survival in phase III trials and have been approved by the US Food and Drug Administration. With so many new therapies now available and in the pipeline, the management of metastatic castration-resistant prostate cancer is undergoing a significant and positive change. This article discusses current and future options for second-line therapy in metastatic castration-resistant prostate cancer, providing insight into the potential roles of these new treatment options in the Australian clinical setting. © 2012 Blackwell Publishing Asia Pty Ltd.
PubMed | Adelaide Cancer Center, University of South Australia and Macquarie University
Type: Journal Article | Journal: BMJ open | Year: 2016
The prevention and management of venous thromboembolism (VTE) is often at variance with guidelines. The CareTrack Australia (CTA) study reported that appropriate care (in line with evidence-based or consensus-based guidelines) is being provided for VTE at just over half of eligible encounters. The aim of this paper is to present and discuss the detailed CTA findings for VTE as a baseline for compliance with guidelines at a population level.The setting was 27 hospitals in 2 states of Australia.A sample of participants designed to be representative of the Australian population was recruited. Participants who had been admitted overnight during 2009 and/or 2010 were eligible. Of the 1154 CTA participants, 481(42%) were admitted overnight to hospital at least once, comprising 751 admissions. There were 279 females (58%), and the mean age was 64 years.The primary measure was compliance with indicators of appropriate care for VTE. The indicators were extracted from Australian VTE clinical practice guidelines and ratified by experts. Participants medical records from 2009 to 2010 were analysed for compliance with 38 VTE indicators.Of the 35,145 CTA encounters, 1078 (3%) were eligible for scoring against VTE indicators. There were 2-84 eligible encounters per indicator at 27 hospitals. Overall compliance with indicators for VTE was 51%, and ranged from 34% to 64% for aggregated sets of indicators.The prevention and management of VTE was appropriate for only half of the at-risk patients in our sample; this provides a baseline for tracking progress nationally. There is a need for national and, ideally, international agreement on clinical standards, indicators and tools to guide, document and monitor care for VTE, and for measures to increase their uptake, particularly where deficiencies have been identified.
Wickham N.,Adelaide Cancer Center |
Gallus A.S.,Flinders University |
Walters B.N.J.,The University of Notre Dame Australia |
Walters B.N.J.,King Edward Memorial Hospital for Women and Royal Perth Hospital |
Wilson A.,Research Translation Group Melbourne
Internal Medicine Journal | Year: 2012
Each year in Australia, about 1 in 1000 people develop a first episode of venous thromboembolism (VTE), which approximates to about 20000 cases. More than half of these episodes occur during or soon after a hospital admission, which makes them potentially preventable. This paper summarises recommendations from the National Health and Medical Research Council's 'Clinical Practice Guideline for the Prevention of Venous Thromboembolism in Patients Admitted to Australian Hospitals' and describes the way these recommendations were developed. The guideline has two aims: to provide advice on VTE prevention to Australian clinicians and to support implementation of effective programmes for VTE prevention in Australian hospitals by offering evidence-based recommendations which local hospital guidelines can be based on. Methods for preventing VTE are pharmacological and/or mechanical, and they require appropriate timing, dosing and duration and also need to be accompanied by good clinical care, such as promoting mobility and hydration whilst in hospital. With some procedures or injuries, the risk of VTE is sufficiently high to require that all patients receive an effective form of prophylaxis unless this is contraindicated; in other clinical settings, the need for prophylaxis requires individual assessment. For optimal VTE prevention, all patients admitted to hospital should have early and formal assessments of: (i) their intrinsic VTE risk and the risks related to their medical conditions; (ii) the added VTE risks resulting from surgery or trauma; (iii) bleeding risks that would contraindicate pharmacological prophylaxis; (iv) any contraindications to mechanical prophylaxis, culminating in (v) a decision about prophylaxis (pharmacological and/or mechanical, or none). The most appropriate form of prophylaxis will depend on the type of surgery, medical condition and patient characteristics. Recommendations for various clinical circumstances are provided as summary tables with relevance to orthopaedic surgical procedures, other types of surgery and medical inpatients. In addition, the tables indicate the grades of supporting evidence for the recommendations (these range from Grade A which can be trusted to guide practice, to Grade D where there is more uncertainty; Good Practice Points are consensus-based expert opinions). © 2012 National Health and Medical Research Council. Internal Medicine Journal © 2012 Royal Australasian College of Physicians.
Wickham N.,Adelaide Cancer Center
The Journal of laryngology and otology | Year: 2013
Osteonecrosis is a benign condition characterised by necrotic exposed bone, and is associated with bisphosphonate use. Osteonecrosis of the external auditory canal is rare, with only a few reported cases. Two case reports of temporal bone osteonecrosis are presented. A 64-year-old man with a history of immunoglobulin G kappa multiple myeloma developed a right external auditory canal ulcer 6 years after commencement on clodronate. A 72-year-old woman taking alendronate for osteoporosis, initially diagnosed and treated for right-sided otitis externa, was found to have underlying exposed bone in the right external auditory canal, with a computed tomography scan confirming destruction of the temporal bone. With increasing use of both oral and intravenous bisphosphonates in the community for benign conditions such as osteoporosis and for malignant conditions such as breast cancer and multiple myeloma, the diagnosis of bisphosphonate-associated osteonecrosis should always be considered in patients with a temporal bone lesion, and a relevant drug history taken.
PubMed | Adelaide Cancer Center
Type: Journal Article | Journal: Journal of clinical oncology : official journal of the American Society of Clinical Oncology | Year: 2016
1101 Background: Numerous options exist for adjuvant chemotherapy in EBC. Docetaxel cyclophosphamide (TC) is increasingly used because of its superiority over doxorubicin and cyclophosphamide (AC) (Jones et al 2009), and the lack of anthracycline induced cardiac injury. Myelosuppression and febrile neutropenia are frequent adverse events (AE) of TC. Jones reported that in the phase III trial FN occurred in 5% of all patients and in 8% of those over 65. There was no requirement for use of prophylactic growth factors or antibiotics in the trial. Subsequent publications have reported rates of FN ranging from 25-50% (Chan 2010, Vandenberg 2010, Soong 2009).We investigated the frequency of FN in consecutive EBC patients treated with TC in a community practice setting of predominantly high socio-economic class, fit patients, and examined the effect of primary prophylaxis with pegfilgrastim. We anticipated low rates of FN.74 EBC patients (median age 58 yrs, range 35-84 yrs) were treated between 1/2008 and 8/2010 with TC (T 75 mg/mWe were surprised to see such high rates of FN in a medically fit and generally well population. Our results are consistent with others, and significantly in excess of the original study. We recommend that all patients receiving TC therapy in EBC receive primary pegfilgrastim prophylaxis or prophylactic antibiotics.