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Biomedical subjects

R G Dale

Publications and source records attributed to R G Dale.

At least 37 records · Page 2Linked to original sources
PubMed1999

BED-time charts and their application to the problems of interruptions in external beam radiotherapy treatments.

PURPOSE: The use of radiobiological modelling to examine the likely consequences of interruptions to radiotherapy schedules and to assess various compensatory measures. METHODS AND MATERIALS: An effect-time graphical display, the BED-time chart, has been developed using the linear-quadratic (LQ) model. This is used to examine the effects on tumour and normal tissues of treatment interruption scenarios representative of clinical situations. The mathematical criteria governing successful salvage have also been drafted and applied to typical situations. RESULTS: The successful salvage of an interrupted treatment is dependent on a number of interacting factors and the method presented here can be used to examine the trade-offs that exist. Although the mathematics may be complex, it is shown that the dilemmas posed by an interrupted treatment may be more easily appreciated with reference to BED-time charts. These may therefore have a useful role as a teaching aid for portraying a wider variety of radiotherapy problems and also in the documentation of interruptions to treatment and the measures taken to compensate for them. CONCLUSIONS: Interruptions to radiotherapy regimes are undesirable and compensatory measures need to be initiated as soon as possible after the gap, with a view to completing the amended treatment within the originally prescribed treatment time. Adequate compensation is particularly difficult for long gaps and gaps which occur towards the end of the scheduled treatment. Modelling exercises can help establish guidelines on the available windows of opportunity.

Algorithms↗
PubMed1999

The assessment of RBE effects using the concept of biologically effective dose.

PURPOSE: To modify existing linear-quadratic (LQ) equations in order to take account of relative biological effectiveness (RBE) using the concept of biologically effective dose (BED). METHODS AND MATERIALS: Clinically useful forms of the LQ model have been modified to incorporate RBE effects in such a way as to allow comparison between high- and low-LET (linear energy transfer) radiations in terms of similar biological dose units. The new parameter in the formulation is RBEM, the intrinsic (or maximum) RBE at zero dose. The principal assumption (following Kellerer and Rossi; ref. 1) is that high-LET radiation modifies the alpha-coefficient of damage while leaving the beta-coefficient unaltered. RESULTS: The equations allow a quantitative estimation of how the apparent RBE will change with changes in dose/fraction or dose-rate and of how the magnitude and rate of change is governed by the low-LET alpha/beta ratio of the irradiated tissue. The modifications are applicable to all types of radiotherapy (fractionated, continuous low dose-rate, therapy with decaying sources, etc.). In cases where the normal tissue RBEM is greater than that for the tumor, the revised formulation helps explain why there will be situations where therapeutic index will be adversely affected by use of high-LET radiation. Such clinical advantages as have been observed are more likely to result from favorable geometrical sparing of critical normal tissues and/or the fact that slowly growing tumors may have alpha/beta values more typical of late-responding normal tissues. CONCLUSIONS: The incorporation of RBE into existing LQ methodology allows quantitative assessment of clinical applications of high-LET radiations via an examination of the associated BEDs. On the basis of such assessments high-LET radiations are shown to confer few advantages.

Dose Fractionation, Radiation↗
PubMed1999

Mathematical models of tumour and normal tissue response.

The historical application of mathematics in the natural sciences and in radiotherapy is compared. The various forms of mathematical models and their limitations are discussed. The Linear Quadratic (LQ) model can be modified to include (i) radiobiological parameter changes that occur during fractionated radiotherapy, (ii) situations such as focal forms of radiotherapy, (iii) normal tissue responses, and (iv) to allow for the process of optimization. The inclusion of a variable cell loss factor in the LQ model repopulation term produces a more flexible clonogenic doubling time, which can simulate the phenomenon of 'accelerated repopulation'. Differential calculus can be applied to the LQ model after elimination of the fraction number integers. The optimum dose per fraction (maximum cell kill relative to a given normal tissue fractionation sensitivity) is then estimated from the clonogen doubling times and the radiosensitivity parameters (or alpha/beta ratios). Economic treatment optimization is described. Tumour volume studies during or following teletherapy are used to optimize brachytherapy. The radiation responses of both individual tumours and tumour populations (by random sampling 'Monte-Carlo' techniques from statistical ranges of radiobiological and physical parameters) can be estimated. Computerized preclinical trials can be used to guide choice of dose fractionation scheduling in clinical trials. The potential impact of gene and other biological therapies on the results of radical radiotherapy are testable. New and experimentally testable hypotheses are generated from limited clinical data by exploratory modelling exercises.

