• 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.
    • Blood flow and Vd (water): both biomarkers required for interpreting the effects of vascular targeting agents on tumor and normal tissue.

      Kötz, Barbara; West, Catharine M L; Saleem, Azeem; Jones, Terry; Price, Patricia M; Academic Department of Radiation Oncology, The University of Manchester, Manchester, UK. (2009-02)
      Positron emission tomography studies with oxygen-15-labeled water provide in vivo quantitative tissue perfusion variables-blood flow and fractional volume of distribution of water [V(d) (water)]. To investigate the relationship between perfusion variables and the effect of vascular-targeting agents on vasculature, we measured tissue perfusion in tumors, spleen, kidney, and liver before and after treatment with combretastatin-A4-phosphate, a combination of nicotinamide and carbogen (N/C), and interferon (IFN). We observed that mean tumor blood flow and V(d) (water) was lower than in kidney, liver, and spleen at baseline. Blood flow and V(d) (water) were related in tumor (r = 0.62; P = 0.004) at baseline, but not in other normal tissues evaluated, where minimal variations in V(d) (water) were observed over a wide range of blood flow. Despite the relationship between blood flow and V(d) (water) in tumors before intervention, vascular-targeting agent-induced changes in these perfusion variables were not correlated. In contrast, changes in blood flow and V(d) (water) correlated in kidney and spleen after N/C and in kidney after combretastatin-A4-phosphate. The close relation between blood flow and V(d) (water) in tumors but not normal tissue may reflect barriers to fluid exchange in tumors because of necrosis and/or increased interstitial fluid pressure and underlies the importance and interdependence of these positron emission tomography perfusion variables under these conditions. As blood flow and V(d) (water) signify different aspects of tissue perfusion, the differential effects of interventions on both variables, flow and V(d) (water), should therefore be reported in future studies.
    • Chemoradiotherapy for locally advanced pancreatic cancer: a radiotherapy dose escalation and organ motion study.

      Henry, Ann M; Ryder, W David J; Moore, Christopher J; Sherlock, David J; Geh, J I; Dunn, P; Price, Patricia M; Academic Department of Radiation Oncology, The University of Manchester, Department of Medical Statistics, Christie Hospital NHS Trust, Manchester, UK. (2008-09)
      AIMS: To determine the efficacy of radiation dose escalation and to examine organ motion during conformal radiotherapy for locally advanced pancreatic cancer. MATERIALS AND METHODS: Thirty-nine patients who were consecutively treated with chemoradiotherapy were studied. Fifteen patients, treated from 1993 to 1997, received 50 Gy in 20 fractions (group I). Twenty-four patients, treated from 1997 to 2003, received an escalated dose of 55 Gy in 25 fractions (group II). Intra-fraction pancreatic tumour motion was assessed in three patients using megavoltage movies during radiation delivery to track implanted radio-opaque markers. RESULTS: Improved survival rates were seen in latterly treated group II patients (P=0.083), who received escalated radiotherapy to smaller treatment volumes due to advances in verification. Worse toxicity effects (World Health Organization grade 3-4) were reported by some patients (<10%), but treatment compliance was similar in both groups, indicating equivalent tolerance. Substantial intra-fraction tumour displacement due to respiratory motion was observed: this was greatest in the superior/inferior (mean=6.6 mm) and anterior/posterior (mean=4.75 mm) directions. Lateral displacements were small (<2 mm). CONCLUSIONS: Dose escalation is feasible in pancreatic cancer, particularly when combined with a reduction in irradiated volume, and enhanced efficacy is indicated. Large, globally applied margins to compensate for pancreatic tumour motion during radiotherapy may be inappropriate. Strategies to reduce respiratory motion, and/or the application of image-guided techniques that incorporate individual patients' respiratory motion into radiotherapy planning and delivery, will probably improve pancreatic radiotherapy.
    • Early clinical evaluation of a novel three-dimensional structure delineation software tool (SCULPTER) for radiotherapy treatment planning.

