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Audeh M.W.,Cedars Sinai Medical Center | Carmichael J.,Astrazeneca | Penson R.T.,Dana-Farber Cancer Institute | Friedlander M.,Prince of Wales Cancer Center | And 11 more authors.
The Lancet | Year: 2010

Background Olaparib is a novel, orally active poly(ADP-ribose) polymerase (PARP) inhibitor that induces synthetic lethality in homozygous BRCA-deficient cells. We aimed to assess the efficacy and safety of olaparib for treatment of advanced ovarian cancer in patients with BRCA1 or BRCA2 mutations. Methods In this international, multicentre, phase 2 study, we enrolled two sequential cohorts of women (aged ≥18 years) with confirmed genetic BRCA1 or BRCA2 mutations, and recurrent, measurable disease. The study was undertaken in 12 centres in Australia, Germany, Spain, Sweden, and the USA. The first cohort (n=33) was given continuous oral olaparib at the maximum tolerated dose of 400 mg twice daily, and the second cohort (n=24) was given continuous oral olaparib at 100 mg twice daily. The primary efficacy endpoint was objective response rate (ORR). This study is registered with ClinicalTrials.gov, number NCT00494442. Findings Patients had been given a median of three (range 1-16) previous chemotherapy regimens. ORR was 11 (33%) of 33 patients (95% CI 20-51) in the cohort assigned to olaparib 400 mg twice daily, and three (13%) of 24 (4-31) in the cohort assigned to 100 mg twice daily. In patients given olaparib 400 mg twice daily, the most frequent causally related adverse events were nausea (grade 1 or 2, 14 [42%]; grade 3 or 4, two [6%]), fatigue (grade 1 or 2, ten [30%]; grade 3 or 4, one [3%]), and anaemia (grade 1 or two, five [15%]; grade 3 or 4, one [3%]). The most frequent causally related adverse events in the cohort given 100 mg twice daily were nausea (grade 1 or 2, seven [29%]; grade 3 or 4, two [8%]) and fatigue (grade 1 or 2, nine [38%]; none grade 3 or 4). Interpretation Findings from this phase 2 study provide positive proof of concept of the efficacy and tolerability of genetically targeted treatment with olaparib in BRCA-mutated advanced ovarian cancer. Source


Tutt A.,Breakthrough Breast Cancer Research Unit | Robson M.,Sloan Kettering Cancer Center | Garber J.E.,Dana-Farber Cancer Institute | Domchek S.M.,University of Pennsylvania | And 11 more authors.
The Lancet | Year: 2010

Background Olaparib, a novel, orally active poly(ADP-ribose) polymerase (PARP) inhibitor, induced synthetic lethality in BRCA-deficient cells. A maximum tolerated dose and initial signal of efficacy in BRCA-deficient ovarian cancers have been reported. We therefore assessed the efficacy, safety, and tolerability of olaparib alone in women with BRCA1 or BRCA2 mutations and advanced breast cancer. Methods Women (aged ≥18 years) with confirmed BRCA1 or BRCA2 mutations and recurrent, advanced breast cancer were assigned to two sequential cohorts in a phase 2 study undertaken in 16 centres in Australia, Germany, Spain, Sweden, the UK, and the USA. The first cohort (n=27) was given continuous oral olaparib at the maximum tolerated dose (400 mg twice daily), and the second (n=27) was given a lower dose (100 mg twice daily). The primary efficacy endpoint was objective response rate (ORR). This study is registered with ClinicalTrials.gov, number NCT00494234. Findings Patients had been given a median of three previous chemotherapy regimens (range 1-5 in cohort 1, and 2-4 in cohort 2). ORR was 11 (41%) of 27 patients (95% CI 25-59) in the cohort assigned to 400 mg twice daily, and six (22%) of 27 (11-41) in the cohort assigned to 100 mg twice daily. Toxicities were mainly at low grades. The most frequent causally related adverse events in the cohort given 400 mg twice daily were fatigue (grade 1 or 2, 11 [41%]; grade 3 or 4, four [15%]), nausea (grade 1 or 2, 11 [41%]; grade 3 or 4, four [15%]), vomiting (grade 1 or 2, three [11%]; grade 3 or 4, three [11%]), and anaemia (grade 1 or 2, one [4%]; grade 3 or 4, three [11%]). The most frequent causally related adverse events in the cohort given 100 mg twice daily were nausea (grade 1 or 2, 11 [41%]; none grade 3 or 4) and fatigue (grade 1 or 2, seven [26%]; grade 3 or 4, one [4%]). Interpretation The results of this study provide positive proof of concept for PARP inhibition in BRCA-deficient breast cancers and shows a favourable therapeutic index for a novel targeted treatment strategy in patients with tumours that have genetic loss of function of BRCA1-associated or BRCA2-associated DNA repair. Toxicity in women with BRCA1 and BRCA2 mutations was similar to that reported previously in those without such mutations. Source


