Graham K.,Beatson West of Scotland Cancer Center |
Burton K.,Royal Infirmary
Current Oncology Reports | Year: 2013
Squamous cell carcinoma of the vulva is an uncommon gynaecological malignancy, but the incidence is increasing. A significant proportion of patients present with locally advanced disease, and management can prove challenging because of the size and/or location of the tumour. Surgery forms the mainstay of treatment, but the role of neoadjuvant therapy in minimizing morbidity is under investigation. Although chemotherapy alone has been largely neglected in favour of chemoradiotherapy, concerns about the toxicity of trimodality therapy and suboptimal results, particularly in node-positive patients, have led to renewed interest in neoadjuvant chemotherapy (NACT). A review of the available literature illustrates that NACT can produce dramatic responses, but operability rates and overall survival differ widely. The effect is dependent on as yet unidentified factors, although we speculate that age and tumour biology are important. Further work is required to delineate the optimal NACT regimen and the patient population(s) most likely to benefit from this practice. © 2013 Springer Science+Business Media New York.
Coleman R.,University of Sheffield |
Cameron D.,University of Edinburgh |
Dodwell D.,University of Leeds |
Bell R.,Andrew Love Cancer Center |
And 12 more authors.
The Lancet Oncology | Year: 2014
Background: The role of adjuvant bisphosphonates in early breast cancer is uncertain. We therefore did a large randomised trial to investigate the effect of the adjuvant use of zoledronic acid on disease-free survival (DFS) in high-risk patients with early breast cancer. Methods: In the AZURE trial, an open-label, international, multicentre, randomised, controlled, parallel-group phase 3 trial, women (age ≥18 years) with stage II or III breast cancer were randomly assigned (1:1) by a central automated 24-h computer-generated telephone minimisation system (balanced for number of involved axillary lymph nodes, tumour stage, oestrogen receptor status, type and timing of systemic therapy, menopausal status, statin use, and treatment centre) to receive standard adjuvant systemic treatment alone (control group) or with 4 mg intravenous zoledronic acid every 3-4 weeks for six doses, then every 3 months for eight doses, followed by every 6 months for five doses, for a total of 5 years of treatment. The primary endpoint was disease-free survival (DFS). Secondary endpoints were invasive DFS (IDFS), overall survival, time to bone metastases, time to distant recurrence, and subgroup analyses of variables included in the randomisation. All patients have completed study treatment. Results from the intention-to-treat final analysis of this fully recruited study are presented after a median follow-up of 84 months (IQR 66-93). This final efficacy analysis was planned to take place after 940 DFS events. This trial is registered with ClinicalTrials.gov, NCT00072020. Findings: 3360 women were recruited from 174 centres in seven countries between Sept 4, 2003, and Feb 16, 2006. The number of DFS events did not differ between groups: 493 in the control group and 473 in the zoledronic acid group (adjusted hazard ratio [HR] 0·94, 95% CI 0·82-1·06; p=0·30). IDFS (HR 0·93, 95% CI 0·82-1·05; p=0·22), overall survival (0·93, 0·81-1·08; p=0·37), and distant recurrences (0·93, 0·81-1·07; p=0·29) were much the same in both groups. Zoledronic acid reduced the development of bone metastases, both as a first event (HR 0·78, 95% CI 0·63-0·96; p=0·020) and at any time during follow-up (0·81, 0·68-0·97; p=0·022). The effects of zoledronic acid on DFS were not affected by oestrogen-receptor status. However, zoledronic acid improved IDFS in those who were over 5 years since menopause at trial entry (n=1041; HR 0·77, 95% CI 0·63-0·96) but not in all other (premenopause, perimenopause, and unknown status) menopausal groups (n=2318; HR 1·03, 95% CI 0·89-1·20). 33 cases of suspected osteonecrosis of the jaw have been reported, with 26 confirmed on central review, all in the zoledronic acid group (1·7%, 95% CI 1·0-2·4). Interpretation: These results suggest no overall benefit from the addition of zoledronic acid to standard adjuvant treatments for early breast cancer. However, zoledronic acid does reduce the development of bone metastases and, for women with established menopause, improved disease outcomes. © 2014 Elsevier Ltd.
Barrett S.,Beatson West of Scotland Cancer Center
Journal of the Royal College of Physicians of Edinburgh | Year: 2010
Breast cancer is now the most common cancer of women in the UK and incidence is increasing. Because of major treatment advances and earlier diagnosis over the past 40 years, survival rates have been improving gradually and women diagnosed with breast cancer today are almost twice as likely to survive for 10 years or longer as women 40 years ago. However, breast cancer remains a major contributor to cancer morbidity and mortality in the UK. The majority of patients present with potentially curative disease and surgery is the mainstay of treatment. Many patients receive adjuvant (post-operative) therapy, which reduces the risk of loco-regional and distant disease recurrence. Treatment options include radiotherapy, chemotherapy, endocrine therapy and biological agents, with treatment increasingly tailored to the individual tumour and patient, aiming to provide maximum survival benefit with minimum toxicity. Many patients participate in clinical trials of radiotherapy, new agents, drug combinations or novel dosing regimens. Patients with metastatic disease can rarely be offered curative treatment, but improved quality of life and prolonged survival may be achieved with palliative treatment, including hormones, chemotherapy, radiotherapy, trastuzumab and bisphosphonates. This overview aims to summarise current knowledge and recent developments in the management of breast cancer. © 2010 Royal College of Physicians of Edinburgh.
