• Monitoring dosimetric impact of weight loss with kilovoltage (kV) cone beam CT (CBCT) during parotid-sparing IMRT and concurrent chemotherapy.

      Ho, Kean F; Marchant, Thomas E; Moore, Christopher J; Webster, Gareth J; Rowbottom, Carl G; Pennington, Hazel; Lee, Lip W; Yap, Beng K; Sykes, Andrew J; Slevin, Nicholas J; et al. (2012-03-01)
      Parotid-sparing head-and-neck intensity-modulated radiotherapy (IMRT) can reduce long-term xerostomia. However, patients frequently experience weight loss and tumor shrinkage during treatment. We evaluate the use of kilovoltage (kV) cone beam computed tomography (CBCT) for dose monitoring and examine if the dosimetric impact of such changes on the parotid and critical neural structures warrants replanning during treatment.
    • Positron emission tomography imaging approaches for external beam radiation therapies: current status and future developments.

      Price, Patricia M; Green, Melanie M; Department of Academic Radiation Oncology, The University of Manchester, The Christie Hospital NHS Foundation Trust, Manchester, UK. pprice@imperial.ac.uk (2011-12)
      In an era in which it is possible to deliver radiation with high precision, there is a heightened need for enhanced imaging capabilities to improve tumour localisation for diagnostic, planning and delivery purposes. This is necessary to increase the accuracy and overall efficacy of all types of external beam radiotherapy (RT), including particle therapies. Positron emission tomography (PET) has the potential to fulfil this need by imaging fundamental aspects of tumour biology. The key areas in which PET may support the RT process include improving disease diagnosis and staging; assisting tumour volume delineation; defining tumour phenotype or biological tumour volume; assessment of treatment response; and in-beam monitoring of radiation dosimetry. The role of PET and its current developmental status in these key areas are overviewed in this review, highlighting the advantages and drawbacks.
    • The impact of clinical factors on the development of late radiation toxicity: results from the Medical Research Council RT01 trial (ISRCTN47772397).

      Barnett, G C; De Meerleer, G; Gulliford, S L; Sydes, M R; Elliott, Rebecca M; Dearnaley, D P; University of Cambridge, Department of Oncology, Oncology Centre, Cambridge University Hospital NHS Foundation Trust, Cambridge, UK. (2011-11)
      A variety of dosimetric parameters have been shown to influence the incidence of late radiation toxicity. The effect of other treatment- and patient-related factors is less well established. The aim of this study was to elucidate the influence of such factors in the development of late symptoms after radical radiotherapy to the prostate.
    • The small-nucleolar RNAs commonly used for microRNA normalisation correlate with tumour pathology and prognosis.

      Gee, H E; Buffa, F M; Camps, C; Ramachandran, A; Leek, R; Taylor, M; Patil, M; Sheldon, H; Betts, Guy N J; Homer, J; et al. (2011-03-29)
      To investigate small-nucleolar RNAs (snoRNAs) as reference genes when measuring miRNA expression in tumour samples, given emerging evidence for their role in cancer.
    • Exon-array profiling unlocks clinically and biologically relevant gene signatures from formalin-fixed paraffin-embedded tumour samples.

      Hall, J S; Leong, Hui Sun; Armenoult, L S C; Newton, G E; Valentine, Helen R; Irlam, Joely J; Möller-Levet, Carla S; Sikand, Kanwal A; Pepper, Stuart D; Miller, Crispin J; et al. (2011-03-15)
      Degradation and chemical modification of RNA in formalin-fixed paraffin-embedded (FFPE) samples hamper their use in expression profiling studies. This study aimed to show that useful information can be obtained by Exon-array profiling archival FFPE tumour samples.
    • Biodistribution, pharmacokinetics and metabolism of interleukin-1 receptor antagonist (IL-1RA) using [¹⁸F]-IL1RA and PET imaging in rats.