      McBain, Catherine A; Moore, Christopher J; Green, Matthew M L; Price, Gareth J; Sykes, Jonathan R; Amer, Aminah; Khoo, Vincent S; Price, Patricia M; Academic Department of Radiation Oncology, The University of Manchester, Manchester, UK. (2008-08)
      Modern radiotherapy treatment planning (RTP) necessitates increased delineation of target volumes and organs at risk. Conventional manual delineation is a laborious, time-consuming and subjective process. It is prone to inconsistency and variability, but has the potential to be improved using automated segmentation algorithms. We carried out a pilot clinical evaluation of SCULPTER (Structure Creation Using Limited Point Topology Evidence in Radiotherapy) - a novel prototype software tool designed to improve structure delineation for RTP. Anonymized MR and CT image datasets from patients who underwent radiotherapy for bladder or prostate cancer were studied. An experienced radiation oncologist used manual and SCULPTER-assisted methods to create clinically acceptable organ delineations. SCULPTER was also tested by four other RTP professionals. Resulting contours were compared by qualitative inspection and quantitatively by using the volumes of the structures delineated and the time taken for completion. The SCULPTER tool was easy to apply to both MR and CT images and diverse anatomical sites. SCULPTER delineations closely reproduced manual contours with no significant volume differences detected, but SCULPTER delineations were significantly quicker (p<0.05) in most cases. In conclusion, clinical application of SCULPTER resulted in rapid and simple organ delineations with equivalent accuracy to manual methods, demonstrating proof-of-principle of the SCULPTER system and supporting its potential utility in RTP.
    • Early tumor drug pharmacokinetics is influenced by tumor perfusion but not plasma drug exposure.

      Saleem, Azeem; Price, Patricia M; Academic Department of Radiation Oncology, The Christie Hospital NHS Foundation Trust, Manchester. azeem.saleem@manchester.ac.uk (2008-12-15)
      PURPOSE: Pharmacokinetic parameters derived from plasma sampling are used as a surrogate of tumor pharmacokinetics. However, pharmacokinetics-modulating strategies do not always result in increased therapeutic efficacy. Nonsurrogacy of plasma kinetics may be due to tissue-specific factors such as tumor perfusion. EXPERIMENTAL DESIGN: To assess the impact of tumor perfusion and plasma drug exposure on tumor pharmacokinetics, positron emission tomography studies were done with oxygen-15 radiolabeled water in 12 patients, with 6 patients undergoing positron emission tomography studies with carbon-11 radiolabeled N-[2-(dimethylamino)ethyl]acridine-4-carboxamide and the other 6 with fluorine-18 radiolabeled 5-fluorouracil. RESULTS: We found that tumor blood flow (mL blood/mL tissue/minute) was significantly correlated to early tumor radiotracer uptake between 4 and 6 minutes [standard uptake value (SUV)4-6; rho = 0.79; P = 0.002], tumor radiotracer exposure over 10 minutes [area under the time-activity curve (AUC)0-10; predominantly parent drug; rho = 0.86; P < 0.001], and tumor radiotracer exposure over 60 minutes (AUC0-60; predominantly radiolabeled metabolites; rho = 0.80; P = 0.002). Similarly, fractional volume of distribution of radiolabeled water in tumor (Vd) was significantly correlated with SUV4-6 (rho = 0.80; P = 0.002), AUC0-10 (rho = 0.85; P < 0.001), and AUC0-60 (rho = 0.66; P = 0.02). In contrast, no correlation was observed between plasma drug or total radiotracer exposure over 60 minutes and tumor drug uptake or exposure. Tumor blood flow was significantly correlated to Vd (rho = 0.69; P = 0.014), underlying the interdependence of tumor perfusion and Vd. CONCLUSIONS: Tumor perfusion is a key factor that influences tumor drug uptake/exposure. Tumor vasculature-targeting strategies may thus result in improved tumor drug exposure and therefore drug efficacy.
    • 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.
    • Hypoxia-associated markers in gastric carcinogenesis and HIF-2alpha in gastric and gastro-oesophageal cancer prognosis.

