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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.


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.


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.


Smee R.I.,Prince of Wales Cancer Center | Broadley K.,Prince of Wales Cancer Center | Williams J.R.,Prince of Wales Cancer Center | Meagher N.S.,University of New South Wales | Bridger G.P.,Prince of Wales Cancer Center
Head and Neck | Year: 2011

Background Olfactory neuroblastoma is a rare paranasal sinus malignancy. The traditional approach was craniofacial resection (CFR) and then postoperative radiotherapy until 1998. This review will chart development of a new protocol. Methods This ethics-approved audit evaluated the number of new patients diagnosed with olfactory neuroblastoma, with information relating to patient, disease, and treatment factors noted. Results There were 24 eligible patients, 16 men, 8 women, 7 Kadish stage B, 17 stage C. The planned treatment was: chemotherapy (cisplatin/etoposide) and determine treatment dependent on response in 6 patients, surgery and radiotherapy in 16 patients, and single-modality treatment only (surgery, radiotherapy 1) in 2 patients. Surgery to radiotherapy occurred in 17 patients. With salvage treatment ultimate local control was 79%. Conclusions There was a higher local control in those patients who had surgery; abandoning this may carry a higher risk of local failure. The use of response to chemotherapy to determine local treatment remains experimental. © 2010 Wiley Periodicals, Inc.


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.


Wilson P.J.,Prince of Wales Cancer Center | Wilson P.J.,University of New South Wales | Williams J.R.,Prince of Wales Cancer Center | Smee R.I.,Prince of Wales Cancer Center | Smee R.I.,University of New South Wales
Journal of Clinical Neuroscience | Year: 2014

Cushing's disease is hypercortisolaemia secondary to an adrenocorticotrophic hormone secreting pituitary adenoma. Primary management is almost always surgical, with limited effective medical interventions available. Adjuvant therapy in the form of radiation is gaining popularity, with the bulk of the literature related to the Gamma Knife. We present the results from our own institution using the linear accelerator (LINAC) since 1990. Thirty-six patients who underwent stereotactic radiosurgery (SRS), one patient who underwent fractionated stereotactic radiotherapy (FSRT) and for the purposes of comparison, 13 patients who had undergone conventional radiotherapy prior to 1990, were included in the analysis. Serum cortisol levels improved in nine of 36 (25%) SRS patients and 24 hour urinary free cortisol levels improved in 13 of 36 patients (36.1%). Tumour volume control was excellent in the SRS group with deterioration in only one patient (3%). The patient who underwent FSRT had a highly aggressive tumour refractory to radiation. © 2013 Elsevier Ltd. All rights reserved.


Smee R.I.,Prince of Wales Cancer Center | Meagher N.S.,Prince of Wales Cancer Center | Williams J.R.,Prince of Wales Cancer Center | Broadley K.,Prince of Wales Cancer Center | Bridger G.P.,Prince of Wales Cancer Center
Head and Neck | Year: 2010

Background. Early glottic carcinoma has a high local control prospect with radiotherapy. This review evaluates a single center's experience. Methods. All patients from 1967 to 2006 diagnosed with Tis/T1/T2/N0 early glottic carcinoma treated definitively with radiotherapy at Prince of Wales Hospital were reviewed. Local control and cancer-specific survival (CSS) rates were primary endpoints, and the impact of various factors on these outcomes was statistically analyzed. Results. This review of 522 patients includes 24 with Tis, 356 with T1, and 142 with T2. Ultimate local control rates were as follows: Tis 87.5%, T1 94.7%, and T2 84.5%. Multivariate analysis found fitness for surgery, no involvement of anterior commissure, normal cord movement, and radiotherapy dose >60 Gy significant for local control. Fitness for surgery, no involvement of the anterior commissure, normal cord movement, and no ventricular involvement were significant prognostic factors for CSS. Conclusion. Definitive radiotherapy for early glottic carcinoma provides high local control rates, with the option of surgical salvage to achieve ultimate local control. © 2009 Wiley Periodicals, Inc.