      Cawthorne, Christopher; Prenant, C; Smigova, A; Julyan, Peter J; Maroy, R; Herholz, K; Rothwell, N; Boutin, H; Wolfson Molecular Imaging Centre, University of Manchester, Manchester, UK. (2011-02)
      Positron emission tomography (PET) has the potential to improve our understanding of the preclinical pharmacokinetics and metabolism of therapeutic agents, and is easily translated to clinical studies in humans. However, studies involving proteins radiolabelled with clinically relevant PET isotopes are currently limited. Here we illustrate the potential of PET imaging in a preclinical study of the biodistribution and metabolism of ¹⁸F-labelled IL-1 receptor antagonist ([¹⁸F]IL-1RA) using a novel [¹⁸F]-radiolabelling technique.
    • Mitochondrial DNA mutations in head and neck cancer are infrequent and lack prognostic utility.

      Challen, C; Brown, H; Cai, C; Betts, Guy N J; Paterson, I; Sloan, P; West, Catharine M L; Birch-Machin, M; Robinson, M; Centre for Oral Health Research, School of Dental Sciences, Newcastle University, Framlington Place, Newcastle-upon-Tyne NE2 4BW, UK (2011)
    • Radiolabeling with fluorine-18 of a protein, interleukin-1 receptor antagonist.

      Prenant, C; Cawthorne, Christopher; Fairclough, M; Rothwell, N; Boutin, H; Wolfson Molecular Imaging Centre, University of Manchester, Manchester, UK. cprenant@cyclopharma.fr (2010-09)
      IL-1RA is a naturally occurring antagonist of the pro-inflammatory cytokine interleukin-1 (IL-1) with high therapeutic promise, but its pharmacokinetic remains poorly documented. In this report, we describe the radiolabeling of recombinant human interleukin-1 receptor antagonist (rhIL-1RA) with fluorine-18 to allow pharmacokinetic studies by positron emission tomography (PET). rhIL-1RA was labeled randomly by reductive alkylation of free amino groups (the epsilon-amino group of lysine residues or amino-terminal residues) using [(18)F]fluoroacetaldehyde under mild reaction conditions. Radiosyntheses used a remotely controlled experimental rig within 100min and the radiochemical yield was in the range 7.1-24.2% (decay corrected, based on seventeen syntheses). We showed that the produced [(18)F]fluoroethyl-rhIL-1ra retained binding specificity by conducting an assay on rat brain sections, allowing its pharmakokinetic study using PET.
    • Point: why choose pulsed-dose-rate brachytherapy for treating gynecologic cancers?

      Davidson, Susan E; Hendry, Jolyon H; West, Catharine M L; Department of Clinical Oncology, The Christie NHS Foundation Trust, Manchester, United Kingdom. Susan.Davidson@christie.nhs.uk (2010-08-09)
    • Radiation and the genome: from risks to opportunities for therapeutic exploitation.

      Robson, T; West, Catharine M L; School of Pharmacy, Queen's University Belfast, 97 Lisburn Road, Belfast BT9 7BL, Northern Ireland, UK. T.Robson@qub.ac.uk (2010-08)
      On 1 December 2009, the Radiation and Cancer Biology Committee of the British Institute of Radiology (BIR) held a one-day conference on the theme of radiation and the genome. Talks covered genomic instability (its importance for radiation-induced carcinogenesis and potential for exploitation in the development of novel chemoradiotherapy combinations) and the prospects of exploiting knowledge of the genome to understand how individual genetic variation can impact on a patient's likelihood of developing toxicity following radiotherapy. The meeting also provided an overview of stem cell biology and its relevance for radiotherapy in terms of both tumour (somatic) and normal tissue (germline) sensitivity to radiation. Moreover, the possibility of manipulating stem cells to reduce radiation-induced normal tissue damage was considered.
    • The hypoxia-selective cytotoxin NLCQ-1 (NSC 709257) controls metastatic disease when used as an adjuvant to radiotherapy.

