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Thorp N.J.,Clatterbridge Cancer Center | Taylor R.E.,University of Swansea
Clinical Oncology | Year: 2014

This article reviews current approaches to management of central nervous system tumours of childhood, highlighting aspects particularly pertinent to the paediatric population. © 2014 The Royal College of Radiologists.


Hoffmann A.L.,Maastricht University | Nahum A.E.,Clatterbridge Cancer Center
Physics in Medicine and Biology | Year: 2013

The simple Linear-Quadratic (LQ)-based Withers iso-effect formula (WIF) is widely used in external-beam radiotherapy to derive a new tumour dose prescription such that there is normal-tissue (NT) iso-effect when changing the fraction size and/or number. However, as conventionally applied, the WIF is invalid unless the normal-tissue response is solely determined by the tumour dose. We propose a generalized WIF (gWIF) which retains the tumour prescription dose, but replaces the intrinsic fractionation sensitivity measure (α/β) by a new concept, the normal-tissue effective fractionation sensitivity, , which takes into account both the dose heterogeneity in, and the volume effect of, the late-responding normal-tissue in question. Closed-form analytical expressions for ensuring exact normal-tissue iso-effect are derived for: (i) uniform dose, and (ii) arbitrary dose distributions with volume-effect parameter n = 1 from the normal-tissue dose-volume histogram. For arbitrary dose distributions and arbitrary n, a numerical solution for exhibits a weak dependence on the number of fractions. As n is increased, increases from its intrinsic value at n = 0 (100% serial normal-tissue) to values close to or even exceeding the tumour (α/β) at n = 1 (100% parallel normal-tissue), with the highest values of corresponding to the most conformal dose distributions. Applications of this new concept to inverse planning and to highly conformal modalities are discussed, as is the effect of possible deviations from LQ behaviour at large fraction sizes. © 2013 Institute of Physics and Engineering in Medicine.


Baldan V.,University of Manchester | Griffiths R.,University of Manchester | Griffiths R.,Clatterbridge Cancer Center | Hawkins R.E.,University of Manchester | Gilham D.E.,University of Manchester
British Journal of Cancer | Year: 2015

Background:Tumour-infiltrating lymphocyte (TIL) therapy is showing great promise in the treatment of patients with advanced malignant melanoma. However, the translation of TIL therapy to non-melanoma tumours such as renal cell carcinoma has been less successful with a major constraint being the inability to reproducibly generate TILs from primary and metastatic tumour tissue.Methods:Primary and metastatic renal cell carcinoma biopsies were subjected to differential tumour disaggregation methods and procedures that stimulate the specific expansion of TILs tested to determine which reliably generated TIL maintained antitumour specificity.Results:Enzymatic or combined enzymatic/mechanical disaggregation resulted in equivalent numbers of TILs being liberated from renal cell carcinoma biopsies. Following mitogenic activation of the isolated TILs with anti-CD3/anti-CD28-coated paramagnetic beads, successful TIL expansion was achieved in 90% of initiated cultures. The frequency of T-cell recognition of autologous tumours was enhanced when tumours were disaggregated using the GentleMACS enzymatic/mechanical system.Conclusion:TILs can be consistently produced from renal cell carcinoma biopsies maintaining autologous tumour recognition after expansion in vitro. While the method of disaggregation has little impact on the success of TIL growth, methods that preserve the cell surface architecture facilitate TIL recognition of an autologous tumour, which is important in terms of characterising the functionality of the expanded TIL population. © 2015 Cancer Research UK.


Lee C.D.,Clatterbridge Cancer Center
British Journal of Radiology | Year: 2014

Brachytherapy has evolved over many decades, but more recently, there have been significant changes in the way that brachytherapy is used for different treatment sites. This has been due to the development of new, technologically advanced computer planning systems and treatment delivery techniques. Modern, three-dimensional (3D) imaging modalities have been incorporated into treatment planning methods, allowing full 3D dose distributions to be computed. Treatment techniques involving online planning have emerged, allowing dose distributions to be calculated and updated in real time based on the actual clinical situation. In the case of early stage breast cancer treatment, for example, electronic brachytherapy treatment techniques are being used in which the radiation dose is delivered during the same procedure as the surgery. There have also been significant advances in treatment applicator design, which allow the use of modern 3D imaging techniques for planning, and manufacturers have begun to implement new dose calculation algorithms that will correct for applicator shielding and tissue inhomogeneities. This article aims to review the recent developments and best practice in brachytherapy techniques and treatments. It will look at how imaging developments have been incorporated into current brachytherapy treatment and how these developments have played an integral role in the modern brachytherapy era. The planning requirements for different treatments sites are reviewed as well as the future developments of brachytherapy in radiobiology and treatment planning dose calculation. © 2014 The Authors.