      Griffiths, Ewen A; Pritchard, S A; McGrath, S M; Valentine, Helen R; Price, Patricia M; Welch, I M; West, Catharine M L; Academic Department of Radiation Oncology, School of Cancer & Imaging Sciences, The University of Manchester, Christie Hospital, Wilmslow Road, Withington, Manchester M20 4BX, UK. (2008-03-11)
      The study investigated hypoxia-associated markers (HIF-2alpha, Epo, Epo-R, Glut-1 and VEGF) along with Ki-67 in a gastric carcinogenesis model, and the prognostic significance of hypoxia-inducible factor (HIF)-2alpha in surgically treated gastro-oesophageal cancer. Protein expression was examined using immunohistochemistry on formalin-fixed, paraffin-embedded biopsies of normal mucosa (n=20), Helicobacter pylori-associated gastritis (n=24), intestinal metaplasia (n=24), dysplasia (n=12) and intestinal (n=19) and diffuse (n=21) adenocarcinoma. Relationships between HIF-2alpha expression and prognosis were assessed in resection specimens from 177 patients with gastric and gastro-oesophageal junction adenocarcinoma. Expression of all markers increased with progression along the gastric carcinogenesis sequence (P=0.0001). Hypoxia-inducible factor-2alpha was expressed in 63% of 177 resection specimens and at a high level in 44%. The median overall survival in patients with HIF-2alpha-expressing tumours was 22 (95% CI 18-26) months, whereas those with HIF-2alpha-negative tumours had a median survival of 37 (95% CI 29-44) months (P=0.015). Hypoxia-inducible factor-2alpha had no independent prognostic significance in multivariate analysis. In view of the lack of independent prognostic significance, HIF-2alpha has no role as a routine prognostic indicator. However, the high expression of HIF-2alpha suggests that it may be of value as a potential therapeutic target.
    • 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.
    • Implementing image-guided radiotherapy in the UK: plans for a co-ordinated UK research and development strategy.

      Price, Patricia M; Heap, Gillian; Academic Clinical Oncology and Radiobiology Research Network, c/o Christie Hospital NHS Foundation Trust, Wilmslow Road, Manchester M20 4BX, UK. (2008-05)
    • Inter-fraction motion and dosimetric consequences during breast intensity-modulated radiotherapy (IMRT).

      Jain, Pooja; Marchant, Thomas E; Green, Melanie M; Watkins, Gillian R; Davies, Julie; McCarthy, Claire; Loncaster, Juliette A; Stewart, Alan L; Magee, Brian; Moore, Christopher J; et al. (2009-01)
      BACKGROUND AND PURPOSE: Intensity-modulated radiotherapy (IMRT) can improve dose homogeneity within the breast planned target volume (PTV), but may be more susceptible to patient/organ motion than standard tangential radiotherapy (RT). We used daily cone-beam CT (CBCT) imaging to assess inter-fraction motion during breast IMRT and its subsequent impact on IMRT and standard RT dose homogeneity. MATERIALS AND METHODS: Ten breast cancer patients selected for IMRT were studied. CBCT images were acquired immediately after daily treatment. Automatic image co-registration was used to determine patient positioning variations. Daily PTV contours were used to calculate PTV variations and daily delivered IMRT and theoretically planned tangential RT dose. RESULTS: Group systematic (and random) setup errors detected by CBCT were 5.7 (3.9)mm laterally, 2.8 (3.5)mm vertically and 2.3 (3.2)mm longitudinally. Rotations >2 degrees in any axis occurred on 53/106 (50%) occasions. Daily PTV volume varied up to 23%. IMRT dose homogeneity was superior at planning and throughout the treatment compared with standard RT (1.8% vs. 15.8% PTV received >105% planned mean dose), despite increased motion sensitivity. CONCLUSIONS: CBCT revealed inadequacies of current patient positioning and verification procedures during breast RT and confirmed improved dose homogeneity using IMRT for the patients studied.
    • A new model for prediction of drug distribution in tumor and normal tissues: pharmacokinetics of temozolomide in glioma patients.