      Lunt, S; Cawthorne, Christopher; Ali, M; Telfer, B; Babur, M; Smigova, A; Julyan, Peter J; Price, Patricia M; Stratford, I; Bloomer, W; et al. (2010-07-13)
      BACKGROUND: Metastases cause most cancer-related deaths. We investigated the use of hypoxia-selective cytotoxins as adjuvants to radiotherapy in the control of metastatic tumour growth. METHODS: The NLCQ-1, RB6145 and tirapazamine were assessed against the spontaneously metastasising KHT model. Subcutaneous KHT tumours (250 mm(3)) were irradiated with 25 Gy (single fraction) to control primary growth. Equitoxic drug treatments (NLCQ-1 (10 mg kg(-1)) once daily; RB6145 (75 mg kg(-1)) and tirapazamine (13 mg kg(-1)) twice daily) were administered 3-6 days post-radiotherapy when hypoxic cells were evident in lung micrometastases. Mice were culled when 50% of controls exhibited detrimental signs of lung metastases. RESULTS: In total, 95% of control mice presented with lung disease. This was significantly reduced by NLCQ-1 (33%; P=0.0002) and RB6145 (60%; P=0.02). Semi-quantitative grading of lung disease revealed a significant improvement with all treatments, with NLCQ-1 proving most efficacious (median grades: control, 4; NLCQ, 0 (P<0.0001); RB6145, 1 (P<0.001), tirapazamine, 3 (P=0.007)). Positron emission tomography (PET) was evaluated as a non-invasive means of assessing metastatic development. Primary and metastatic KHT tumours showed robust uptake of [(18)F]fluorodeoxyglucose ([(18)F]FDG). Metastatic burden discernable by [(18)F]FDG PET correlated well with macroscopic and histological lung analysis. CONCLUSION: The hypoxia-selective cytotoxin NLCQ-1 controls metastatic disease and may be a successful adjuvant to radiotherapy in the clinical setting.
    • Use of multiple biological markers in radiotherapy-treated head and neck cancer.

      Silva, Priyamal; Slevin, Nicholas J; Sloan, Philip; Valentine, Helen R; Ryder, W David J; Price, Patricia M; West, Catharine M L; Homer, Jarrod J; School of Cancer & Enabling Sciences, The University of Manchester, Manchester, UK. (2010-06)
      OBJECTIVE: Management of patients with head and neck squamous cell carcinoma is often based on clinical parameters, with little appreciation of the underlying tumour biology. Single biological marker studies fail to acknowledge the complexity of these tumours. Our aim was to define a profile of biological markers associated with outcome. DESIGN: This retrospective study involved consecutive patients with oropharyngeal squamous cell carcinoma treated with primary radiotherapy between 1996 and 2001. Pre-treatment biopsies were used to study the immunohistochemical expression of nine biological markers. Markers were chosen to reflect biologically relevant pathways. RESULTS: Following analysis of nine markers, a profile of two markers was derived (carbonic anhydrase 9 and major vault protein), the co-expression of which conferred a significantly poor probability of locoregional control. The prognostic effect of these biomarkers in combination was greater than their effect individually. CONCLUSION: Biomarker profiles can be established which highlight large differences in locoregional control. Identifying tumours that express both carbonic anhydrase 9 and major vault protein may facilitate patient selection for more aggressive treatment.
    • Radiotherapy in the management of unresectable locally advanced pancreatic cancer: a survey of the current UK practice of clinical oncologists.

