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Biomedical subjects

R G Dale

Publications and source records attributed to R G Dale.

At least 19 recordsLinked to original sources
PubMed2006

A theoretical investigation into post-operative, intracavitary beta therapy of high-grade glioblastomas using yttrium-90.

Beta therapy with yttrium-90 (90Y) has recently been introduced as a post-operative intra-cavitary treatment for malignant glioblastoma, a generally radioresistant tumour for which cure rates with conventional radiotherapy are usually very disappointing. This short theoretical study investigates the conditions under which 90Y treatment might be most effective and assesses the likely amounts of activity which must be infused in order to successfully cope with the low radiosensitivities which characterize such tumours. The radiobiological and physical analysis is investigated using the linear quadratic (LQ) model and a range of possible scenarios for the distribution and density of the tumour cells surrounding the surgically formed cavities are considered. The results suggest that, in the absence of diffusion of 90Y from the cavity, the activity typically required for 50% tumour cure is well over 40 mCi (1480 MBq), this being considerably more than the clinically determined activities which may be tolerated. Suggestions are provided for improving the versatility of the model.

Apoptosis↗
PubMed2006

Radiobiological modelling of dose-gradient effects in low dose rate, high dose rate and pulsed brachytherapy.

This paper presents a generalization of a previously published methodology which quantified the radiobiological consequences of dose-gradient effects in brachytherapy applications. The methodology uses the linear-quadratic (LQ) formulation to identify an equivalent biologically effective dose (BED(eq)) which, if applied uniformly to a specified tissue volume, would produce the same net cell survival as that achieved by a given non-uniform brachytherapy application. Multiplying factors (MFs), which enable the equivalent BED for an enclosed volume to be estimated from the BED calculated at the dose reference surface, have been calculated and tabulated for both spherical and cylindrical geometries. The main types of brachytherapy (high dose rate (HDR), low dose rate (LDR) and pulsed (PB)) have been examined for a range of radiobiological parameters/dimensions. Equivalent BEDs are consistently higher than the BEDs calculated at the reference surface by an amount which depends on the treatment prescription (magnitude of the prescribed dose) at the reference point. MFs are closely related to the numerical BED values, irrespective of how the original BED was attained (e.g., via HDR, LDR or PB). Thus, an average MF can be used for a given prescribed BED as it will be largely independent of the assumed radiobiological parameters (radiosensitivity and alpha/beta) and standardized look-up tables may be applicable to all types of brachytherapy treatment. This analysis opens the way to more systematic approaches for correlating physical and biological effects in several types of brachytherapy and for the improved quantitative assessment and ranking of clinical treatments which involve a brachytherapy component.

Algorithms↗
PubMed2006

A four-dimensional computer simulation model of the in vivo response to radiotherapy of glioblastoma multiforme: studies on the effect of clonogenic cell density.

Tumours behave as complex, self-organizing, opportunistic dynamic systems. In an attempt to better understand and describe the highly complicated tumour behaviour, a novel four-dimensional simulation model of in vivo tumour growth and response to radiotherapy has been developed. This paper presents the latest improvements to the model as well as a parametric validation of it. Improvements include an advanced algorithm leading to conformal tumour shrinkage, a quantitative consideration of the influence of oxygenation on radiosensitivity and a more realistic, imaging based description of the neovasculature distribution. The tumours selected for the validation of the model are a wild type and a mutated p53 gene glioblastomas multiforme. According to the model predictions, a whole tumour with larger cell cycle duration tends to repopulate more slowly. A lower oxygen enhancement ratio value leads to a more radiosensitive whole tumour. Higher clonogenic cell density (CCD) produces a higher number of proliferating tumour cells and, therefore, a more difficult tumour to treat. Simulation predictions agree at least semi-quantitatively with clinical experience, and particularly with the outcome of the Radiation Therapy Oncology Group (RTOG) Study 83-02. It is stressed that the model allows a quantitative study of the interrelationship between the competing influences in a complex, dynamic tumour environment. Therefore, the model can already be useful as an educational tool with which to study, understand and demonstrate the role of various parameters in tumour growth and response to irradiation. A long term quantitative clinical adaptation and validation of the model aiming at its integration into the treatment planning procedure is in progress.