Brachytherapy↗
PubMed1999

A new incomplete-repair model based on a 'reciprocal-time' pattern of sublethal damage repair.

A radiobiological model for closely spaced non-instantaneous radiation fractions is presented, based on the premise that the time process of sublethal damage (SLD) repair is 'reciprocal-time' (second order), rather than exponential (first order), in form. The initial clinical implications of such an incomplete-repair model are assessed. A previously derived linear-quadratic-based model was revised to take account of the possibility that SLD may repair with time such that the fraction of an element of initial damage remaining at time t is given as 1/(1 + zt), where z is an appropriate rate constant; z is the reciprocal of the first half-time (tau) of repair. The general equation so derived for incomplete repair is applicable to all types of radiotherapy delivered at high, low and medium dose-rate in fractions delivered at regular time intervals. The model allows both the fraction duration and interfraction intervals to vary between zero and infinity. For any given value of z, reciprocal repair is associated with an apparent 'slowing-down' in the SLD repair rate as treatment proceeds. The instantaneous repair rates are not directly governed by total dose or dose per fraction, but are influenced by the treatment duration and individual fraction duration. Instantaneous repair rates of SLD appear to be slower towards the end of a continuous treatment, and are also slower following 'long' fractions than they are following 'short' fractions. The new model, with its single repair-rate parameter, is shown to be capable of providing a degree of quantitative explanation for some enigmas that have been encountered in clinical studies. A single-component reciprocal repair process provides an alternative explanation for the apparent existence of a range of repair rates in human tissues, and which have hitherto been explained by postulating the existence of a multi-exponential repair process. The build-up of SLD over extended treatments is greater than would be inferred using a single-exponential repair model and this has important implications in several areas of radiotherapy.

Brachytherapy↗
PubMed1999

High dose rate brachytherapy practice for the treatment of gynaecological cancers in the UK.

A summary of UK high dose rate brachytherapy practice in gynaecological cancer is presented. There appears to be relatively good uniformity in dose prescription and biological effective doses, which represents a considerable improvement from the findings of a previous report of UK low dose rate brachytherapy practice in 1991. Individual details of the dose schedules used at each treatment centre are presented.

Brachytherapy↗
PubMed1999

Enhanced normal tissue doses caused by tumour shrinkage during brachytherapy.

Published data concerning shrinkage rates of low-grade gliomas implanted with 125I seeds have been used to determine the likely influence of such shrinkage on normal tissue doses. It is demonstrated that a tumour volume shrinkage of 50% over 6 months can bring about a 30% increase in the dose delivered to tissues which shrink centripetally towards the implanted volume. The use of radionuclides with a half-life shorter than that of 125I would substantially reduce shrinkage-induced dose increments.

Brachytherapy↗
PubMed1998

Radiobiologically based assessments of the net costs of fractionated focal radiotherapy.

PURPOSE: To assess the potential changes in the net costs of focal radiotherapy techniques at differing doses per fraction and interfraction intervals. METHODS: Linear quadratic radiobiological modeling is used with appropriate variations in the radiosensitivity and tumor cell proliferation parameters. The notional cost of treatment is calculated from the number of fractions, cost per fraction and the cost of treatment failure, which is itself related to (1-TCP) where TCP is the tumor cure probability. Additional Monte Carlo calculations from ranges of radiobiological parameters have been used to simulate the cost of treatment of tumor populations. RESULTS: The optimum dose per fraction (and optimum overall cost) for conventional (nonfocal) radiotherapy is generally at low doses of around 2 Gy per fraction. The use of hyperfractionated and accelerated radiotherapy in addition to focal radiotherapy techniques appear to be indicated for more radioresistant tumors and if tumor proliferation is extremely rapid, but the need for treatment acceleration is much reduced where effective focal techniques are used. CONCLUSIONS: Radiobiological and economic modeling can be used to guide clinical choices of dose fractionation techniques providing the key radiobiological parameters are known or if the ranges of likely parameters in a tumor population are known. Focal radiotherapy, by the introduction of changes in the physical dose distribution, produces an upward shift in the optimum dose per fraction and a reduced dependency on overall treatment time.

Cell Division↗
PubMed1998

Radiobiological prediction of normal tissue toxicities and tumour response in the radiotherapy of advanced non-small-cell lung cancer.