      Rosso, Lula; Brock, Cathryn S; Gallo, James M; Saleem, Azeem; Price, Patricia M; Turkheimer, Federico E; Aboagye, E O; Clinical Sciences Centre, Imperial College, Faculty of Medicine, Hammersmith Hospital Campus, London, UK. (2009-01-01)
      Difficulties in direct measurement of drug concentrations in human tissues have hampered the understanding of drug accumulation in tumors and normal tissues. We propose a new system analysis modeling approach to characterize drug distribution in tissues based on human positron emission tomography (PET) data. The PET system analysis method was applied to temozolomide, an important alkylating agent used in the treatment of brain tumors, as part of standard temozolomide treatment regimens in patients. The system analysis technique, embodied in the convolution integral, generated an impulse response function that, when convolved with temozolomide plasma concentration input functions, yielded predicted normal brain and brain tumor temozolomide concentration profiles for different temozolomide dosing regimens (75-200 mg/m(2)/d). Predicted peak concentrations of temozolomide ranged from 2.9 to 6.7 microg/mL in human glioma tumors and from 1.8 to 3.7 microg/mL in normal brain, with the total drug exposure, as indicated by the tissue/plasma area under the curve ratio, being about 1.3 in tumor compared with 0.9 in normal brain. The higher temozolomide exposures in brain tumor relative to normal brain were attributed to breakdown of the blood-brain barrier and possibly secondary to increased intratumoral angiogenesis. Overall, the method is considered a robust tool to analyze and predict tissue drug concentrations to help select the most rational dosing schedules.
    • No relationship between 18F-fluorodeoxyglucose positron emission tomography and expression of Glut-1 and -3 and hexokinase I and II in high-grade glioma.

      Charnley, Natalie; Airley, R; Du Plessis, D; West, Catharine M L; Brock, Cathryn S; Barnett, C; Matthews, Julian C; Symonds, Kirsten; Bottomly, M; Swindell, Ric; et al. (2008-09)
      The purpose of this study was to compare glucose metabolism, measured using 18F-fluorodeoxyglucose positron emission tomography ([18F]FDG-PET), with the expression of Glut-1 and -3 and hexokinase I (Hex I) and II in high-grade glioma. The retrospective study involved 27 patients with WHO classification grade III and IV glioma, with either newly diagnosed or recurrent tumours. Patients underwent dynamic and static [18F]FDG-PET to glucose metabolic rate (MRGlu) and standardised uptake value (SUV), respectively. Tumour biopsies were obtained and stained using immunohistochemistry for the expression of Glut-1, -3, Hex I and II. Relationships between variables were studied using Spearman's rank correlation test. Results showed that the expression of Glut-1, Glut-3, Hex I and Hex II varied between and within the tumour samples. The mean of MRGlu was 0.2 (range 0.09-0.25) micromol/min/ml and that of SUV was 4.2 (range 3.2-5.2). There were no significant relationships among the tumour expression of any of the proteins studied with either MRGlu or SUV (p>0.21 for all). In conclusion, the lack of relationship between the immunohistochemical expression of Glut-1, -3, Hex I or II and glucose metabolism measured using [18F]FDG-PET in patients with high-grade glioma may be due to the tissue heterogeneity and presence of necrosis in high-grade tumours.
    • Optimization of the injected activity in dynamic 3D PET: a generalized approach using patient-specific NECs as demonstrated by a series of 15O-H2O scans.

      Walker, Mathew D; Matthews, Julian C; Asselin, Marie-Claude; Saleem, Azeem; Dickinson, Clare; Charnley, Natalie; Julyan, Peter J; Price, Patricia M; Jones, Terry; School of Cancer and Imaging Sciences, Wolfson Molecular Imaging Centre, University of Manchester, Manchester, United Kingdom. (2009-01-30)
    • Plasma pharmacokinetic evaluation of cytotoxic agents radiolabelled with positron emitting radioisotopes.