Algorithms↗
PubMed2006

Calculation of high-LET radiotherapy dose required for compensation of overall treatment time extensions.

A method is presented that allows biological effective dose (BED) equations to be used to calculate compensatory doses for treatment time extensions when high-LET (linear energy transfer) radiotherapy schedules are used. The principles involved are the same as those for low-LET radiations, but incorporate two relative biological effectiveness (RBE) factors, RBE(max) and RBE(min), which represent the RBE at very low and very high fraction doses, respectively, with the actual RBE changing between these extremes. The method has the advantage that low-LET alpha/beta ratios and low-LET daily dose-equivalent repopulation factors are used in the calculations. The daily dose repopulation equivalents and increments in dose per fraction in the case of high LET radiotherapy are smaller than those for low LET.

Algorithms↗
PubMed2005

The potential for mathematical modelling in the assessment of the radiation dose equivalent of cytotoxic chemotherapy given concomitantly with radiotherapy.

The linear quadratic (LQ) concept of biological effective dose (BED) is used with Poisson statistics to estimate the radiation equivalent BED of cytotoxic chemotherapy (CBED) that would provide improvements in tumour control probability (TCP) typically achieved in randomized clinical trials of chemoradiation. The concepts of pure radio-sensitization and independent chemotherapy cell kill are represented by mathematical equations. Small values of sensitizer enhancement ratios (s) can provide modest increases in TCP when large numbers of radiotherapy fractions are sensitized; larger s values are required if only a small number of radiotherapy fractions are sensitized. Independent chemotherapy induced cell kill is sufficient to explain the benefits achieved with concomitant chemoradiotherapy in situations where a sufficiently high chemotherapy dose intensity is used (i.e. the dose-time intensity of cytotoxic chemotherapy without radiation is considered to be sufficient to cause significant tumour regression although not cure). Care is required in the use of the Poisson cure probability model because of the associated steep dose-response curves that may underestimate both s and the CBED. By use of random sampling methods and estimation over a theoretical population of different tumours, more robust results are obtained with dose-response curves that correspond better to those in clinical data sets. These predict a 2-4 Gy(10) equivalent for each pulse of chemotherapy such as single agent Cis-Platinum when used weekly during radiotherapy for a maximum of 4 cycles. This preliminary paper does not consider normal tissue complication probabilities, of which there are relatively few mature results for modern chemoradiotherapy. The BED concept can be used to estimate the equivalent dose of radiotherapy that will achieve the same cell kill as concomitant cytotoxic chemotherapy. Relatively simple radiobiological modelling can be used to guide decision-making regarding the assessment of the most appropriate combined modality schedules, and has important implications in the design of clinical trials.

Antineoplastic Agents↗
PubMed2003

The effects of delays in radiotherapy treatment on tumour control.

There is often a considerable delay from initial tumour diagnosis to the start of radiotherapy treatment, which may be due to factors such as waiting lists and referral delays. This paper uses widely published models and clinical parameters to calculate the effect of delays in treatment on local tumour control for four different types of tumour-squamous cell carcinoma (head and neck), breast, cervix and prostate. The Poisson model for tumour control probability (TCP), an exponential function for tumour growth and the linear quadratic model of cell kill are used to calculate the change in TCP for delays between diagnosis and treatment of up to 100 days. Typical values of the clinical parameters have been taken from the literature; these include alpha and beta, sigma(alpha), tumour size at diagnosis, pre-treatment doubling time, delay in onset of accelerated repopulation and doubling time during treatment. It is acknowledged that there are limitations in the reliability of these data for predicting absolute values of tumour control, but models are still useful for predicting how changes in treatment parameters are likely to affect the outcome. It is shown that for fast-growing tumours a delay of 1-2 months can have a significant adverse effect on the outcome, whereas for slow-growing tumours such as Ca prostate a delay of a few months does not significantly reduce the probability of tumour control. These calculations show the importance of ensuring that delays from diagnosis through to treatment are minimized, especially for patients with rapidly proliferating tumours.

