• Magnetic order in a spin-half interpolating square-triangle Heisenberg antiferromagnet

      Bishop, R F; Li, P H Y; Farnell, Damian J J; Campbell, C E; School of Physics and Astronomy, Schuster Building, The University of Manchester, Manchester, M13 9PL, UK (2009)
    • 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.
    • 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.
    • High-order coupled cluster method study of frustrated and unfrustrated quantum magnets in external magnetic fields.

      Farnell, Damian J J; Zinke, R; Schulenburg, J; Richter, J; Academic Department of Radiation Oncology, Faculty of Medical and Human Sciences, University of Manchester, c/o The Christie NHS Foundation Trust, Manchester M20 4BX, UK (2009)
    • 21st L H Gray Conference: the radiobiology/radiation protection interface.

      West, Catharine M L; Martin, C J; Sutton, D G; Wright, Eric G; Academic Department of Radiation Oncology, University of Manchester, Christie Hospital, UK. catharine.west@manchester.ac.uk (2009-05)
      The 21st L H Gray Conference, organised by the L H Gray Trust with the Society for Radiological Protection, brought together international experts in radiobiology, epidemiology and risk assessment, and scientists involved in diagnostic and therapeutic radiation exposure. The meeting - held in Edinburgh, Scotland, on 4-6 June 2008 - aimed to raise awareness, educate and share knowledge of important issues in radiation protection. A distinguished group of speakers discussed topics that included (i) non-targeted effects of radiation, (ii) exposure to high natural background radiation, (iii) non-cancer effects in Japanese bomb survivors, (iv) lessons learnt from Chernobyl, (v) radiation in the workplace, (vi) biokinetic modelling, (vii) uncertainties in risk estimation, (viii) issues in diagnostic medical exposures, (ix) lessons leant from the polonium-210 incidence and (x) how the radiobiology/radiation oncology community is needed to help society prepare for potential future acts of radiation terrorism. The conference highlighted the importance, relevance and topicality of radiobiology today.
    • Measurement tools for gastrointestinal symptoms in radiation oncology.

      West, Catharine M L; Davidson, Susan E; Academic Department of Radiation Oncology, The University of Manchester, UK. Catharine.West@manchester.ac.uk (2009-03)
      PURPOSE OF REVIEW: To review the use of measurement tools for reporting gastrointestinal toxicity in radiation oncology to highlight recent findings of potential interest to those involved in the treatment of tumors in the pelvis, assessment of survivorship issues or management of bowel effects. RECENT FINDINGS: Multiple measurement tools are being used in radiation oncology studies involving both clinician and patient-reported outcomes. The increasing availability of accurate data on radiation doses and dose-volumes to normal tissues is enabling identification of critical areas where dose should be reduced to minimize organ damage. SUMMARY: Measurement tools for gastrointestinal symptoms are important to highlight therapeutic benefit for the expanding investigations of treatment intensification approaches and methods for toxicity reduction. The increasing use of the CTCAEv3 scales is a step forward, but further research is required to refine the system and improve its ease of use within routine clinical practice.
    • 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.
    • 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.
    • Dynamic contrast-enhanced MRI for prostate cancer localization.

      Jackson, Andrew; Reinsberg, S A; Sohaib, S A; Charles-Edwards, E M; Jhavar, S; Christmas, T J; Thompson, A C; Bailey, M J; Corbishley, C M; Fisher, C; et al. (2009-02)
      Radiotherapy dose escalation improves tumour control in prostate cancer but with increased toxicity. Boosting focal tumour only may allow dose escalation with acceptable toxicity. Intensity-modulated radiotherapy can deliver this, but visualization of the tumour remains limiting. CT or conventional MRI techniques are poor at localizing tumour, but dynamic contrast-enhanced MRI (DCE-MRI) may be superior. 18 patients with prostate cancer had T(2) weighted (T2W) and DCE-MRI prior to prostatectomy. The prostate was sectioned meticulously so as to achieve accurate correlation between imaging and pathology. The accuracy of DCE-MRI for cancer detection was calculated by a pixel-by-pixel correlation of quantitative DCE-MRI parameter maps and pathology. In addition, a radiologist interpreted the DCE-MRI and T2W images. The location of tumour on imaging was compared with histology, and the accuracy of DCE-MRI and T2W images was then compared. Pixel-by-pixel comparison of quantitative parameter maps showed a significant difference between the benign peripheral zone and tumour for the parameters K(trans), v(e) and k(ep). Calculation of areas under the receiver operating characteristic curve showed that the pharmacokinetic parameters were only "fair" discriminators between cancer and benign gland. Interpretation of DCE-MRI and T2W images by a radiologist showed DCE-MRI to be more sensitive than T2W images for tumour localization (50% vs 21%; p = 0.006) and similarly specific (85% vs 81%; p = 0.593). The superior sensitivity of DCE-MRI compared with T2W images, together with its high specificity, is arguably sufficient for its use in guiding radiotherapy boosts in prostate cancer.
    • 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.
    • High-order coupled cluster method (CCM) calculations for quantum magnets with valence-bond ground states.