Wilson P.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: 2014

Nelson's syndrome is a unique clinical phenomenon of growth of a pituitary adenoma following bilateral adrenalectomies for the control of Cushing's disease. Primary management is surgical, with limited effective medical therapies available. We report our own institution's series of this pathology managed with radiation: prior to 1990, 12 patients were managed with conventional radiotherapy, and between 1990 and 2007, five patients underwent stereotactic radiosurgery (SRS) and two patients fractionated stereotactic radiotherapy (FSRT), both using the linear accelerator (LINAC). Tumour control was equivocal, with two of the five SRS patients having a reduction in tumour volume, one patient remaining unchanged, and two patients having an increase in volume. In the FSRT group, one patient had a decrease in tumour volume whilst the other had an increase in volume. Treatment related morbidity was low. Nelson's syndrome is a challenging clinical scenario, with a highly variable response to radiation in our series. © 2014 Elsevier Ltd. All rights reserved.


Smee R.I.,Prince of Wales Cancer Center | De-Loyde K.J.,Prince of Wales Cancer Center | Broadley K.,Prince of Wales Cancer Center | Williams J.R.,Prince of Wales Cancer Center
Head and Neck | Year: 2013

Background The purpose of this study was to define prognostic factors for supraglottic laryngeal cancer that may influence management. Methods This ethics-approved study captured information on patients who presented with supraglottic laryngeal cancer between 1967 and 2008. Endpoints were local/ultimate failure and cancer-specific survival (CSS). Analysis was performed using chi-square, Fisher exact test, and logistic regression. Kaplan-Meier and Cox regression analysis were used to describe time-to-event data. Results Three hundred sixty-nine patients were analyzed. Two hundred seventeen patients received radiotherapy, 30 were treated with surgery, and 122 were treated with radiotherapy and surgery. The 5-year ultimate local control and CSS rates were 79.5% and 62.8%. Treatment type was a univariate predictor for outcome; however, it was not an independent predictor for ultimate local control or CSS. Conclusions This study highlights the fact that by documenting information it is possible to define prognostic factors. It also shows the importance of adjusting for clinical predictors such as patients being unfit for surgery. Copyright © 2012 Wiley Periodicals, Inc.


Wilson P.J.,Prince of Wales Cancer Center | 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: 2013

Primary treatment for growth-hormone secreting pituitary adenomas usually involves surgery, with treatment options for recurrent and persistent disease including repeat surgery, medication and radiation therapy. The majority of previously published series for radiation therapy in acromegaly in the past 20 years have been based on Gamma-Knife (Elekta, Stockholm, Sweden) surgery. To our knowledge, we present the largest series of linear accelerator-based treatment for this disease, with a review of 121 patients treated at our institution; since 1990, 86 patients underwent stereotactic radiosurgery (SRS), 10 patients underwent fractionated stereotactic radiotherapy (FSRT), and for the purposes of comparison we also reviewed 25 patients who underwent conventional radiotherapy prior to 1990. Tumour volume control in all three groups was excellent and consistent with previously reported literature - only three of 86 (4%) patients undergoing SRS had a documented increase in tumour size, and none of the patients undergoing FSRT had a documented increase in size following a median follow-up of 5.5 and 5.1 years for SRS and FSRT, respectively. Target growth hormone levels of <2.5 ng/mL were met by 12 of 86 (14%) of the SRS group, and by two of 10 (20%) in the FSRT group. Target insulin-like growth factor-1 levels of age and sex matched controls were achieved in 16 of 86 patients (18.6%) post-SRS and five of 10 patients (50%) post-FSRT. New hormonal deficits requiring replacement therapy were identified in 17 of 86 (19.8%) patients post-SRS which is consistent with previously published radiosurgical series. Identified non-hormonal morbidity was low (<5%). © 2013 Elsevier Ltd. All rights reserved.

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