Appointments and Schedules↗
PubMed2002

Practical methods for compensating for missed treatment days in radiotherapy, with particular reference to head and neck schedules.

Unscheduled interruption of a radiotherapy treatment can lead to significant loss in local tumour control, particularly in tumours that repopulate rapidly. General guidelines for dealing with such treatment gaps have been issued by the Royal College of Radiologists and more specific advice on the use of compensation methods has been published previously [Hendry et al., Clin Oncol 1996;8:297-307; Slevin et al., Radiother Oncol 1992;24:215-220]. This article further elaborates on the practical application of these methods. It sets out the main considerations arising in the especially critical case of head and neck treatments and simple calculations are used to illustrate the approaches which may be adapted for particular situations. Radiobiological parameter values are suggested for use in the calculations, but these may require modification in the light of further research in this important area.

Appointments and Schedules↗
PubMed2001

The role of biologically effective dose (BED) in clinical oncology.

There are many clinical situations in which radiobiological considerations can be usefully applied and all clinicians should be aware of the potential benefits of developing a quantitative radiobiological approach to their practice. The concept of biologically effective dose (BED) in particular is useful for quantifying treatment expectations, but clinical oncologists should recognize that careful interpretation of modelling results is required before clinical decisions can be made and that there is a lack of reliable human parameters for application in some situations. Correct use of the BED concept will, in more complex treatment situations, sometimes involve the use of multiple parameters and BED calculations. Examples include: 1. Where the dose per fraction is being altered and it is possible that normal tissue tolerance may be compromised, calculations should include two or more alpha/beta ratio values, some being less than 3 Gy, in order to estimate the 'worst case scenario'. 2. A single one-point BED calculation will not be representative of the biological effect throughout a large planning target volume where there are significant 'hot spots'. Multiple BED evaluations are then indicated. 3. Where there are combinations of radiotherapy treatments or phases of treatments, these can be quantitatively assessed by the addition of BEDs, although the volume of tissue is not inherently included in the BED calculation and any high-dose region needs to be separately assessed as in point 2. 4. Allowance for tumour clonogen repopulation during therapy is required for some tumour types. 5. Different histological classes of cancers require the use of different alpha/beta ratios. Where there is reasonable doubt regarding this parameter, a suitable range should be used. The principles involved are illustrated by worked examples. Attention to detail and the examination of ranges of possible results should offer a safer guide to alternative dose fractionation schedules, although the ultimate choice will be tempered by clinical circumstances.

Dose Fractionation, Radiation↗
PubMed2001

A theoretical investigation into the role of tumour radiosensitivity, clonogen repopulation, tumour shrinkage and radionuclide RBE in permanent brachytherapy implants of 125I and 103Pd.

There is growing clinical interest in the use of 125I (half-life 59.4 days) and 103Pd (half-life 16.97 days) for permanent brachytherapy implants. These radionuclides pose interesting radiobiological challenges because, even with slowly growing tumours, significant tumour cell repopulation may occur during the long period taken to deliver the full radiation dose. This results in a considerable amount of the prescribed dose being wasted. There may also be changes in the tumour volume during treatment (due to oedema and/or shrinkage), thus altering the relative geometry of the implanted seeds and causing additional dose rate variations. This assessment examines the interaction between the above effects and additionally includes allowance for the influence of the relative biological effectiveness (RBE) of the radiations emitted by the two radionuclides. The results are presented in terms of the biologically effective doses (BEDs) and likely tumour control probabilities (TCPs) associated with the various parameter combinations. The overall BED enhancement due to the RBE effect is shown always to be greater than the RBE itself and is greatest in tumours which are radio-resistive and/or fast growing. The biological dose uncertainties are found to be less with 103Pd and the TCPs associated with this radionuclide are expected to be significantly higher in the treatment of some 'difficult' tumours. Using typically prescribed doses 125i appears to be better for treating radiosensitive tumours with long doubling times and which shrink fairly rapidly. However, unless 125I doses are reduced, this advantage may well be offset by the greatly enhanced biological doses delivered to adjacent normal structures.

