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Bujko K.,The Maria Sklodowska Curie Memorial Cancer Center | Glynne-Jones R.,Mount Vernon Cancer Center | Bujko M.,The Maria Sklodowska Curie Memorial Cancer Center
Annals of Oncology | Year: 2010

Background: The results of the recently published large European randomised study in rectal cancer (European Organisation for Research and Treatment of Cancer 22921 trial) do not support current guidelines recommending postoperative chemotherapy for patients who have previously undergone preoperative radiochemotherapy or radiotherapy [radio(chemo)therapy]. To evaluate this discrepancy further, a systematic review of relevant randomised trials was undertaken. Materials and methods: A systematic literature search was carried out in order to identify randomised studies exploring adjuvant chemotherapy against observation in patients with rectal cancer previously treated with preoperative radio(chemo)therapy.Results: A statistically significant benefit of adjuvant chemotherapy was not found in any of the four relevant randomised trials. Non-protocolised subgroup analysis of one study indicated a beneficial effect of adjuvant chemotherapy for high rectal tumours and for patients downstaged to ypT0-2N0 but no effect for low-lying rectal tumours. However, the body of evidence indicates that patients downstaged after radio(chemo)therapy to ypT0-2N0 disease are not candidates for testing adjuvant chemotherapy in future trials due to the considerable over-treatment anticipated by this manoeuvre.Conclusions: To resolve the issue in question, a meta-analysis of relevant studies is required, and new trials should be launched to explore new drug combinations against observation. Currently, delivery of adjuvant chemotherapy in patients undergoing preoperative radio(chemo)therapy is not evidence based. © The Author 2010. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved.


Zweifel M.,Mount Vernon Cancer Center | Padhani A.R.,Mount Vernon Hospital
European Journal of Nuclear Medicine and Molecular Imaging | Year: 2010

Introduction: Classically, the first step in the clinical development of drugs in oncology involves assessments of dose limiting toxicity (DLT) and maximum tolerated dose (MTD). New paradigms are needed for antiangiogenic drugs and vascular disrupting agents (VDAs) as they are active at doses well below the MTD and as single agents their use might not translate into anti-tumour efficacy. MRI is able to assess the antivascular effects of antivascular drugs via changes in functional kinetic parameters; however, the usefulness of MRI in decision making has been questioned by many. Objectives: Our aim is to review the experience of using dynamic contrast-enhanced MRI (DCE-MRI) in early clinical development of vascular directed anticancer therapies over the last decade. Thirty-nine phase I and II studies including data on more than 700 patients have been published as abstracts and/or papers, documenting DCE-MRI changes after the administration of antiangiogenic drugs and VDAs. Discussion: Perfusion MRI is helpful in assessing whether mechanistic goals are achieved, in assisting dose selection for phase II studies, in selecting subpopulations enriched for response and in predicting patient benefit. Imaging tools are increasingly available. Future challenges for imaging include correlation with clinical measures of efficacy and determining relationships with blood and serum biomarkers. © 2010 Springer-Verlag.


Morton G.C.,University of Toronto | Hoskin P.J.,Mount Vernon Cancer Center
Clinical Oncology | Year: 2013

