ORCID Profile
0000-0002-8402-8670
Current Organisations
NHS Grampian
,
University of Aberdeen
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Publisher: Springer Science and Business Media LLC
Date: 27-05-2012
DOI: 10.1038/NG.2293
Publisher: Oxford University Press (OUP)
Date: 30-09-2019
DOI: 10.1634/THEONCOLOGIST.2019-0291
Abstract: Bevacizumab, a VEGF-A inhibitor, in combination with chemotherapy, has proven to increase progression-free survival (PFS) and overall survival in multiple lines of therapy of metastatic colorectal cancer (mCRC). The angiogenic factor angiopoetin-2 (Ang-2) is associated with poor prognosis in many cancers, including mCRC. Preclinical models demonstrate improved activity when inhibiting both VEGF-A and Ang-2, suggesting that the dual VEGF-A and Ang-2 blocker vanucizumab (RO5520985 or RG-7221) may improve clinical outcomes. This phase II trial evaluated the efficacy of vanucizumab plus modified (m)FOLFOX-6 (folinic acid (leucovorin), fluorouracil (5-FU) and oxaliplatin) versus bevacizumab/mFOLFOX-6 for first-line mCRC. All patients received mFOLFOX-6 and were randomized 1:1 to also receive vanucizumab 2,000 mg or bevacizumab 5 mg/kg every other week. Oxaliplatin was given for eight cycles other agents were continued until disease progression or unacceptable toxicity for a maximum of 24 months. The primary endpoint was investigator-assessed PFS. One hundred eighty-nine patients were randomized (vanucizumab, n = 94 bevacizumab, n = 95). The number of PFS events was comparable (vanucizumab, n = 39 bevacizumab, n = 43). The hazard ratio was 1.00 (95% confidence interval, 0.64–1.58 p = .98) in a stratified analysis based on number of metastatic sites and region. Objective response rate was 52.1% and 57.9% in the vanucizumab and bevacizumab arm, respectively. Baseline plasma Ang-2 levels were prognostic in both arms but not predictive for treatment effects on PFS of vanucizumab. The incidence of adverse events of grade ≥3 was similar between treatment arms (83.9% vs. 82.1%) gastrointestinal perforations (10.8% vs. 8.4%) exceeded previously reported rates in this setting. Hypertension and peripheral edema were more frequent in the vanucizumab arm. Vanucizumab/mFOLFOX-6 did not improve PFS and was associated with increased rates of antiangiogenic toxicity compared with bevacizumab/mFOLFOX-6. Our results suggest that Ang-2 is not a relevant therapeutic target in first-line mCRC.
Publisher: BMJ
Date: 12-12-2017
DOI: 10.1136/GUTJNL-2017-315333
Abstract: Colorectal cancer (CRC) leads to significant morbidity/mortality worldwide. Defining critical research gaps (RG), their prioritisation and resolution, could improve patient outcomes. RG analysis was conducted by a multidisciplinary panel of patients, clinicians and researchers (n=71). Eight working groups (WG) were constituted: discovery science risk prevention early diagnosis and screening pathology curative treatment stage IV disease and living with and beyond CRC. A series of discussions led to development of draft papers by each WG, which were evaluated by a 20-strong patient panel. A final list of RGs and research recommendations (RR) was endorsed by all participants. Fifteen critical RGs are summarised below: RG1 : Lack of realistic models that recapitulate tumour/tumour micro/macroenvironment RG2 : Insufficient evidence on precise contributions of genetic/environmental/lifestyle factors to CRC risk RG3 : Pressing need for prevention trials RG4 : Lack of integration of different prevention approaches RG5 : Lack of optimal strategies for CRC screening RG6 : Lack of effective triage systems for invasive investigations RG7 : Imprecise pathological assessment of CRC RG8 : Lack of qualified personnel in genomics, data sciences and digital pathology RG9 : Inadequate assessment/communication of risk, benefit and uncertainty of treatment choices RG10 : Need for novel technologies/interventions to improve curative outcomes RG11 : Lack of approaches that recognise molecular interplay between metastasising tumours and their microenvironment RG12 : Lack of reliable biomarkers to guide stage IV treatment RG13 : Need to increase understanding of health related quality of life (HRQOL) and promote residual symptom resolution RG14 : Lack of coordination of CRC research/funding RG15 : Lack of effective communication between relevant stakeholders. Prioritising research activity and funding could have a significant impact on reducing CRC disease burden over the next 5 years.
Location: United Kingdom of Great Britain and Northern Ireland
Location: United Kingdom of Great Britain and Northern Ireland
No related grants have been discovered for Leslie Samuel.