      Saleem, Azeem; Aboagye, E O; Matthews, Julian C; Price, Patricia M; Academic Department of Radiation Oncology, Christie Hospital NHS Foundation Trust, Wilmslow Road, and The University of Manchester Wolfson Molecular Imaging Centre, Manchester M20 4BX, UK. azeem.saleem@manchester.ac.uk (2008-04)
      PURPOSE: This study aimed to evaluate the utility of plasma pharmacokinetic analyses of anti-cancer agents from data obtained during positron emission tomography (PET) oncology studies of radiolabelled anti-cancer agents. PATIENTS AND METHODS: Thirteen patients were administered fluorine-18 radiolabelled 5-FU ([(18)F]5-FU) admixed with 5-FU, corresponding to a total 5-FU dose of 380-407 mg/m2 (eight patients) and 1 mg/m2 (five patients). Nine patients received 2.2-19.2 microg/m2 of carbon-11 radiolabelled N-[2-(dimethylamino)ethyl]acridine-4-carboxamide ([11C]DACA) at 1/1,000th of phase I dose, as part of phase 0 microdosing study. Radioactivity of parent drug obtained from arterial blood samples, the injected activity of the radiolabelled drug, and the total dose of injected drug were used to obtain plasma drug concentrations. Plasma pharmacokinetic parameters were estimated using model-dependent and model-independent methods. RESULTS: 5-FU plasma concentrations at therapeutic doses were above the Km and a single compartment kinetic model was best used to fit the kinetics, with a mean half-life of 8.6 min. Clearance and volumes of distribution (Vd) obtained using both model-dependent and model-independent methods were similar. Mean (SE) clearance was 1,421(144), ml min(-1) and 1,319 (119) ml min(-1) and the mean (SE) Vd was 17.3 (1.8) l and 16.3 (1.9) l by the model-independent method and model-dependent methods, respectively. In contrast, with 1 mg/m2, plasma concentrations of 5-FU were less than the Km and a two-compartment model was used to best fit the kinetics, with the mean 5-FU half-life of 6.5 min. The mean (SE) clearances obtained by the model-independent method and model-dependent methods were 3,089 (314) ml min(-1) and 2,225 (200) ml min(-1), respectively and the mean (SE) Vd were 27.9 (7.0) l and 2.3 (0.4) l, by the model independent and dependent methods, respectively. Extrapolation of AUC0-Clast to AUC0-infinity was less than 3% in both these cohort of patients. A two-compartment model with a mean half-life of 42.1 min was used to best fit the kinetics of DACA; considerable extrapolation (mean 26%) was required to obtain AUC0-infinity from AUC0-Clast. Mean (SE) clearance of DACA was 1,920 (269) ml min(-1), with the model-independent method and 1,627 (287) ml min(-1) with the model-dependent method. Similarly, Vd [mean (SE)] of DACA with the model-independent and model-dependent methods were 118 (22) l and 50 (15) l, respectively. CONCLUSIONS: Pharmacokinetic parameters can be estimated with confidence from PET studies for agents given at therapeutic doses, whose half-lives are significantly less than the total sampling time during the scan. Tracer studies performed alone, wherein plasma levels below the Km are expected, may also provide valuable information on drug clearance for the entire range of linear kinetics. However, drugs with half-lives longer than the sampling duration are inappropriate for PET plasma pharmacokinetic evaluation.
    • 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.
    • Radical chemoradiotherapy for adenocarcinoma of the distal oesophagus and oesophagogastric junction: what planning margins should we use?