A number of randomized studies have been carried out in the UK and USA to determine the optimal radiotherapy dose schedule for advanced non-small-cell lung cancer (NSCLC). We have examined eight radiotherapy regimens from data taken from four randomized phase III studies carried out in the UK (1264 patients): 10 Gy single fraction; 17 Gy in two fractions over 8 days; 30 Gy in ten fractions over 14 days; 22.5 Gy in five fractions in 5 days; 27 Gy in six fractions over 11 days; 30 Gy in six fractions over 11 days; 36 Gy in 12 fractions over 16 days; and 39 Gy in 13 fractions over 17 days. We compared the clinical results in palliation, toxicity and survival with four regimens taken from one randomized study from the USA (365 patients): 40 Gy in 20 fractions over 4 weeks; 40 Gy 'split course' in ten fractions in 4 weeks; 50 Gy in 25 fractions over 5 weeks; and 60 Gy in 30 fractions over 6 weeks. Using the linear-quadratic (LQ) radiobiological model, we have calculated the radiobiological equivalent dose (BED) for acute-reacting tissues (BED10), late-reacting tissues (BED1.7) and tumour (BED25), and related the predicted response to the observed response in each tissue. There was a good correlation between the predicted response and the reported response in the case of late-reacting tissue toxicity and tumour response. The model confirmed that, in good performance status patients, a higher value for BED25 correlated with a higher degree of local control and survival and that radiotherapy regimens with a higher value for BED1.7 were associated with five cases of cord myelopathy, if the spinal cord was not shielded. In poor performance status patients the model suggested that the optimal regimen was a single fraction of 10 Gy because this resulted in an equivalent degree of symptom control as other regimens, needed only one hospital visit and was less likely to result in cord damage, thus, allowing for the possibility of retreatment at a later date.

Carcinoma, Non-Small-Cell Lung↗
PubMed1998

Estimation of tumour hypoxic fraction from clinical data sets compatible with accelerated repopulation.

By extrapolation to zero time, the initial and final slopes of data sets which probably demonstrate the existence of accelerated repopulation during radiotherapy can be used to estimate the lower limits of the initial tumour hypoxic fraction. The slow repopulation phase (initial slope) is assumed to reflect treatment in mixed oxic and hypoxic conditions and the later fast repopulation (final slope) phase that of a well-oxygenated cell population. The method assumes that accelerated repopulation in tumours results from an improvement in oxygen status during radiotherapy, but quantitative knowledge of repopulation factors is not required in the calculations. Using the data of (a) Withers et al. (for head and neck squamous cell cancer) and (b) Maciejewski & Majewski (for bladder cancer), the lower limits of initial hypoxic fraction appear to be between 10 and 52%, the exact values depending on the value assumed for the oxygen-enhancement ratio (OER) of the hypoxic compartment. The analysis also suggests that the half-life of effective tumour reoxygenation is probably less than 5 days.

Cell Hypoxia↗
PubMed1998

The clinical radiobiology of brachytherapy.

The unique geometrical features of brachytherapy, together with the wide variety of temporal patterns of dose delivery, result in important interactions between physics and radiobiology. These interactions exert a major influence on the way in which brachytherapy treatments should be evaluated, both in absolute and comparative terms. This article reviews the main physical and radiobiological aspects of brachytherapy and considers examples of their influence on specific types of treatment. The issues relating to the optimization of high dose rate brachytherapy are presented, together with the implications of multiphasic repair kinetics for low dose-rate and pulsed high dose rate brachytherapy. The opportunities for application of radiobiological principles to improve various brachytherapy techniques, together with the integration of brachytherapy with teletherapy, are also outlined. Equations for the numerical evaluation of brachytherapy treatments are presented in the Appendices.

Brachytherapy↗
PubMed1997

Calculation of integrated biological response in brachytherapy.

