- Email: [email protected]
Response to A. Niemierko and M. Goitein
Letters to the EditorsIRadiother. Oncol. 31 (1994) 265-267 nal cord tolerance In: Radiation Research (Proceedings of the 8th International Congress of Radiation Research), vol. 1, p. 352. Editors: E. M. Fielden, J. F. Fowler, J. H. Hendry and D. Scott. Taylor & Francis, London, New York, Philadelphia, 1987. 13 van der Kogel, A.J. Central nervous system radiation injury in
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small animal models. In: Radiation Injury to the Nervous System, pp. 91-111. Editors: P. H. Gutin, S.A. Leihel and G. E. Sheline. Raven Press, New York, 1991. 14 van der Kogel, A.J. Dose-volume effects in the spinal cord. Radiother. Oncol. 29: 105-109, 1993.
AND M. GOITEIN
To the Editors, In their letter [l], Drs Niemierko and Goitein support the main conclusion of my recent paper on volume effects in the spinal cord, namely to be very skeptical in the use of the current biophysical models to predict patient responses [l]. Intended as a critical review of the current knowledge and clinical implementation of dose-volume relationships in the central nervous system, and in particular the spinal cord, one of the aims of my paper was to stimulate the discussion between the various disciplines involved in this field. The interaction between modelling and experimental radiobiology has always been very productive and mutually stimulating, due to the quantitative nature of radiobiology. It clearly would be a misunderstanding if the ‘modelers’ would interpret critical notes as representing the ‘scorn’ of radiobiologists. The main point of disagreement raised by Niemierko and Goitein [l] is in their claim that the current models do provide a good fit to the data. In their example a general probability model is used [2] which includes a minimum of biological assumptions underscoring the mostly cosmetic role of the incorporation of biological parameters related to functional subunits in the latest generation of models. Obviously, when several parameters in a model are interdependent and changed accordingly, in many cases a better Iit will be obtained as demonstrated by Niemierko and Goitein in Figs. 1 and 2 of their letter. However, as I asked in my article [3], does a reasonable Iit validate the model, and is the tit really as good as it looks at first sight? In the case of the spinal cord the assumption of a series of critical elements is mathematically a sound first approximation, although there is no biological basis for the presence of a functional subunit which is serially organized. When fitting a probability model with k critical elements, I agree that the value of k should be adjusted with changing reference volumes. For relatively large volumes of cord (5 cm vs. 100 cm in Fig. 1 in Ref. [l]) the associated ED,, values only differ by 0.6 Gy. Such a difference would be impossible to detect in the kind of large animal studies needed to test for statistical significance. This range of volumes, albeit clinically very relevant, is clearly not the sensitive range to test the validity of the model. On the other hand, the most critical volumes are of the order
of 1 cm or less, and the EDso of 26.7 Gy associated with the best Iit for a reference length of 1 cm is nowhere near a realistic value for the rat spinal cord. The highest ED,, values reported are about 22-23 Gy for photons of > 1 MV energy, and 10-l% less for orthovoltage X-rays. That this is not a trivial difference becomes clear when calculating a ratio of 1.4- 1.5 for the difference in biological effectiveness of these single doses based on the LQ model (o/j3 ratio of 2 Gy for spinal cord). A striking observation in the rat spinal cord is that at any length above 1 cm no noticeable changes in ED,, occur, but that in millimeter steps below 1 cm a steep rise in ED,, dose is observed. The probability-based models do not account for such an almost discontinuous dose volume relationship. Although it is stated by Niemierko and Goitein [l] that no additional biology is needed to Iit the model to the data, it would be of interest to see the addition of a critical migration distance to a model instead of the FSU concept which lacks a biological basis. To me the value of modelling is not primarily in demonstrating a reasonable lit and then wait for better data, but to guide the experimentalist to the most critical and discriminating experimental conditions needed to get closer to the underlying mechanisms. Sincerely, Albert J. van der Kogel (received 14 April 1994; accepted 18 April 1994) Institute of Radiotherapy, University of Nijmegen, Geert Grooteplein 32, 6525 GA Nijmegen, The Netherlands
References 1 Niemierko, A. and Goitein, M. Dose-volume effects in the spinal cord. Radiother. Oncol. 1994. 2 Schultheiss, T.E., Orton, C.G. and Peck, R.A. Models in radiotherapy: volume effects. Med. Phys. IO: 410-415, 1983. 3 van der Kogel, A.J. Dose-volume effects in the spinal cord. Radiother. Oncol. 29: 105-109, 1993.