      Saleem, Azeem; Jackson, A; Mukherjee, S; Stones, N; Crosby, T; Tait, D; Price, Patricia M; University of Manchester Academic Radiation Oncology, The Christie NHS Foundation Trust, Manchester, UK. azeem.saleem@manchester.ac.uk (2010-05)
      A survey was conducted by the Academic Clinical Oncology and Radiobiology Research Network (ACORRN) to evaluate current radiotherapy practice and to inform future research needs in patients with locally advanced pancreatic cancer. A clear need for a co-ordinated multicentre approach, given the limited number of patients who may qualify for such UK trials, was identified. Such trials should incorporate evidence-based treatment protocols and appropriate quality assurance procedures to ensure delivery of the highest standards of radiation-based therapy within, and without, clinical trials.
    • An efficient synthetic strategy for obtaining 4-methoxy carbon isotope labeled combretastatin A-4 phosphate and other Z-combretastatins.

      Pettit, George R; Minardi, Mathew D; Hogan, Fiona; Price, Patricia M; Cancer Research Institute and Department of Chemistry and Biochemistry, Arizona State University, Tempe, Arizona 85287-1604, USA. bpettit@asu.edu (2010-03-26)
      Human cancer and other clinical trials under development employing combretastatin A-4 phosphate (1b, CA4P) should benefit from the availability of a [(11)C]-labeled derivative for positron emission tomography (PET). In order to obtain a suitable precursor for addition of a [(11)C]methyl group at the penultimate step, several new synthetic pathways to CA4P were evaluated. Geometrical isomerization (Z to E) proved to be a challenge, but it was overcome by development of a new CA4P synthesis suitable for 4-methoxy isotope labeling.
    • Preliminary study of oxygen-enhanced longitudinal relaxation in MRI: a potential novel biomarker of oxygenation changes in solid tumors.

      O'Connor, James P B; Naish, Josephine H; Parker, Geoff J M; Waterton, John C; Watson, Yvonne; Jayson, Gordon C; Buonaccorsi, Giovanni A; Cheung, Susan; Buckley, David L; McGrath, Deirdre M; et al. (2009-11-15)
      PURPOSE: There is considerable interest in developing non-invasive methods of mapping tumor hypoxia. Changes in tissue oxygen concentration produce proportional changes in the magnetic resonance imaging (MRI) longitudinal relaxation rate (R(1)). This technique has been used previously to evaluate oxygen delivery to healthy tissues and is distinct from blood oxygenation level-dependent (BOLD) imaging. Here we report application of this method to detect alteration in tumor oxygenation status. METHODS AND MATERIALS: Ten patients with advanced cancer of the abdomen and pelvis underwent serial measurement of tumor R(1) while breathing medical air (21% oxygen) followed by 100% oxygen (oxygen-enhanced MRI). Gadolinium-based dynamic contrast-enhanced MRI was then performed to compare the spatial distribution of perfusion with that of oxygen-induced DeltaR(1). RESULTS: DeltaR(1) showed significant increases of 0.021 to 0.058 s(-1) in eight patients with either locally recurrent tumor from cervical and hepatocellular carcinomas or metastases from ovarian and colorectal carcinomas. In general, there was congruency between perfusion and oxygen concentration. However, regional mismatch was observed in some tumor cores. Here, moderate gadolinium uptake (consistent with moderate perfusion) was associated with low area under the DeltaR(1) curve (consistent with minimal increase in oxygen concentration). CONCLUSIONS: These results provide evidence that oxygen-enhanced longitudinal relaxation can monitor changes in tumor oxygen concentration. The technique shows promise in identifying hypoxic regions within tumors and may enable spatial mapping of change in tumor oxygen concentration.
    • An analysis of breast motion using high-frequency, dense surface points captured by an optical sensor during radiotherapy treatment delivery.