Onjukka E.,Karolinska University Hospital | Baker C.,Clatterbridge Cancer Center | Nahum A.,Clatterbridge Cancer Center
Medical Physics | Year: 2015

Purpose: This work explores different methods for accounting for patient-specific factors in normal-tissue complication probability (NTCP) modeling, and compares the performance of models using pseudoclinical datasets for "lung" and "rectum" complications. Methods: Datasets consisting of dose distributions and resulting normal-tissue complications were simulated, letting varying levels of confounding factors (i.e., nondosimetric factors) influence the outcome. The simulated confounding factors were patient radiosensitivity and health status. Seven empirical NTCP models were fitted to each dataset; this is analogous to fitting alternative models to datasets from different populations, treated with the same technique. The performance of these models was compared using the area under the ROC curve (AUC) and the impact of confounding factors on the model performance was studied. The patient-specific factors were then accounted for by (1) stratification and (2) two ways of modifying the traditional NTCP models to include these factors. Results: Confounding factors had a greater impact on model performance than the choice of model. All models performed similarly well on the rectum datasets (except the maximum dose model), while critical-volume type models were slightly better than the mean dose-, the Lyman-Kutcher-Burman-, and the relative seriality models for lung. This difference was more apparent without confounding factors in the dataset. The two alternative functions including patient-specific factors used in this work (one logistic and one cumulative normal function) were found to be equivalent, and more e fficient than stratifying datasets according to patient-specific factors and fitting models to subgroups individually. For datasets including confounding factors, the performance improved greatly when using models accounting for these; AUC increased from around 0.7 to close to unity. Conclusions: This work shows that identifying confounding factors, and developing methods to quantify them, is more important than the choice of NTCP model. Most dose-volume histogram (DVH)-based NTCP models can be generalized to include confounding factors. © 2015 American Association of Physicists in Medicine.


Nahum A.E.,Clatterbridge Cancer Center | Uzan J.,Clatterbridge Cancer Center
Computational and Mathematical Methods in Medicine | Year: 2012

"Biological optimization" (BIOP) means planning treatments using (radio)biological criteria and models, that is, tumour control probability and normal-tissue complication probability. Four different levels of BIOP are identified: Level I is isotoxic individualization of prescription dose D presc at fixed fraction number. Dpresc is varied to keep the NTCP of the organ at risk constant. Significant improvements in local control are expected for non-small-cell lung tumours. Level II involves the determination of an individualized isotoxic combination of Dpresc and fractionation scheme. This approach is appropriate for "parallel" OARs (lung, parotids). Examples are given using our BioSuite software. Hypofractionated SABR for early-stage NSCLC is effectively Level-II BIOP. Level-III BIOP uses radiobiological functions as part of the inverse planning of IMRT, for example, maximizing TCP whilst not exceeding a given NTCP. This results in non-uniform target doses. The NTCP model parameters (reflecting tissue architecture) drive the optimizer to emphasize different regions of the DVH, for example, penalising high doses for quasi-serial OARs such as rectum. Level-IV BIOP adds functional imaging information, for example, hypoxia or clonogen location, to Level III; examples are given of our prostate dose painting protocol, BioProp. The limitations of and uncertainties inherent in the radiobiological models are emphasized. © 2012 Alan E. Nahum and Julien Uzan.


Thorp N.,Clatterbridge Cancer Center
Clinical Oncology | Year: 2013

This article gives an introduction to the fundamentals of paediatric radiotherapy, describing the historical development of the speciality and its organisation in the UK, the clinical pathway (including issues around immobilisation) and an overview of indications for radiotherapy in the paediatric population. Late effects of radiotherapy, their mitigation and the role of the late effects clinic are summarised. © 2012 The Royal College of Radiologists.