PURPOSE: To present analytical methods for calculating or estimating the integrated biological response in brachytherapy applications, and which allow for the presence of dose gradients. METHODS AND MATERIALS: The approach uses linear-quadratic (LQ) formulations to identify an equivalent biologically effective dose (BEDeq) which, if applied to a specified tissue volume, would produce the same biological effect as that achieved by a given brachytherapy application. For simple geometrical cases, BED multiplying factors have been derived which allow the equivalent BED for tumors to be estimated from a single BED value calculated at a dose reference point. For more complex brachytherapy applications a voxel-by-voxel determination of the equivalent BED will be more accurate. Equations are derived which when incorporated into brachytherapy software would facilitate such a process. RESULTS: At both high and low dose rates, the BEDs calculated at the dose reference point are shown to be lower than the true values by an amount which depends primarily on the magnitude of the prescribed dose; the BED multiplying factors are higher for smaller prescribed doses. The multiplying factors are less dependent on the assumed radiobiological parameters. In most clinical applications involving multiple sources, particularly those in multiplanar arrays, the multiplying factors are likely to be smaller than those derived here for single sources. The overall suggestion is that the radiobiological consequences of dose gradients in well-designed brachytherapy treatments, although important, may be less significant than is sometimes supposed. The modeling exercise also demonstrates that the integrated biological effect associated with fractionated high-dose-rate (FHDR) brachytherapy will usually be different from that for an "equivalent" continuous low-dose-rate (CLDR) regime. For practical FHDR regimes involving relatively small numbers of fractions, the integrated biological effect to tissues close to the treatment sources will be higher with HDR than for LDR. Conversely, the integrated biological effect on structures more distant from the sources will be less with HDR. This provides quantitative confirmation of an idea proposed elsewhere, and suggests the existence of a potentially useful biological advantage for HDR brachytherapy delivered in relatively small fraction numbers and which is not apparent when considering radiobiological effect only at discrete reference points. CONCLUSION: The estimation and direct calculation of integrated biological response in brachytherapy are both relatively straightforward. Although the tabular data presented here result from considering only simple geometrical cases, and may thus overestimate the consequences of dose gradients in multiplanar clinical applications, the methods described may open the way to the development of more realistic radiobiological software, and to more systematic approaches for correlating physical dose and biological effect in brachytherapy.

Brachytherapy↗
PubMed1996

Radiobiologically based assessments of the net costs of fractionated radiotherapy.

PURPOSE: To examine how the long-term costs of radiation therapy may be influenced by modifications to fractionation schemes, and how any improvements in tumor control might, in principle, be translated into a potential cost saving for the responsible healthcare organization. METHODS AND MATERIALS: Standard radiobiological modeling based on the linear-quadratic (LQ) model is combined with financial parameters relating to the estimated costs of different aspects of radiotherapy treatment delivery. The cost model includes provision for the long-term costs of treatment failure and enables the extra costs of near optimal radiotherapy to be balanced against suboptimal alternatives, which are more likely to be associated with further radiotherapy, salvage surgery, and continuing care. RESULTS: A number of caveats are essential in presenting a model such as this for the first time, and these are clearly stated. However, a recurring observation is that, in terms of the whole cost of supporting a patient from first radiotherapy treatment onwards, high quality radiotherapy (i.e., based on individual patterns of fractionation that are near optimal for particular subpopulations of tumor) will frequently be associated with the lowest global cost. CONCLUSIONS: This work adds weight to the case for identifying fast and accurate predictive assay techniques, and supports the argument that suboptimal radiotherapy is usually more costly in the long term. Although the article looks only at the cost-benefit consequences of altered patterns of fractionation, the method will, in principle, have application to other changes in the way radiotherapy can be performed, e.g., to examining the cost-benefit aspects of tumor dose escalation as a consequence of using advanced conformal treatment planning (10).

Cost-Benefit Analysis↗
PubMed1996

Active minimisation of radiation scatter during breast radiotherapy: management implications for young patients with good-prognosis primary neoplasms.

BACKGROUND AND PURPOSE: Radiotherapy is used to reverse or prevent local tumour growth but is also a carcinogen in its own right. A recent audit of post-radiotherapy second malignancies in this institution revealed a striking preponderance of tumours originating near the outside edge of the treatment field. Since this finding suggests the existence of a critical subtherapeutic dose range predisposing to tumourigenesis, we attempted to define and reduce this radiation scatter dose. MATERIALS AND METHODS: We undertook a dosimetric review of 6 MV scatter from a linear accelerator in sites matching the putative tumourigenic region, and then extended this analysis to patients and tissue phantoms. RESULTS: A wide range of radiation scatter doses was confirmed-for example, doses 3 cm from the field edge varied from 1.7 to 22% of the therapeutic dose depending upon the field parameters. Scatter doses were then assessed in a sample of eight patients undergoing standard breast radiotherapy. Contralateral breast sites 4-12 cm from the midline received 4-10% of the therapeutic dose, or 200-500 cGy for a 50 Gy treatment, approximating historical estimates of the tumourigenic range. The deep component of this scatter dose from medial field breast irradiation was reduced 19% simply by replacing the 15 degrees medial tangential field wedge with a 30 degrees lateral wedge. Other manoeuvres which reduced contralateral breast dose by up to 46% included making the posterior field edges co-planar and shielding the breast during medial field irradiation. CONCLUSIONS: These results suggest that the risk of radiogenic second malignancies could be significantly decreased by careful attention to the treatment details. Greater awareness of these measures may prove particularly relevant to the conservative management of young patients with good-prognosis breast neoplasms such as ductal carcinoma in situ.