      Price, Gareth J; Sharrock, Phillip J; Marchant, Thomas E; Parkhurst, J M; Burton, D; Jain, Pooja; Price, Patricia M; Moore, Christopher J; North Western Medical Physics, The Christie NHS Foundation Trust, Manchester, UK. Gareth.Price@physics.cr.man.ac.uk (2009-11-07)
      Patient motion is an important factor affecting the quality of external beam radiotherapy in breast patients. We analyse the motion of a dense set of surface points on breast patients throughout their treatment schedule to assess the magnitude and stability of motion, in particular, with respect to breast volume. We use an optical sensor to measure the surface motion of 13 breast cancer patients. Patients were divided into two cohorts dependent upon breast volume. Measurements were made during radiotherapy treatment beam delivery for an average of 12 fractions per patient (total 158 datasets). The motion of each surface point is parameterized in terms of its period, amplitude and relative phase. Inter-comparison of the motion parameters across treatment schedules and between patients is made through the creation of corresponding regions on the breast surfaces. The motion period is spatially uniform and is similar in both patient groups (mean 4 s), with the small volume cohort exhibiting greater inter-fraction period variability. The mean motion amplitude is also similar in both groups with a range between 2 mm and 4 mm and an inter-fraction variability generally less than 1 mm. There is a phase lag of up to 0.4 s across the breast, led by the sternum. Breast patient motion is reasonably stable between and during treatment fractions, with the large volume cohort exhibiting greater repeatability than the small volume one.
    • Assessment of bladder motion for clinical radiotherapy practice using cine-magnetic resonance imaging.

      McBain, Catherine A; Khoo, Vincent S; Buckley, David L; Sykes, Jonathan S; Green, Melanie M; Cowan, Richard A; Hutchinson, Charles E; Moore, Christopher J; Price, Patricia M; Academic Department of Radiation Oncology, The University of Manchester, Christie Hospital NHS Foundation Trust, Wilmslow Road, Manchester, United Kingdom. (2009-11-01)
      PURPOSE: Organ motion is recognized as the principal source of inaccuracy in bladder radiotherapy (RT), but there is currently little information on intrafraction bladder motion. METHODS AND MATERIALS: We used cine-magnetic resonance imaging (cine-MRI) to study bladder motion relevant to intrafraction RT delivery. On two occasions, a 28 minute cine-MRI sequence was acquired from 10 bladder cancer patients and 5 control participants immediately after bladder emptying, after abstinence from drinking for the preceding hour. From the resulting cine sequences, bladder motion was subjectively assessed. To quantify bladder motion, the bladder was contoured in imaging volume sets at 0, 14, and 28 min to measure changes to bladder volumes, wall displacements, and center of gravity (COG) over time. RESULTS: The dominant source of bladder motion during imaging was bladder filling (up to 101% volume increase); rectal and small bowel movements were transient, with minimal impact. Bladder volume changes were similar for all participants. However for bladder cancer patients, wall displacements were larger (up to 58 mm), less symmetrical, and more variable compared with nondiseased control bladders. CONCLUSIONS: Significant and individualized intrafraction bladder wall displacements may occur during bladder RT delivery. This important source of inaccuracy should be incorporated into treatment planning and verification.
    • A novel imaging technique for fusion of high-quality immobilised MR images of the head and neck with CT scans for radiotherapy target delineation.

      Webster, Gareth J; Kilgallon, J E; Ho, Kean F; Rowbottom, Carl G; Slevin, Nicholas J; Mackay, Ranald I; North Western Medical Physics, Christie Hospital NHS Foundation Trust, Manchester, UK. gareth.webster@physics.cr.man.ac.uk (2009-06)
      Uncertainty and inconsistency are observed in target volume delineation in the head and neck for radiotherapy treatment planning based only on CT imaging. Alternative modalities such as MRI have previously been incorporated into the delineation process to provide additional anatomical information. This work aims to improve on previous studies by combining good image quality with precise patient immobilisation in order to maintain patient position between scans. MR images were acquired using quadrature coils placed over the head and neck while the patient was immobilised in the treatment position using a five-point thermoplastic shell. The MR image and CT images were automatically fused in the Pinnacle treatment planning system using Syntegra software. Image quality, distortion and accuracy of the image registration using patient anatomy were evaluated. Image quality was found to be superior to that acquired using the body coil, while distortion was < 1.0 mm to a radius of 8.7 cm from the scan centre. Image registration accuracy was found to be 2.2 mm (+/- 0.9 mm) and < 3.0 degrees (n = 6). A novel MRI technique that combines good image quality with patient immobilization has been developed and is now in clinical use. The scan duration of approximately 15 min has been well tolerated by all patients.
    • Ultrasound Imaging to Assess Inter- and Intra-fraction Motion during Bladder Radiotherapy and its Potential as a Verification Tool.