Brachytherapy delivers the most conformal high dose radiotherapy possible to the prostate, using either a low dose rate (LDR) or high dose rate (HDR) technique. It may be used either alone as monotherapy or in combination with external beam radiotherapy (EBRT) as a local boost. Comparative efficacy studies, including one randomised controlled trial, consistently show higher cancer control rates when brachytherapy is used compared with EBRT alone, with even some evidence of improvement in survival. There are now extensive mature data supporting the use of LDR as monotherapy for patients with low-risk and selected intermediate-risk disease, with most series reporting long-term disease control rates of over 90% after high-quality implants. HDR is most commonly combined with EBRT to treat intermediate- and high-risk disease, with disease control rates of over 90% reported. The low alpha/beta ratio of prostate cancer combined and the ability to optimally sculpt dose distribution provides the biological and dosimetric rationale for HDR. HDR enables more consistent implant quality than LDR, with evidence of lower acute and late toxicity. Many dose and fractionation schedules of HDR in combination with EBRT have been investigated, but a single fraction of 10-15Gy is commonly combined with EBRT to a dose of 40-50Gy to treat intermediate- and high-risk disease. High disease control rates are also reported with HDR as monotherapy, particularly in patients with low- and intermediate-risk disease. Although older series have delivered four to six fractions of HDR, there is growing evidence to support the delivery of HDR in three or even two fractions. Single-fraction HDR monotherapy is nowbeing investigated and if early data are confirmed with longer follow-up, may well become the treatment of choice for many men with localised prostate cancer. © 2013 The Royal College of Radiologists.


The increasing use of tomotherapy and volumetric-modulated arc therapy in UK centres will result in more centres choosing to use this technology in a clinical trial setting. The Radiotherapy Trials Quality Assurance (RTTQA) group has developed a new procedure to integrate into the UK intensity-modulated radiotherapy (IMRT) credentialing programme to cover rotational IMRT delivery techniques. A planning test [three-dimensional treatment planning system (3DTPS)] was designed specifically for rotational IMRT techniques. The feasibility of using this test in the credentialing programme for rotational IMRT was validated by 10 experienced UK centres. The study included five centres using Varian RapidArc™ (RA) (Varian Medical Systems, Milpitas, CA), two using Elekta VMAT™ (VMAT) (Elekta Inc., Norcross, GA) and three using helical tomotherapy (HT) plans. Centres were asked to carry out their own in-house quality assurance (QA) for the plans submitted for this study. A survey was sent out to centres aiming to gather information on their experience in undertaking the exercise and their QA results. All centres fulfilled the primary goal by achieving the dose constraints of the primary planning target volume and organ at risk. Seven centres (three RA, one VMAT and three HT plans) were able to fulfil the secondary goal. Among those seven centres, three centres (two RA and one VMAT plans) achieved the tertiary goal. The results of the survey indicated that the 3DTPS test is a clinically relevant and practical planning test to be used. A planning test for rotational therapy techniques was developed for the RTTQA IMRT credentialing programme. ADVANCES IN KNOWLEDGE: This study validated the feasibility of a 3DTPS test to be used as part of a credentialing programme for rotational IMRT techniques in the UK.


Background: Only one randomized trial has examined the value of performing routine CA125 measurements during follow-up of ovarian cancer. The results of this trial and implications of frequent CA125 measurements are examined. Patients and methods: The Medical Research Council OV05/European Organisation for Research and Treatment of Cancer 55955 trial enrolled 1442 patients with a CA125 level within the normal range following platinum-based chemotherapy for epithelial ovarian cancer. If CA125 levels rose to more than twice the upper limit of normal, patients were randomized to immediate or delayed chemotherapy. Results: Those randomized in the early arm started chemotherapy a median of 4.8 months earlier than those on the delayed arm. There was no difference in survival between the early and delayed arms. Conclusions: Women should be advised not to have routine CA125 measurements, providing they are well and have no symptoms suggesting relapse. In asymptomatic patients with a rising CA125 level, chemotherapy can be delayed. Earlier stopping of maintenance therapy just because of rising CA125 might deny patients continuing benefit from that therapy. Use of CA125 to define progression could result in platinum-sensitive patients being falsely classified as platinum resistant. ©The Author 2011. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved.