Glasspool R.M.,Beatson West of Scotland Cancer Center |
McNeish I.A.,Beatson West of Scotland Cancer Center |
McNeish I.A.,University of Glasgow
Current Oncology Reports | Year: 2013
Clear cell carcinomas of the female genital tract are rare tumours with a fearsome reputation for having poor responses to conventional platinum-based chemotherapy and poor prognosis. However, it is now clear that early-stage ovarian clear cell carcinoma has an excellent prognosis and may not require any adjuvant therapy. In addition, radiotherapy may also have a key role to play in adjuvant management of clear cell tumours. Identification of patients who truly do not need adjuvant chemotherapy is important. The past 3 years has seen a significant improvement in our understanding of clear cell carcinoma biology - in particular, the role of mutations in the chromatin remodelling gene ARID1A as key drivers that are common to clear cell carcinomas of ovarian and endometrial origin. Moreover, gynaecological clear cell carcinomas appear to share many features with renal clear cell tumours, suggesting a common pathogenesis. This raises the possibility of clinical trials that include patients with clear cell tumours from different organs of origin. Dissecting the role of disordered chromatin organisation in clear cell carcinoma pathogenesis is a key priority. Finally, the role of endometriosis and the attendant chronic inflammation are recognised. The inflammatory cytokine interleukin-6 appears to play a key role in clear cell carcinoma biology and is an excellent potential therapeutic target. © 2013 Springer Science+Business Media New York.
Graham J.S.,Beatson West of Scotland Cancer Center |
Cassidy J.,University of Glasgow
Expert Review of Anticancer Therapy | Year: 2012
Huge advances have been made in the treatment of colon cancer over the last decade. Success has been most noticeable in stage IV disease - where careful selection of patients with small-volume disease for treatment with surgical resection ± perioperative chemotherapy has resulted in an improvement in survival of approximately 5-50%; and stage III - disease where the advent of 5-fluorouracil/oxaliplatin, as adjuvant treatment has also resulted in a significant prolongation in survival. Progression-free survival is now an established surrogate for overall survival, and has resulted in more timely reporting of adjuvant studies and therefore faster integration of promising agents into the clinic. Targeted agents, which have shown promise in the metastatic setting, are currently being examined in the adjuvant setting, although results so far are disappointing. Patients with high-risk stage II cancer remain a challenging group. They have a poorer prognosis than those with stage IIIA disease, and national and international guidance recommend offering chemotherapy after careful discussion of the pros and cons. Despite the fact that we have identified many of the biological features that make stage II disease higher risk, we still struggle to achieve the same improvement in survival for this subgroup compared with others. It may be that these patients required treatment with alternative regimens and predictive biomarkers would be particularly helpful. © 2012 Expert Reviews Ltd.
Huddart R.A.,Institute of Cancer Research |
Gabe R.,Medical Research Council Clinical Trials Unit |
Cafferty F.H.,Medical Research Council Clinical Trials Unit |
Pollock P.,Medical Research Council Clinical Trials Unit |
And 4 more authors.
European Urology | Year: 2015
Background Standard chemotherapy for poor-prognosis metastatic nonseminoma has remained bleomycin, etoposide, and cisplatin (BEP) for many years; more effective regimens are required. Objective To explore whether response rates with a new intensive chemotherapy regimen, CBOP/BEP (carboplatin, bleomycin, vincristine, cisplatin/BEP), versus those in concurrent patients treated with standard BEP justify a phase 3 trial. Design, setting, and participants We conducted a phase 2 open-label randomised trial in patients with germ cell tumours of any extracranial primary site and one or more International Germ Cell Cancer Collaborative Group poor-prognosis features. Patients were randomised between 2005 and 2009 at 16 UK centres. Intervention BEP (bleomycin 30 000 IU) was composed of four cycles over 12 wk. CBOP/BEP was composed of 2 × CBOP, 2 × BO, and 3 × BEP (bleomycin 15 000 IU). Outcome measurements and statistical analysis Primary end point was favourable response rate (FRR) comprising complete response or partial response and normal markers. Success required the lower two-sided 90% confidence limit to exclude FRRs <60%; 44 patients on CBOP/BEP gives 90% power to achieve this if the true FRR is ≤80%. Equal numbers were randomised to BEP to benchmark contemporary response rates. Results and limitations A total of 89 patients were randomised (43 CBOP/BEP, 46 BEP); 40 and 41, respectively, completed treatment. CBOP/BEP toxicity, largely haematologic, was high (96% vs 63% on BEP had Common Terminology Criteria for Adverse Events v.3 grade ≤3). FRRs were 74% (90% confidence interval [CI], 61-85) with CBOP/BEP, 61% with BEP (90% CI, 48-73). After a median of 58-mo follow-up, 1-yr progression-free survival (PFS) was 65% and 43%, respectively (hazard ratio: 0.59; 95% CI, 0.33-1.06); 2-yr overall survival (OS) was 67% and 61%. Overall, 3 of 14 CBOP/BEP and 2 of 18 BEP deaths were attributed to toxicity, one after an overdose of bleomycin during CBOP/BEP. The trial was not powered to compare PFS. Conclusions The primary outcome was met, the CI for CBOP/BEP excluding FRRs <61%, but CBOP/BEP was more toxic. PFS and OS data are promising but require confirmation in an international phase 3 trial. Patient summary In this study we tested a new, more intensive way to deliver a combination of drugs often used to treat men with testicular cancer. We found that response rates were higher but that the CBOP/BEP regimen caused more short-term toxicity. Because most patients are diagnosed when their cancer is less advanced, it took twice as long to complete the trial as expected. Although we plan to carry out a larger trial, we will need international collaboration. © 2014 European Association of Urology.