      Whitfield, Gillian A; Jackson, Andrew; Moore, Christopher J; Price, Patricia M; Academic Department of Radiation Oncology, University of Manchester, Manchester, UK. gillian.whitfield@manchester.ac.uk (2008-12)
      Distal oesophageal and Type I-II oesophagogastric junctional adenocarcinomas have a poor prognosis. In radical chemoradiotherapy, consensus is lacking on radiotherapy margins. Here, we review the effect of common imaging modalities on the extent of the gross tumour volume (GTV) and the evidence for margins. To do this, papers were identified from PubMed, and geometric uncertainties were combined using the British Institute of Radiology formula. CT and endoscopic ultrasound were best for GTV delineation, but the role of positron emission tomography is uncertain. Evidence suggests 3 cm proximal and 5 cm distal GTV-CTV (clinical target volume) margins (along the mucosa) for advanced tumours, but is lacking for early tumours and radial margins. Nodal spread, present in most pT2 tumours, is strongly prognostic and is initially to regional nodes (not wholly covered by typical radiotherapy). Calculated CTV-PTV (planning target volume) margins for three-dimensional conformal radiotherapy using literature estimates of tumour motion and set-up errors with bony online set-up correction, ignoring delineation errors, are 2.2 cm superiorly (sup) and inferiorly (inf) and 1.2-1.3 cm radially (1.3 cm sup-inf; 0.8 cm radially if the tumour's mid-position is known). As these margins may risk excessive toxicity, we propose treating microscopic disease for potentially curable tumours (cT2N0, some cT3N0), but gross disease only for advanced tumours. Recommended GTV-CTV margins are a maximum of 3 cm proximally and 5 cm distally up to cT2N0; 3 cm proximally and 5 cm distally for cT3N0 if anticipated toxicity allows; and 0 cm for cT4 and most node-positive tumours. The CTV-PTV margins above must be added to this for all stages. Methods of including elective nodal areas close to the GTV should be researched, e.g. nodal maps and intensity-modulated radiotherapy.
    • 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.
    • Rectal motion can reduce CTV coverage and increase rectal dose during prostate radiotherapy: A daily cone-beam CT study.

      Sripadam, Raj; Stratford, Julia; Henry, Ann M; Jackson, Andrew; Moore, Christopher J; Price, Patricia M; Clatterbridge Centre for Oncology, Bebington, Wirral, UK. (2009-03)
      BACKGROUND AND PURPOSE: Daily on-treatment verification cone-beam CT (CBCT) was used to study the effect of rectal motion on clinical target volume (CTV) coverage during prostate radiotherapy. MATERIAL AND METHODS: CBCT scans were acquired from 15 patients immediately after daily treatment. From these images, the rectum was contoured allowing the analysis of rectal volume cross-sectional area (CSA) and the determination of rectal dose. Rectal wall motion was quantified as a surrogate measure of prostate displacement and CTV coverage was subjectively assessed. RESULTS: Rectal volume decreased over the treatment course in 13 patients (P<0.001). Rectal wall regions corresponding to the prostate base displayed the greatest motion; larger displacements were seen in patients with larger rectal planning volumes. CTV coverage was inadequate, at the prostate base only, in 38% of the fractions delivered to 4/7 patients with a large rectum at planning (>100 cm(3)). In patients with small rectum at planning (<50 cm(3)) up to 25% more rectal volume than predicted was included in the high-dose region. CONCLUSIONS: Rectal motion during treatment in prostate cancer patients has implications for CTV coverage and rectal dose. Measures to ensure consistency in daily rectal volume or image-guided strategies should be considered.
    • The role of PET in target localization for radiotherapy treatment planning.

      Rembielak, Agata; Price, Patricia M; Academic Department of Radiation Oncology, Division of Cancer Studies, The University of Manchester, Christie Hospital NHS Trust, Manchester, United Kingdom. agata.rembielak@manchester.ac.uk (2008-02)
      Positron emission tomography (PET) is currently accepted as an important tool in oncology, mostly for diagnosis, staging and restaging purposes. It provides a new type of information in radiotherapy, functional rather than anatomical. PET imaging can also be used for target volume definition in radiotherapy treatment planning. The need for very precise target volume delineation has arisen with the increasing use of sophisticated three-dimensional conformal radiotherapy techniques and intensity modulated radiation therapy. It is expected that better delineation of the target volume may lead to a significant reduction in the irradiated volume, thus lowering the risk of treatment complications (smaller safety margins). Better tumour visualisation also allows a higher dose of radiation to be applied to the tumour, which may lead to better tumour control. The aim of this article is to review the possible use of PET imaging in the radiotherapy of various cancers. We focus mainly on non-small cell lung cancer, lymphoma and oesophageal cancer, but also include current opinion on the use of PET-based planning in other tumours including brain, uterine cervix, rectum and prostate.