Nahum A.E.,Clatterbridge Cancer Center
Clinical Oncology | Year: 2015

If the α/β ratio is high (e.g. 10Gy) for tumour clonogen killing, but low (e.g. 3Gy) for late normal tissue complications, then delivering external beam radiotherapy in a large number (20-30) of small (≈2Gy) dose fractions should yield the highest 'therapeutic ratio'; this is demonstrated via the linear-quadratic model of cell killing. However, this 'conventional wisdom' is increasingly being challenged, partly by the success of stereotactic body radiotherapy (SBRT) or stereotactic ablative radiotherapy (SABR) extreme hypofractionation regimens of three to five large fractions for early stage non-small cell lung cancer and partly by indications that for certain tumours (prostate, breast) the α/β ratio may be of the same order or even lower than that characterising late complications. It is shown how highly conformal dose delivery combined with quasi-parallel normal tissue behaviour (n close to 1) enables 'safe' hypofractionation; this can be predicted by the (α/β)eff concept for normal tissues. Recent analyses of the clinical outcomes of non-small cell lung cancer radiotherapy covering 'conventional' hyper- to extreme hypofractionation (stereotactic ablative radiotherapy) regimens are consistent with linear-quadratic radiobiology, even at the largest fraction sizes, despite there being theoretical reasons to expect 'LQ violation' above a certain dose. Impairment of re-oxygenation between fractions and the very high (α/β) for hypoxic cells can complicate the picture regarding the analysis of clinical outcomes; it has also been suggested that vascular damage may play a role for very large dose fractions. Finally, the link between high values of (α/β)eff and normal-tissue sparing for quasi-parallel normal tissues, thereby favouring hypofractionation, may be particularly important for proton therapy, but more generally, improved conformality, achieved by whatever technique, can be translated into individualisation of both prescription dose and fraction number via the 'isotoxic' (iso-normal tissue complication probability) concept. © 2015 The Royal College of Radiologists.


Uzan J.,Clatterbridge Cancer Center | Nahum A.E.,Clatterbridge Cancer Center
British Journal of Radiology | Year: 2012

Objective: Radiobiological models provide a means of evaluating treatment plans. Keeping in mind their inherent limitations, they can also be used prospectively to design new treatment strategies which maximise therapeutic ratio. We propose here a new method to customise fractionation and prescription dose. Methods: To illustrate our new approach, two non-small cell lung cancer treatment plans and one prostate plan from our archive are analysed using the in-house software tool BioSuite. BioSuite computes normal tissue complication probability and tumour control probability using various radiobiological models and can suggest radiobiologically optimal prescription doses and fractionation schemes with limited toxicity. Results: Dose-response curves present varied aspects depending on the nature of each case. The optimisation process suggests doses and fractionation schemes differing from the original ones. Patterns of optimisation depend on the degree of conformality, the behaviour of the normal tissue ( i.e. "serial" or "parallel"), the volume of the tumour and the parameters of clonogen proliferation. Conclusion: Individualising the prescription dose and number of fractions with the help of BioSuite results in improved therapeutic ratios as evaluated by radiobiological models. © 2012 The British Institute of Radiology.


Konstantinidis L.,University of Liverpool | Roberts D.,University of Liverpool | Errington R.D.,Clatterbridge Cancer Center | Kacperek A.,Clatterbridge Cancer Center | Damato B.,University of Liverpool
British Journal of Ophthalmology | Year: 2013

Aim: To report the results of whole anterior segment proton beam radiotherapy (PBR) for diffuse iris melanoma. Methods: Between 2000 and 2011, 12 patients with iris melanoma received PBR to the entire iris and ciliary body. Results: Patients had a mean age of 57 years and a median follow-up of 3.5 years (range 1-11.6 years). Tumour iris involvement was 1-4 h in five patients, 5-8 h in four and 9-12 h in three. Angle involvement was 6-8 h in five patients and 9-12 h in seven. The visual acuity (VA) before treatment was 6/5-6/6 in six patients, 6/8-6/9 in three and 6/18-6/38 in three. No tumour recurrence occurred during the follow-up period. Glaucoma treatment was required in 11 of 12 patients. The visual acuity at the last follow-up was 6/5-6/9 in five patients, 6/18-6/24 in three, 6/60-1/60 in two and no light perception in two. Four patients developed varying non-severe degrees of limbal stem cell deficiency, which was treatable with conservative measures. Conclusions: Whole anterior segment PBR is a useful alternative to enucleation for diffuse iris melanoma. Most patients will need treatment for glaucoma and some may require treatment for tear-film instability and/or stem cell failure.

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