• 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.
    • 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.
    • 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.
    • Suboptimal use of intravenous contrast during radiotherapy planning in the UK.

      Kim, Su Woon; Russell, Wanda; Price, Patricia M; Saleem, Azeem; Department of Clinical Oncology, Christie Hospital, Manchester, UK. (2008-12)
      We aimed to evaluate the use of intravenous (IV) contrast during acquisition of radiotherapy planning (RTP) scans and to compare current usage with the Royal College of Radiologists' (RCR) recommendations. Questionnaires were circulated via the Academic Clinical Oncology and Radiobiology Research Network (ACORRN) website, email and post to 60 UK radiotherapy centre managers. Questions were asked regarding the (i) tumour sites where IV contrast was used, (ii) person administering the contrast, (iii) availability of dynamic pump, (iv) tumour sites that centres wished to use contrast, (v) reasons for not using contrast and (vi) awareness of RCR recommendations. 50 (83%) centres responded to the questionnaire, of which 27 responded via the ACCORN website and 18 by e-mail. Despite 38 out of 50 responding centres using IV contrast, and accessibility to dynamic pumps existing in 39 centres, IV contrast usage was suboptimal, with more than half of the centres (27/50; 54%) wishing to use it at more tumour sites. IV contrast was most often used during RTP of the brain, with suboptimal usage in lung tumours. None of the 50 centres administered IV contrast during RTP scan acquisition in all of the 8 RCR recommended tumour sites. Radiographers were mainly responsible for contrast administration, and a lack of staff was cited as the main reason for suboptimal contrast usage. Disappointingly, only 35 of the 50 radiotherapy managers (70%) were aware of the RCR recommendations. Redress of the underlying reasons for suboptimal IV contrast administration during RTP, including acquisition of the necessary skill mix by staff and implementation of RCR recommendations, would help standardize UK practice.