Maher E.J.,Mount Vernon Cancer Center
Acta Oncologica | Year: 2013

Background. In 2007 the English National Cancer Survivorship initiative was launched as a partnership between a national charity, Macmillan Cancer Support, the English Department of Health (DH) and the quality improvement agency NHS Improvement. The initiative involved a number of work streams, one of which was to improve the detection and management of the Consequences of adult cancer Treatment (COT). Material and methods. The adult COT group took evidence from a range of stakeholders and published a vision and work programme focused on awareness raising, linking self-administered questionnaires to routine activity data collection and testing new models of care with a particular focus on pelvic cancers. Results. Key outputs include national media campaigns, publications demonstrating the value of linking cancer treatment episodes to routine recording of chronic illness, identification of sensitive Patient Reported Outcome Measures (PROMs) items for use in national surveys, evidence reviews and published national guidelines, together with the development of a three level risk stratified model of care. Pilot testing with survivors treated for pelvic cancers, and adult survivors with radiation-induced brachial plexopathy has been completed. Conclusion. Early results suggest that a systematic approach to the prevention, detection and management of some treatment-related consequences can significantly improve the ability of patients to manage their conditions. As a result of these findings, new services have now been commissioned by the NHS, initially for those with complex problems. © 2013 Informa Healthcare.


Rustin G.J.,Mount Vernon Cancer Center
International journal of gynecological cancer : official journal of the International Gynecological Cancer Society | Year: 2010

Based on the results of the Medical Research Council OVO5/European Organisation for Research and Treatment of Cancer 55955 trial, the follow-up plan I recommend for patients in remission after completion of first-line therapy for advanced ovarian cancer is appointments: every 3 months for 2 years, every 4 months on the third year, then every 6 months thereafter, and discharge if no relapse by 10 years. History and examination (not internal) should be performed at each appointment. CA-125 should only be measured if there is a suspicion of relapse or at patient's request. No scans should be performed unless clinical indication or rising CA-125.


King J.W.,Mount Vernon Cancer Center | Nathan P.D.,Mount Vernon Cancer Center
Future Oncology | Year: 2014

Approximately 50% of patients with cutaneous metastatic melanoma harbor a somatic BRAF mutation. BRAF inhibitors are now established in the treatment paradigm of BRAF mutant melanoma, following the approval of vemurafenib by the US FDA in 2011. The vast majority of patients obtain some degree of tumor shrinkage with oral BRAF inhibitors, and responses are often rapid. However, resistance inevitably develops, with a median progression-free survival of 5-7 months. The oral MEK inhibitor trametinib has also shown activity in BRAF mutant melanoma in Phase Iii trials. We review the rationale for treating BRAF mutant melanoma with trametinib, as single-agent therapy and in combination with BRAF inhibitors, as well as the clinical data to date. © 2014 Future Medicine Ltd.


Alonzi R.,Mount Vernon Cancer Center
Clinical Oncology | Year: 2015

Various quantitative and semi-quantitative imaging biomarkers have been identified that may serve as valid surrogates for the risk of recurrence after radiotherapy. Tumour characteristics, such as hypoxia, vascularity, cellular proliferation and clonogen density, can be geographically mapped using biological imaging techniques. The potential gains in therapeutic ratio from the precision targeting of areas of intrinsic resistance makes focused dose escalation an exciting field of study. This overview will explore the issues surrounding biologically optimised radiotherapy, including its requirements, feasibility, technical considerations and potential applicability. © 2015 The Royal College of Radiologists.


Benafif S.,Mount Vernon Cancer Center | Hall M.,Mount Vernon Cancer Center
OncoTargets and Therapy | Year: 2015

The development of poly (adenosine diphosphate [ADP]) ribose polymerase (PARP) inhibitors (PARPi) has progressed greatly over the last few years and has shown encouraging results in the BRCA1/2 mutation–related cancers. This article attempts to summarize the rationale and theory behind PARPi, the clinical trials already reported, as well as ongoing studies designed to determine the role of PARPi in patients with and without germline mutations of BRCA genes. Future plans for PARPi both as monotherapy and in combination with standard cytotoxics, other biological agents, and as radiosensitizers are also covered. The widening scope of PARPi adds another important targeted agent to the growing list of molecular inhibitors; future and ongoing trials will identify the most effective role for PARPi, including for patients other than BRCA germline mutation carriers. © 2015 Benafif and Hall.

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