ORCID Profile
0000-0001-5303-0017
Current Organisation
University of Newcastle Faculty of Health
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Publisher: Wiley
Date: 10-05-2023
DOI: 10.1002/CPT.2922
Publisher: Wiley
Date: 06-03-2019
DOI: 10.1111/AJCO.13144
Abstract: 5-Fluorouracil (5-FU) is administered with leucovorin (LV) to enhance clinical activity. However, simultaneous administration is not feasible due to their chemical incompatibility, so conditions for the maximum possible beneficial interaction cannot be met. To overcome this, we developed a novel all-in-one, pH neutral stable solution of 5-FU plus LV with β-cyclodextrin (termed Deflexifol) and assessed its safety and tolerability in a first-in-human phase I trial. Patients with advanced solid malignancy received Deflexifol as weekly bolus (375-575 mg/m²) or two-weekly 46 h infusion (1200-3600 mg/m²) for six cycles in a 3+3 dose escalation design. Adverse events, pharmacokinetics and tumor response rates were assessed by standard methods. Forty patients were treated (19 bolus, 21 infusional, median age 67) with no grade 4 adverse events reported. Dose-limiting toxicities of grade 3 diarrhea and myelosuppression were reported for the bolus schedule at 575 mg/m Deflexifol is safer and effective in bolus and infusion schedules at higher doses than that permitted by separate infusion of 5-FU and LV. A phase II study evaluating Deflexifol is planned.
Publisher: Wiley
Date: 12-06-2022
DOI: 10.1002/CPT.2667
Abstract: Fluoropyrimidines (FP 5‐fluorouracil, capecitabine, and tegafur) are a commonly prescribed class of antimetabolite chemotherapies, used for various solid organ malignancies in over 2 million patients globally per annum. Dihydropyrimidine dehydrogenase (DPD), encoded by the DPYD gene, is the critical enzyme implicated in FP metabolism. DPYD variant genotypes can result in decreased DPD production, leading to the development of severe toxicities resulting in hospitalization, intensive care admission, and even death. Management of toxicity incurs financial burden on both patients and healthcare systems alike. Upfront DPYD genotyping to identify variant carriers allows an opportunity to identify patients who are at high risk to suffer from serious toxicities and allow prospective dose adjustment of FP treatment. This approach has been shown to reduce patient morbidity, as well as improve the cost‐effectiveness of managing FP treatment. Upfront DPYD genotyping has been recently endorsed by several countries in Europe and the United Kingdom. This review summarizes current knowledge about DPD deficiency and upfront DPYD genotyping, including clinical and cost‐effectiveness outcomes, with the intent of supporting implementation of an upfront DPYD genotyping service with in idualized dose‐personalization.
Publisher: Wiley
Date: 19-02-2013
DOI: 10.1111/AJCO.12065
Publisher: Springer Science and Business Media LLC
Date: 17-04-2020
Publisher: Springer Science and Business Media LLC
Date: 12-2019
DOI: 10.1186/S12885-019-6405-7
Abstract: Retrospective studies show improved outcomes in colorectal cancer patients if taking statins, including overall survival, pathological response of rectal cancer to preoperative chemoradiotherapy (pCRT), and reduced acute and late toxicities of pelvic radiation. Major tumour regression following pCRT has strong prognostic significance and can be assessed in vivo using MRI-based tumour regression grading (mrTRG) or after surgery using pathological TRG (pathTRG). A double-blind phase 2 trial will randomise 222 patients planned to receive long-course fluoropyrimidine-based pCRT for rectal adenocarcinoma at 18+ sites in New Zealand and Australia. Patients will receive simvastatin 40 mg or placebo daily for 90 days starting 1 week prior to standard pCRT. Pelvic MRI 6 weeks after pCRT will assess mrTRG grading prior to surgery. The primary objective is rates of favourable (grades 1–2) mrTRG following pCRT with simvastatin compared to placebo, considering mrTRG in 4 ordered categories (1, 2, 3, 4–5). Secondary objectives include comparison of: rates of favourable pathTRG in resected tumours incidence of toxicity compliance with intended pCRT and trial medication proportion of patients undergoing surgical resection cancer outcomes and pathological scores for radiation colitis. Tertiary objectives include: association between mrTRG and pathTRG grouping inter-observer agreement on mrTRG scoring and pathTRG scoring studies of T-cell infiltrates in diagnostic biopsies and irradiated resected normal and malignant tissue and the effect of simvastatin on markers of systemic inflammation (modified Glasgow prognostic score and the neutrophil-lymphocyte ratio). Trial recruitment commenced April 2018. When completed this study will be able to observe meaningful differences in measurable tumour outcome parameters and/or toxicity from simvastatin. A positive result will require a larger RCT to confirm and validate the merit of statins in the preoperative management of rectal cancer. Such a finding could also lead to studies of statins in conjunction with chemoradiation in a range of other malignancies, as well as further exploration of possible mechanisms of action and interaction of statins with both radiation and chemotherapy. The translational substudies undertaken with this trial will provisionally explore some of these possible mechanisms, and the tissue and data can be made available for further investigations. ANZ Clinical Trials Register ACTRN12617001087347 . ( www.anzctr.org.au , registered 26/7/2017) Protocol Version: 1.1 (June 2017).
Publisher: Wiley
Date: 08-2020
DOI: 10.1111/IMJ.14948
Publisher: Informa UK Limited
Date: 05-2013
DOI: 10.1586/ERA.13.37
Abstract: The medical treatment of colorectal cancer (CRC) has evolved greatly in the last 10 years, involving complex combined chemotherapy protocols and, in more recent times, new biologic agents. Advances in adjuvant therapy have been limited to the addition of oxaliplatin and the substitution of oral fluoropyrimidine (e.g., capecitabine) for intravenous 5-fluorouracil with no evidence for improved outcome with biological agents. Clinical benefit from the use of the targeted monoclonal antibodies, bevacizumab, cetuximab and panitumumab, in the treatment of metastatic CRC is now well established, but the optimal timing of their use requires careful consideration to derive the maximal benefit. Evidence to date suggests potentially distinct roles for bevacizumab and EGF receptor-targeted biological agents (cetuximab and panitumumab) in the treatment of metastatic CRC. This article reviews the evidence in support of modern treatments for CRC and the decision-making behind the treatment choices, their benefits and toxicities.
No related grants have been discovered for Stephen Ackland.