      Farnell, Damian J J; Academic Department of Radiation Oncology, Division of Cancer Studies, Faculty of Medical and Human Science, University of Manchester, c/o Christie Hospital NHS Foundation Trust, Manchester m20 4BX, UK (2009)
    • 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.
    • Clinical impact of tumour involvement of the anastomotic doughnut in oesophagogastric cancer surgery.

      Sillah, Abdul Karim; Griffiths, Ewen A; Pritchard, S A; Swindell, Ric; West, Catharine M L; Page, Richard; Welch, I M; Department of Gastrointestinal Surgery, University Hospital of South Manchester NHS Foundation Trust, UK. (2009-04)
      INTRODUCTION: Published colorectal cancer surgery data suggest no role for the analysis of the anastomotic doughnuts following anterior resection. The usefulness of routine histological analysis of the upper gastrointestinal doughnut is not clear. Our study assessed the impact of cancer involvement of the doughnut on clinical practice. Factors associated with doughnut involvement and the effect on patients' survival were also analysed. PATIENTS AND METHODS: The clinicopathological details of 462 patients who underwent potentially curative oesophagogastrectomy for cancer with a stapled anastomosis between 1994 and 2006 in two specialist centres were retrospectively analysed. Univariate, multivariate and survival analyses were carried out. RESULTS: Approximately 5% of doughnuts (22 of 462) were histologically involved with cancer. Microscopic involvement of the proximal resection margin, local lymph node metastasis and lymphatic invasion within the main resected specimen were independently associated with doughnut involvement (all P < 0.05). However, these three factors taken together failed to predict doughnut involvement. Doughnut involvement was an independent adverse prognostic factor for overall survival (P = 0.0013). CONCLUSIONS: In contrast to findings in colorectal surgery, doughnut involvement with cancer appears to have useful prognostic information following oesophagogastrectomy. Routine histological analysis of upper gastrointestinal doughnuts is justified. Doughnut involvement could potentially strengthen the indications for adjuvant therapy in the future.
    • IMRT dose fractionation for head and neck cancer: variation in current approaches will make standardisation difficult.

      Ho, Kean F; Fowler, Jack F; Sykes, Andrew J; Yap, Beng K; Lee, Lip W; Slevin, Nicholas J; Academic Department of Radiation Oncology, University of Manchester, Christie Hospital, Wilmslow Road, Manchester, UK. (2009)
      INTRODUCTION: Altered fractionation has demonstrated clinical benefits compared to the conventional 2 Gy/day standard of 70 Gy. When using synchronous chemotherapy, there is uncertainty about optimum fractionation. IMRT with its potential for Simultaneous Integrated Boost (SIB) adds further to this uncertainty. This survey will examine international practice of IMRT fractionation and suggest possible reasons for diversity in approach. MATERIAL AND METHODS: Fourteen international cancer centres were surveyed for IMRT dose/fractionation practised in each centre. RESULTS: Twelve different types of dose fractionation were reported. Conventional 70-72 Gy (daily 2 Gy/fraction) was used in 3/14 centres with concurrent chemotherapy while 11/14 centres used altered fractionation. Two centres used >1 schedule. Reported schedules and number of centres included 6 fractions/week DAHANCA regime (3), modest hypofractionation (< or =2.2 Gy/fraction) (3), dose-escalated hypofractionation (> or =2.3 Gy/fraction) (4), hyperfractionation (1), continuous acceleration (1) and concomitant boost (1). Reasons for dose fractionation variability include (i) dose escalation; (ii) total irradiated volume; (iii) number of target volumes; (iv) synchronous systemic treatment; (v) shorter overall treatment time; (vi) resources availability; (vii) longer time on treatment couch; (viii) variable GTV margins; (ix) confidence in treatment setup; (x) late tissue toxicity and (xi) use of lower neck anterior fields. CONCLUSIONS: This variability in IMRT fractionation makes any meaningful comparison of treatment results difficult. Some standardization is needed particularly for design of multi-centre randomized clinical trials.
    • Enhancement of blood vessels in digital fundus photographs via the application of multiscale line operators

      Farnell, Damian J J; Hatfield, F N; Knox, P; Reakes, M; Spencer, S; Parry, D; Harding, S P; Academic Department of Radiation Oncology, Division of Cancer Studies, Faculty of Medical and Human Science, University of Manchester, c/o Christie Hospital NHS Foundation Trust, Manchester M20 4BX UK (2008)
    • Odd and even behavior with LSUBm approximation level in high-order coupled cluster method (CCM) calculations

      Farnell, Damian J J; Academic Department of Radiation Oncology, Division of Cancer Studies, Faculty of Medical and Human Science, University of Manchester, c/o Christie Hospital NHS Foundation Trust, Manchester M20 4BX, United Kingdom (2008)
    • 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.
    • 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.
    • 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.
    • 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.