Adenocarcinoma↗
PubMed2000

Estimation of optimum dose per fraction for high LET radiations: implications for proton radiotherapy.

PURPOSE: For high linear energy transfer (LET) radiations, the relative biologic effect (RBE) changes with dose per fraction. Methods for calculating the optimum dose per fraction for high LET radiations should therefore include an allowance for RBE. METHODS AND MATERIALS: The linear-quadratic (LQ) model, and the associated biologic effective dose (BED) concept, has previously been extended to incorporate the RBE effect. Differential calculus is now used to calculate the optimum dose per fraction (z), when high-LET radiation is used, which is given by the solution for z of (g - LATE(alpha/beta)(L)/TUM(alpha/beta)L . RBE(M( z(2))) - 2 . f . g . K . z - (LATE)(alpha/beta)(L) . f . K . RBE(M) = 0 where g is the normal tissue sparing factor, RBE(M) is the maximum RBE value, f the mean interfraction interval, K the daily low-LET BED equivalent dose for clonogen repopulation and (LATE)(alpha/beta)(L) and (TUM)(alpha/beta)(L) are the respective late reacting normal tissue and tumor fractionation sensitivities for low-LET radiation. RESULTS: The optimum dose per fraction for proton therapy is generally lower than that calculated for photons but there is not a simple relationship between the magnitude of the reduction and the assumed value of RBE(M.) Thus(,) generic values of RBE(M) cannot always be used in such calculations. In some cases, where tumor alpha/beta ratios are low (around 5-6 Gy) and where there is good normal tissue sparing, the optimum dose per fraction is relatively large, typically 4-8 Gy. CONCLUSION: BED equations that include the RBE parameter, together with low-LET alpha/beta ratios and repopulation dose equivalents, constitute a rational model of high-LET radiotherapy. In the case of proton beam therapy, a wide range of optimum dose per fraction is predicted.

Dose Fractionation, Radiation↗
PubMed2000

Radiobiological modeling and clinical trials.

PURPOSE: Standard clinical trial designs can lead to restrictive conclusions: the "best recommended treatments" based on trial results, although generally applicable to patient populations, do not necessarily apply to individual patients. In theory, radiobiological modeling, coupled with reliable predictive assays, can be used to rationalize the selection of patients for particular schedules in trials. MATERIALS AND METHODS: Linear-quadratic modeling of radiotherapy can be used to simulate a clinical trial. This is achieved by random sampling techniques where the key radiobiological parameters (alpha, beta, T(pot) and clonogen number) are selected from known or expected ranges. Clinical trial design in radiotherapy may be improved by formal radiobiological assessment designed to estimate the likely changes in tumor cure probability (TCP) and the likely normal tissue biologically effective dose (BED). Modeling may also be used to rationalize the allocation of patients to a test or standard schedule or for individual optimization of a treatment schedule. Such approaches depend on there being reliable predictive assays of the radiobiological parameters in individual patients. The influence of variations in predictive assay accuracy on the improved outcomes are assessed. RESULTS: Clinical trials, which have been preceded by modeling simulation, offer potentially substantial improvements in the results of cancer treatment by radiotherapy. These exceed the usual gains found in standard clinical trials. CONCLUSION: Future preclinical trial design should include modeling assessments that indicate how best to structure the trial.