      McBain, Catherine A; Green, M M; Stratford, Julia; Davies, Julie; McCarthy, Claire; Taylor, Benjamin; McHugh, D; Swindell, Ric; Khoo, Vincent S; Price, Patricia M; et al. (2009-06)
      AIMS: Organ motion is the principle source of error in bladder cancer radiotherapy. The aim of this study was to evaluate ultrasound bladder volume measurement as a surrogate measure of organ motion during radiotherapy: (1) to assess inter- and intra-fraction bladder variation and (2) as a potential treatment verification tool. MATERIALS AND METHODS: Twenty patients receiving radical radiotherapy for bladder cancer underwent post-void ultrasound bladder volume measurement at the time of radiotherapy treatment planning (RTP), and immediately before (post-void) and after receiving daily fractions. RESULTS: Ultrasound bladder volume measurement was found to be a simple and acceptable method to estimate relative bladder volume changes. Six patients showed significant changes to post-void bladder volume over the treatment course (P<0.05). The mean inter-fraction post-void bladder volume of five patients exceeded their RTP ultrasound bladder volume by more than 50%. Intra-fraction bladder volume increased on 275/308 (89%) assessed fractions, with the mean intra-fraction volume increases of seven patients exceeding their RTP ultrasound bladder volume by more than 50%. CONCLUSIONS: Both day-to-day bladder volume variation and bladder filling during treatment should be considered in RTP and delivery. Ultrasound may provide a practical daily verification tool by: supporting volume limitation as a method of treatment margin reduction; allowing detection of patients who may require interventions to promote bladder reproducibility; and identifying patients with prominent volume changes for the selective application of more advanced adaptive/image-guided radiotherapy techniques.
    • The radiobiology/radiation protection interface in healthcare.

      Martin, C J; Sutton, D G; West, Catharine M L; Wright, Eric G; Department of Clinical Physics and Bio-engineering, Gartnavel Royal Hospital, Glasgow, UK. (2009-06)
      The current knowledge of radiation effects is reviewed and implications for its application in healthcare considered. The 21st L H Gray conference gathered leading experts in radiobiology, radiation epidemiology, radiation effect modelling, and the application of radiation in medicine to provide an overview of the subject. The latest radiobiology research in non-targeted effects such as genomic instability and the bystander effect challenge the old models, but the implications for health effects on humans are uncertain. Adaptive responses to external stresses, of which radiation is one, have been demonstrated in cells and animal models, but it is not known how these might modify human dose-effect relationships. Epidemiological evidence from the Japanese A-bomb survivors provides strong evidence that there is a linear relationship between the excess risk of cancer and organ dose that extends from about 50 mSv up to 2.5 Sv, and results from pooled data for multiple epidemiological studies indicate that risks extend down to doses of 20 mSv. Thus linear extrapolation of the A-bomb dose-effect data provides an appropriate basis for radiological protection standards at the present time. Risks from higher dose diagnostic procedures fall within the range in which health effects can be demonstrated. There is therefore reason for concern about the rise in the number of computed tomography (CT) scans performed in many countries, and in particular the use of CT for screening of asymptomatic individuals. New radiotherapy techniques allow high dose radiation fields to be conformed more effectively to target volumes, and reduce doses to critical organs, but they tend to give a higher and more uniform dose to the whole body which may increase the risk of second cancer. It is important that radiation protection practitioners keep abreast of developments in understanding of radiation effects and advise the medical community about the implications of fundamental research when planning medical applications for the future.