Wilson P.J.,Wollongong Hospital | De-Loyde K.J.,Prince of Wales Cancer Center | Williams J.R.,Prince of Wales Cancer Center | Smee R.I.,Prince of Wales Cancer Center
Journal of Clinical Neuroscience | Year: 2012

Non-functioning pituitary adenomas are primarily a surgically managed pathology, but recurrence or regrowth is not uncommon. Previous large series have retrospectively validated the use of the Gamma Knife (GK) as an adjuvant treatment. To our knowledge, we present the largest case series to date with the Linear Accelerator (Linac) for the management of this pathology. In this study we review the clinical course of 118 patients, 51 of whom had stereotactic radiosurgery (SRS) and 67 who had fractionated stereotactic radiotherapy (FSRT); the discriminatory feature being proximity to the optic chiasm. For comparison purposes a population of 53 patients who had conventional radiotherapy (CRT) is included. The local control rates at 5 years for SRS, FRST and CRT were 100%, 93% and 87% respectively. Treatment-related morbidity was low. These data confirm that Linac SRS and FSRT are safe and effective for the treatment of non-functioning pituitary adenomas. © 2011 Elsevier Ltd. All rights reserved. Source


Kangas M.,Macquarie University | Tate R.L.,University of Sydney | Williams J.R.,Prince of Wales Cancer Center | Smee R.I.,Prince of Wales Cancer Center
Neuro-Oncology | Year: 2012

A paucity of studies have evaluated the biopsychosocial factors contributing to quality of life (QoL) in adults with a primary brain tumor (BT). Our objective was to investigate (i) the effects of radiotherapy on the psychosocial (ie, posttraumatic stress symptoms [PTSS]) and cognitive functioning of adults with a primary BT, assessed preradiotherapy [T1] and postradiotherapy [T2], and (ii) predictors of PTSS and QoL postradiotherapy. Seventy adults with a BT were assessed at T1, and 67 patients were reassessed 3.5 months postradiotherapy. At each assessment, participants completed measures of PTSS, mood, QoL, and quality of social support and neurocognitive tests focusing on memory and executive functioning. Minimal differences in functioning were found between patients according to BT type (benign [n 45] vs malignant [n 25]) and tumor laterality (left vs right hemisphere), with 2 exceptions. Individuals with a left hemisphere benign BT experienced greater distress at T1, which declined at T2, whereas individuals with a left hemisphere malignant BT reported poorer social support at T2. The full sample performed poorly on tests of executive functioning, and 17 reported clinically elevated PTSS at T1, which reduced to 13 at T2. Younger age (<65 y), reduced QoL, and elevated anger symptoms at T1 predicted PTSS at T2, whilst having a benign BT, low PTSS, and depressive symptoms at T1 were predictive of improved QoL at T2. Findings highlight the importance of screening for psychosocial and cognitive disturbances in BT patients undergoing treatment to identify those at risk for acute and more prolonged problems. © 2012 The Author(s). Source


Vaidya K.,Prince of Wales Cancer Center | Smee R.,Prince of Wales Cancer Center | Smee R.,University of New South Wales | Williams J.R.,Prince of Wales Cancer Center
Journal of Clinical Neuroscience | Year: 2012

The aim of this study was to determine factors of prognostic relevance for paediatric ependymomas, and evaluate the efficacy of treatment modalities. This is a retrospective study of 43 patients with ependymoma (<18 years) who underwent a combination of surgical excision, chemotherapy, and/or radiotherapy treatment at The Prince of Wales Cancer Centre between 1969 and 2009. Statistical analysis was performed to assess the prognostic relevance of various parameters affecting the two-year and five-year overall survival (OS) and progression-free survival (PFS). The five-year OS and PFS were 50.3% and 44.8% respectively (median follow-up 50 months). Eighteen patients (41.9%) experienced tumour recurrence: 13 had a local recurrence (LR) and five had both LR and distant recurrence. On univariate analysis, a more favourable prognosis in terms of both OS and PFS was evident for supratentorial tumours compared to infratentorial tumours (OS p = 0.007, PFS p = 0.045), stereotactic radiosurgery/ fractionated stereotactic radiotherapy compared to craniospinal irradiation or local posterior fossa/local brain ± boost radiotherapy modalities (OS p = 0.047, PFS p = 0.031), total radiotherapy dose >50 Gy compared to ≤50 Gy (OS p = 0.008, PFS p = 0.005), and in patients with no tumour recurrence compared to those with recurrence (OS p = 0.03, PFS p < 0.001). Although not statistically significant, a more favourable multivariate outcome was evident in patients who underwent complete surgical resection. Chemotherapy treatment and histopathological grade, however, were not relevant to prognosis. This study supports the need to pursue more aggressive treatment for infratentorial and/or recurrent tumours. Ideal treatment involves maximal surgical resection, followed by adjuvant radiotherapy (>50 Gy). © 2012 Elsevier Ltd. All rights reserved. Source

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