Cell Division↗
PubMed2000

Biological equivalent dose assessment of the consequences of hypofractionated radiotherapy.

PURPOSE: To investigate the changes in biological effective dose (BED) that occur in high-dose regions within a target volume when radiotherapy is hypofractionated. METHODS AND MATERIALS: By comparing a standard prescription of 2 Gy per fraction that is matched to give the same BED as a hypofractionated schedule at a standard intersectional prescription point, the BED increments for late-tissue effects at a higher dose region within the planning target volume (PTV) are compared. The alternative approach of BED matching between a conventional and hypofractionated schedule at the high-dose region is also considered. The results are presented as a sequence of calculations that can be understood by practicing radiation oncologists and in graphical form. RESULTS: The BED increment at the high-dose region is marginally increased by hypofractionation, although the latter effect is relatively small: up to 5% additional BED due to hypofractionation for a 20% increase in physical dose when the prescribed fraction size is 6-7 Gy. BED matching for late effects between a conventional and hypofractionated schedule at the high-dose region produces lower BED values throughout the remaining PTV, but at the expense of a reduced tumor control BED. CONCLUSION: Clinical trials that use BED isoeffect matching for late reacting tissue effects to design a hypofractioned test schedule should include comprehensive calculations of the likely BED in high-dose regions.

Algorithms↗
PubMed2000

Dose equivalents of tumour repopulation during radiotherapy: the potential for confusion.

When employing linear quadratic equations to calculate compensation for changes in overall treatment time, a potential confusion exists regarding use of the parameter commonly described as the dose equivalent of tumour repopulation. The more correct term for this factor is the biologically effective dose equivalent of tumour repopulation. The distinction between the two concepts is discussed and the potential errors arising from their confusion are illustrated by means of an example.

Dose Fractionation, Radiation↗
PubMed1999

Inclusion of molecular biotherapies with radical radiotherapy: modeling of combined modality treatment schedules.

PURPOSE: The use of molecular biology based therapies concurrently with radical radiotherapy is likely to offer potential benefits, but there is relatively little use of classical radiobiology in the rationale for such applications. The biological mechanisms that govern the outcomes of radiotherapy need to be completely understood before rational application and optimization of such adjuvant biotherapies with radiotherapy. METHODS AND MATERIALS: Existing biomathematical models of radiotherapy can be used to explore the possible impact of biotherapies that modify tumor proliferation rates and/or radiosensitivity parameters during radiotherapy. Equations that show how to incorporate biotherapies with the linear-quadratic model of radiation cell kill are presented. Also considered are changes in tumor physiology, such as improved blood flow with enhanced delivery of biotherapy to the tumor cells and accelerated clonogen repopulation during radiotherapy. Monte Carlo random sampling methods are used to simulate these effects in heterogenous tumor populations with variation in radiosensitivities, clonogen numbers, and doubling times, as well as variations in repopulation onset rates and in vascular perfusion rates with time. RESULTS: The time onset and duration of exposure of each type of biotherapy during radical radiotherapy can influence the predicted tumor cure probabilities in subtle ways. In general, the efficacy of biotherapies that radiosensitize will depend upon the number of radiotherapy fractions that are sensitized and the change in blood flow with time during radiotherapy. Biotherapies that control repopulation will depend not only on the duration of exposure but also, where accelerated repopulation occurs, on the time at which biotherapy is initiated during radiotherapy. From the ranges of radiobiological parameters and biotherapy efficacies assumed for exploratory examples, large changes of tumor control probability (TCP) are encountered in individual tumors from the application of cytostatic therapy. There are predictions of smaller increments in TCP in heterogenous tumor populations from the application of cytostatic and radiosensitizing biotherapies in combination. CONCLUSIONS: The exercises show how the scheduling of biotherapies may critically influence tumor cure probabilities in subtle ways and give considerable insight into the interacting biological mechanisms that influence these changes. Future therapeutic developments should be guided by these principles.

Cell Division↗