Lindsay C.R.,Beatson West of Scotland Cancer Center |
Spiliopoulou P.,Beatson West of Scotland Cancer Center |
Waterston A.,Beatson West of Scotland Cancer Center
Therapeutic Advances in Medical Oncology | Year: 2015
Until recently, treatment for metastatic melanoma was characterised by a limited availability of treatment options that offer objective survival benefit. Cytotoxic agents fundamentally lack the ability to achieve disease control and cytokine therapy with interleukin-2 has an unacceptably high - for the use across all patient cohorts - rate of toxicities. The validation of braf as an oncogene driving melanoma tumorigenesis, as well as the discovery of the role of CTLA-4 receptor in the evasion of anticancer immune response by melanoma, has revolutionised our treatment options against a disease with dismal prognosis. Quick implementation of translational discoveries brought about BRAF/MEK inhibition in clinic, while at the same time, wider experience with CTLA-4 blockade enabled clinicians to manage previously fatal immune-related toxicities with greater confidence. The suitability for clinical use of other oncogenic drivers such as NRAS and c-kit is currently being tested whilst the PD-1/PD-L1/PD-L2 axis has emerged as a new immunotherapy target with exciting early phase results. The recent exponential progress in treatment of melanoma has set an example of translational medicine and the current review aims to explain why, as well as suggesting new goals for the future. © The Author(s), 2015.
Jones R.,Beatson West of Scotland Cancer Center |
Desantis M.,Ludwig Boltzmann Research Institute
Seminars in Oncology | Year: 2013
There is limited access to targeted therapies for renal cancer in many parts of the western world. This is driven by reimbursement rather than regulatory issues. Indeed, only a small fraction of the global population benefits from unlimited reimbursement of targeted therapies. Dedicated bodies, such as the UK National Institute for Clinical Excellence, assess agents on their cost-effectiveness as well as their efficacy. The results have been disappointing for patients, with the majority of agents being rejected for reimbursement. Despite this trend, there is a general appetite to address cost and value in many part of the world. This article gives a current overview of this rapidly changing field. © 2013 Elsevier Inc.
Zubairi I.,Beatson West of Scotland Cancer Center |
Jones R.,Beatson West of Scotland Cancer Center |
Jones R.,University of Glasgow
European Urology Focus | Year: 2016
Patients with metastatic clear cell renal cancer should still be considered for cytoreductive nephrectomy, even though the evidence for this relates mainly to the period before modern systemic therapy. Metastasectomy should also be considered when there is a chance of complete surgical clearance. For patients with inoperable progressive metastases there are now a number of effective systemic therapies that should be considered. In the first-line setting, the options include the tyrosine kinase inhibitors sunitinib and pazopanib. © 2015 European Association of Urology.
Glen H.,Beatson West of Scotland Cancer Center
Future Oncology | Year: 2016
Despite advances in metastatic renal cell carcinoma (mRCC) treatments, patients eventually progress and develop resistance to therapies targeting a single pathway. Lenvatinib inhibits VEGFR1-3, FGFR1-4, PDGFRβ, RET and KIT proto-oncogenes. In a randomized, Phase II trial evaluating patients with mRCC who had progressed after one prior VEGF-targeted therapy, progression-free survival was significantly improved with lenvatinib alone or in combination with everolimus versus everolimus alone. This review summarizes the clinical development of lenvatinib in mRCC, and how simultaneous targeting of multiple pathways involved in carcinogenesis and/or therapeutic resistance may improve patient outcomes. Lenvatinib plus everolimus may be a promising second-line treatment in patients with mRCC. © 2016 Future Medicine Ltd.