0167-8140/94/$07.00 0 1994 Elsevier Science Ireland Ltd. All rights reserved SSDI 0167-8140(94)01393-H
RESPONSE TO A. NIEMIERKO
267
small animal models. In: Radiation Injury to the Nervous System, pp. 91-111. Editors: P. H. Gutin, S.A. Leihel and G. E. Sheline. Raven Press, New York, 1991. 14 van der Kogel, A.J. Dose-volume effects in the spinal cord. Radiother. Oncol. 29: 105-109, 1993.
AND M. GOITEIN
To the Editors, In their letter [l], Drs Niemierko and Goitein support the main conclusion of my recent paper on volume effects in the spinal cord, namely to be very skeptical in the use of the current biophysical models to predict patient responses [l]. Intended as a critical review of the current knowledge and clinical implementation of dose-volume relationships in the central nervous system, and in particular the spinal cord, one of the aims of my paper was to stimulate the discussion between the various disciplines involved in this field. The interaction between modelling and experimental radiobiology has always been very productive and mutually stimulating, due to the quantitative nature of radiobiology. It clearly would be a misunderstanding if the ‘modelers’ would interpret critical notes as representing the ‘scorn’ of radiobiologists. The main point of disagreement raised by Niemierko and Goitein [l] is in their claim that the current models do provide a good fit to the data. In their example a general probability model is used [2] which includes a minimum of biological assumptions underscoring the mostly cosmetic role of the incorporation of biological parameters related to functional subunits in the latest generation of models. Obviously, when several parameters in a model are interdependent and changed accordingly, in many cases a better Iit will be obtained as demonstrated by Niemierko and Goitein in Figs. 1 and 2 of their letter. However, as I asked in my article [3], does a reasonable Iit validate the model, and is the tit really as good as it looks at first sight? In the case of the spinal cord the assumption of a series of critical elements is mathematically a sound first approximation, although there is no biological basis for the presence of a functional subunit which is serially organized. When fitting a probability model with k critical elements, I agree that the value of k should be adjusted with changing reference volumes. For relatively large volumes of cord (5 cm vs. 100 cm in Fig. 1 in Ref. [l]) the associated ED,, values only differ by 0.6 Gy. Such a difference would be impossible to detect in the kind of large animal studies needed to test for statistical significance. This range of volumes, albeit clinically very relevant, is clearly not the sensitive range to test the validity of the model. On the other hand, the most critical volumes are of the order
of 1 cm or less, and the EDso of 26.7 Gy associated with the best Iit for a reference length of 1 cm is nowhere near a realistic value for the rat spinal cord. The highest ED,, values reported are about 22-23 Gy for photons of > 1 MV energy, and 10-l% less for orthovoltage X-rays. That this is not a trivial difference becomes clear when calculating a ratio of 1.4- 1.5 for the difference in biological effectiveness of these single doses based on the LQ model (o/j3 ratio of 2 Gy for spinal cord). A striking observation in the rat spinal cord is that at any length above 1 cm no noticeable changes in ED,, occur, but that in millimeter steps below 1 cm a steep rise in ED,, dose is observed. The probability-based models do not account for such an almost discontinuous dose volume relationship. Although it is stated by Niemierko and Goitein [l] that no additional biology is needed to Iit the model to the data, it would be of interest to see the addition of a critical migration distance to a model instead of the FSU concept which lacks a biological basis. To me the value of modelling is not primarily in demonstrating a reasonable lit and then wait for better data, but to guide the experimentalist to the most critical and discriminating experimental conditions needed to get closer to the underlying mechanisms. Sincerely, Albert J. van der Kogel (received 14 April 1994; accepted 18 April 1994) Institute of Radiotherapy, University of Nijmegen, Geert Grooteplein 32, 6525 GA Nijmegen, The Netherlands
References 1 Niemierko, A. and Goitein, M. Dose-volume effects in the spinal cord. Radiother. Oncol. 1994. 2 Schultheiss, T.E., Orton, C.G. and Peck, R.A. Models in radiotherapy: volume effects. Med. Phys. IO: 410-415, 1983. 3 van der Kogel, A.J. Dose-volume effects in the spinal cord. Radiother. Oncol. 29: 105-109, 1993.
0167-8140/94/$07.00 0 1994 Elsevier Science Ireland Ltd. All rights reserved SSDI 0167-8140(94)01393-H