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Commentary |
University of Wisconsin Medical School, Madison, USA
Correspondence: Jack F Fowler, University of Wisconsin Medical School, Madison, USA. E-mail: jackfowler{at}btinternet.com
The subject was covered more widely than the terse title suggests. One might say that radiobiological treatment planning involves most of radiobiology and all of radiation pathology. There was much of interest from seven excellent speakers. Modelling is now entirely respectable scientifically, being used in economic and weather forecasting, climate, voting predictions and cosmology. For radiotherapy, modelling is highly practical and is necessary in optimization of treatment plans and in any new modality being developed.
The first speaker, Prof. Bleddyn Jones (Birmingham), spoke on "The clinical aspects, what should modelling provide?" The answer was greater confidence in clinical decision making, especially now, when new treatments are breaching standard methods. Intensity-modulated radiation therapy (IMRT ) involves essentially "simultaneous boost in a field" and so depends on non-standard dose per fraction for selected subvolumes. We need to know how much improvement in tumour control probability (TCP) might be expected, and how much increase or decrease in normal tissue complication probability (NTCP). Although absolute values of these in percentage points cannot be predicted accurately, their ranking order can be helpful in optimization of treatment planning already. He pointed out that tumour cure statistics have provided much of the data for modelling, but that tumour regrowth delay data can be useful too. His list of practical current uses for modelling with BED (biologically effective dose) included the following "bullets": treatment gap compensation; correction of treatment dose delivery errors; choice of dose per fraction in altered radiotolerance; comparative assessments of dose–time fractionation schedules; assessment of new techniques; analysis of optimum dose per fraction; dose rate compensations; and high linear energy transfer (LET) compensations. All these are now being aided by active modelling.
Dr Danielle Powers (Hammersmith Hospital) gave a beautifully illustrated presentation on "The clinical perspective of radiobiological modelling". She described the recent technological developments in radiotherapy (imaging, positioning devices, forward and inverse planning programmes, tumour tracking and real-time dose recording) and listed seven "bullets" of modern treatment delivery: 3D conformal RT; intensity-modulated RT; brachytherapy at HDR (high dose rate); respiratory gating; stereotactic bodyframe RT; proton beam (and heavy-ion) RT; and 4D RT (tumour size tracking). She emphasized the potential advantages but the present uncertainties of predicting individual patient's radiosensitivities. Her final emphasis was on the necessity for further accurate data collection. An interinstitutional data bank of treatment protocols and outcomes was needed, for which the Academic Clinical Oncology and Radiobiology Research Network (ACORRN) could be helpful.
Prof. John Hopewell (Oxford) showed that revisiting old (30 years) radiobiological experimental animal data (from the acknowledged peacefulness of partial retirement) could lead to fresh insights. His special contribution had been to show that repair of radiobiological damage after irradiation is not monoexponential but consists of two (or more) rates of repair, most simply one of 5–15 min and a slow one of 3–5 h. It was not allowing for these which has led to much confusion about repair.
Prof. Alan Nahum (Clatterbridge) described assumptions involved in calculating TCP and NTCP for various radiotherapy situations. He mentioned the BIOPLAN programme (published by himself and Beatriz Sanchez-Nieta), which they generously offer from alan.nahum@ccotrust.nhs.uk and which the present reporter has used successfully for clinical cases. He mentioned that hypofractionation (fewer and larger fractions) is appropriate in certain limited circumstances and can save resources.
Prof. Roger Dale (Imperial College), delivering the 2006 Sylvanus Thompson lecture "Radiobiological treatment planning – how near, how far?", gave a masterful and superbly logical review with many memorable slides. He questioned – in a restrained way – modelling's reliability for quantitative treatment planning, beyond the clinically derived parameters that we use today. Normal tissues have complex hierarchical processes usually represented by observations of surrogate processes which may require non-linear models, based on critical feedback loops of the kind encountered in many aspects of systems engineering. He emphasized that the real costs of any cancer treatment should include costs of treating failed patients. The primary aim of all treatment plans is to optimize the therapeutic index (TI, which could be described as TCP divided by NTCP, or arguably more robustly as "BED in Gy10 divided by BED in Gy3 or Gy2"). It becomes complicated, as all clinicians know, when there are several different critical normal tissues involved in one treatment.
Dr Glen Flux (Institute of Cancer Research, Sutton) described the treatment-scheduling problems remaining for targeted nuclide therapy, starting with the wide uncertainties in radio-iodine therapy many years ago, uncertainties that are still with us. Cocktails of nuclides emitting particles of different path lengths were envisioned.
Dr Aswin Hoffman (Nijmegen, The Netherlands) gave a fascinating talk featuring the therapeutic operating curve (plotting TCP vertically against NTCP horizontally). At a chosen slope, sometimes 45 degrees, optimum treatment conditions occur. These appeared to be, for 5 days a week, doses of 1.6 or 1.7 Gy per fraction, which implies two fractions a day in 4 or 5 weeks. At once the (opposing) conditions for hypofractionation also appear, by exclusion, to be possible for parallel normal tissues, especially lung, liver and kidney; but also with treatment for tumours which have their alpha/beta ratios (
/β = radiosensitivity/repair capacity) lower than those of normal tissues such as prostate tumours, instead of higher as for most types of tumour. Composite biological objectives can be studied and specified by physicians, by combining TCP and NTCP in the Therapeutic Operating Characteristic (TOC) space on the graph of TCP vs NTCP.
Prof. Bleddyn Jones gave a forward-looking talk on the "Radiobiology for planning high LET radiotherapy". This starts with proton therapy; although the RBE (relative biological effectiveness) is only about 1.1 and no hypoxic-tumour advantage is evident, the terms necessary to deal with higher LET can be introduced, such as maximum RBE (at very low doses) and minimum LET (at very high doses per fraction). The point is that BED is then not just "total dose x (1+d/[/β])" but is "total dose x (max RBE+d/[/β]). Since RBE varies rapidly with dose per fraction this must be allowed for correctly with heavier ion beams such as the carbon ions that are displaying good clinical results in Chiba, Japan.
The last talk was a review by Dr Philip Mayles (Clatterbridge) about "Achieving clinical acceptance of radiobiological planning". He asked why a number of attempts to introduce this have not been accepted, in spite of examples to show that radiobiological considerations were important, such as the prediction of a big dose reduction for HDR brachytherapy. He noted that particularly strong evidence was required for clinicians to "step outside the comfort zone of 5x2 Gy per week" although this might change with commercially available radiobiological programmes being available. Steps to build confidence in radiobiological planning should resemble quality control. They should include a set of model parameters to be obtained from literature sources that are well documented and agreed, and the model should be shown to predict outcomes for a number of patients in prospective clinical trials. Radiobiological models should be simple enough to be understood by the majority of mathematically competent users (this raises a big question) and should preferably not be used for big steps forward. This last dictum seems to make it harder to obtain a statistically significant difference in order that any notice of it could be taken at all. He added "Are the doses delivered as intended?" as one of the remaining doubts.
This reporter is able to make a final remark about radiotherapy compared with chemotherapy or targeted nuclides and even genetic modifiers. Radiation does go, reasonably accurately, to where we plan it, as we can now verify with on-line techniques such as helical tomotherapy.
Received for publication September 6, 2007. Accepted for publication September 10, 2007.
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