Breast↗
PubMed1996

A modelled comparison of the effects of using different ways to compensate for missed treatment days in radiotherapy.

There is much evidence for the detrimental effect on tumour control of missed treatment days during radiotherapy, amounting for example to approximately a 1.6% absolute decrease in local control probability per day of treatment prolongation in the case of head and neck squamous cell cancer. Various methods to compensate for missed treatment days are compared quantitatively in this article, using the linear-quadratic formalism. The overall time and fraction size can be maintained by either treating on weekend days (the preferred way (Method 1a), although with unsocial hours and at extra cost) or using two fractions per day to "catch up' (Method 1b). The latter might incur a small loss of tolerance regarding late reactions, when intervals of 6-8 h are used rather than 24 h, and there may be logistical/scheduling difficulties with larger numbers of patients in some centres when using this method. A second type of strategy retains overall treatment time, and also one fraction per day, but the size of the dose per fraction is increased. For example, this may be done for the same number of "post-gap' days as gap days (Method 2). However, with this method, calculated isoeffect doses regarding late reactions indicate a probable decrease in tumour control rate (Method 2a). Otherwise, isoeffective doses regarding tumour control result in an increase in late reactions (Method 2b). In addition, this method is unsuitable for short regimens already using high doses per fraction. To reduce this problem, overall treatment time can also be retained by using fewer fractions, all of greater size in the case of planned gaps (statutory holidays), or larger remaining fractions after unplanned gaps (Method 2c). The problem also with this method is that equivalence for tumour control gives an increase in late reactions. The least satisfactory strategy (Method 3) is to accept the protraction caused by the missed treatment days, and give either the same prescribed number of (slightly larger) fractions or the planned treatment followed by one (or more) extra fraction to compensate for the gap. This would retain the expected local control rate, but there would be an increase in late reactions. An example of this, using average parameter values, is that a 3-day gap (necessitating four extra days to complete treatment with one fraction of 2.4 Gy) might maintain a 70% local control rate for glottic carcinoma, but severe reactions might rise from 1% to 4% and minor/moderate reactions from 37% to 50%. In this example, the inclusion of an extra weekend would increase the required extra dose and hence may further increase the morbidity rates. A final point is that the effect of treatment interruptions for an individual patient is expected to be greater than that for a group of patients because of interpatient heterogeneity tending to flatten dose-response curves. Calculations show that the above value of 1.6% loss of local control per day for a group of patients may reflect values for individual patients that range around a median value of as much as 5% per day, so stressing further the importance of gaps in treatment. It is concluded that, wherever possible, treatment days should not be missed. If they are missed, it is important to compensate for them, preferably by one of the first of the above methods (1a or 1b), in order to keep as close as possible to the original/standard prescription in terms of total dose, dose per fraction and overall time.

Brachytherapy↗
PubMed1996

Dose-rate effects in targeted radiotherapy.

The physical dose delivered in radio-immunotherapy (RIT) may not, by itself, be a reliable indicator of the likely effectiveness of the treatment. Radiobiological considerations, in particular those relating to the dose-rate, are also very relevant. Dose-rate effects are important in conventional radiotherapy because of their ability to produce differential sparing effects between normal and malignant tissue. With targeted radiotherapy, in which dose-rates are likely to vary both spatially and temporally, the instantaneous dose-rate is additionally relevant since it determines whether or not any on-going clonogenic tumour re-population can be controlled. Therefore, for RIT in particular, there are two separate facets to the dose-rate effect, one concerned with the relative ability of different tissues to recover from radiation damage, the other concerned with the absolute ability to control concurrent tumour re-growth. In this article these two aspects are examined in terms of the linear-quadratic model and the implications assessed. Other radiobiological issues, such as re-oxygenation and cell cycle re-distribution are not discussed here.

Animals↗