Correspondence in your September issue on the use of the Vygon tube for small bowel enemas (Ashleigh et al, 1991) from North Manchester, UK. Dr Hartnell makes the point that authors in non-European journals fail to acknowledge previous reports in European journals. This is true but factors of time as well as geography result in the "failure" of literature searches. Midline searches seem to go in 5, 10 or 15 year lengths (with 5 being the cheapest). I published a paper describing the use of a nasojejunal tube made by Vygon Ltd. (trade names were banned then) for small bowel enemas in children in Booth Hall Children's Hospital, North Manchester (Ratcliffe, 1983), to which no reference is made by Ashleigh et al. My paper was written in the same city of the same country as the paper by Ashleigh et al, and it appeared in Clinical Radiology which is published in the same city, country and continent as the British Journal of Radiology, but more than 5 years ago. Out of time is out of mind and apparently out of conscious memory too, because it would have been I who left several years' supply of the lurid green Vygon tubes in the store cupboard at Booth Hall. It may well be that my successor at Booth hall considered these tubes to belong to that category of apparatus which everyone's antecedent seems to have over- ordered and for which one can think of no rational and decent use. As a point of historical accuracy and to get the attribution right it was Dr Victor Miller, gastroenterologist at Booth Hall Hospital who suggested that I should use the Vygon tube when I was discussing with him the difficulty of getting the standard Nolan tube around the duodenum which has a tighter curve in children than in adults. Having used Vygon tubes for 10 years I endorse everything that Ashleigh et al say about them. I have tried several other types of tube but I still think the Vygon is the best tube for SBEs in children and have them imported specially to Australia. I am glad that they have been found and proved suitable for use in adults. It is worth making the point that if you want to know the nicest as well as the most effective way of doing something — ask a paediatric radiologist. We have usually got round to doing it years before the adult radiologists have thought of it. Yours etc., J. RATCLIFFE
X-ray Department, Royal Children's Hospital, Brisbane, Australia (Received 6 January 1992, accepted 30 January 1992)
Altered radiotherapy fractionation in medulloblastoma THE EDITOR—SIR,
Plowman and Doughty have recently described a partial transmission block technique for the treatment of children with medulloblastoma or similar tumours, who require total neuraxis radiotherapy (Plowman & Doughty, 1991). In this technique, the neuraxis radiotherapy is given in a larger number of smaller fractions, and it is proposed that this will reduce the neurological morbidity associated with the treatment without reducing tumour control rates. While we agree that late side effects are likely to be less severe, we do not accept that tumour control will be unchanged; indeed we expect that it will be significantly impaired. Using the linear-quadratic model, a prediction of the biological effect of a fractionated course of radiotherapy can be obtained by rearranging the expression:
where SF((ii is the fraction of cells surviving after n radiation doses, each ofdby. The biologically effective dose (BED) (Fowler, 1989) is given by: BED = nd (1 +d
)
In Table I we have used this equation to compare possible neuraxis treatments for the child with high-risk disease described by Plowman and Doughty. Normally, 35 Gy in 20 fractions over 4 weeks would be given, and this is shown as Regimen A. The proposed new treatment, Regimen B, is 35 Gy in 35 fractions over 7 weeks. Regimen C also gives 35 fractions over 7 weeks, but the total dose is calculated to give the same predicted late nervous system toxicity as the standard, shorter course. The BED is shown for three values of alpha/beta. 3 Gy represents normal neural tissue, while 20 Gy and 50 Gy have been chosen as approximations of the medulloblastoma response. It is difficult to give precise values for the tumour alpha/beta ratio as there is little published data. Neuroblastoma is probably not analagous to medulloblastoma as its radiobiological behaviour is different (Deacon et al, 1984). The alpha/beta ratios for two medulloblastoma cell lines have been measured at 51 Gy and 82 Gy (Fertil & Malaise, 1981), but these values may be artefactually elevated (Williams et al, 1985), as sublethal damage is probably less effectively repaired
References ASHLEIGH, R. J., SPINKS, B. C. & BISSET, R., 1991. The use of a
disposable nasoduodenal feeding tube for the small bowel enema examination. British Journal of Radiology, 64, 869—870. HARTNELI, G. G., 1991. A sense of deja vu. British Journal of Radiology, 64, 976. HINWOOD, D. & MANHIRE, A. R., 1991. Percutaneous nephrostomy
to relieve renal tract obstruction in pregnancy. British Journal of Radiology, 64, 976. RATCLIFFE, J. F., 1983. The small bowel enema in children. A description of a technique. Clinical Radiology, 34, 287-289. RENNY, F. H., 1991. Percutaneous nephrostomy to relieve renal tract obstruction in pregnancy. British Journal of Radiology, 64, 976.
460
Table I. The biologically effective dose of various treatment regimens at different alpha/beta ratios. Regimen
Total dose (Gy)
A. 20 x 1.75 Gy 35.0 B. 35 x 1.0 Gy
35.0
C. 35 X 1.145 Gy 40.1
Biologically effective dose by alpha/beta ratio (Gy) 3Gy 20 Gy 50 Gy " 55.4 46.7 55.4
38.1 36.8 42.4
36.2 35.7 41.0
The British Journal of Radiology, May 1992
Correspondence in vitro than in vivo. Table I shows that Regimen B, as proposed by Plowman and Doughty, gives a lower BED than Regimen A for all values of alpha/beta. The difference is small when alpha/beta is high, but becomes significant at lower levels of alpha/beta. It is quite possible that the true alpha/beta ratio of medulloblastoma is low enough for Regimen B to represent an important reduction in BED. Regimen C illustrates the predicted reduction in neural toxicity obtained by using an increased number of fractions. Theoretically, 40.1 Gy could be given over 35 fractions with no more late nervous tissue damage than 35 Gy in 20 fractions. In practice, however, nervous tissue tolerance may not increase as predicted with reduced fraction size at these low fraction doses (Ang et al, 1985). A further effect of the new regimen is to extend overall treatment time by 21 days. This is unlikely to result in any sparing of neural tissue injury (Van der Kogel, 1986), but would permit tumour proliferation. There is evidence that squamous cell head and neck malignancies enter a phase of rapid proliferation 3 or 4 weeks after starting radiotherapy (Withers et al, 1988). It is certainly possible that proliferation may accelerate even earlier (Fowler, 1989). The proposed new treatment duration would not only allow more proliferation at pre-treatment rates, but would extend into the period in which accelerated proliferation may be expected. For both these reasons, the new regime proposed by Plowman and Doughty represents a reduction in the effective dose to the tumour, and we would expect this to worsen control rates. In the absence of cell kinetic data on medulloblastoma it is not possible to predict the increase in dose required to counteract proliferation. In view of this we would advocate caution before changing from a clinically tested treatment. Yours etc., N. P. BATES M. V. WILLIAMS
Department of Clinical Oncology, Addenbrooke's Hospital, Hills Road, Cambridge CB2 2QQ, UK (Received I November 1991, accepted 12 February 1992) References ANG, K. K., VAN DER KOGEL, A. J. & VAN DER SCHUEREN, E., 1985.
Lack of evidence for increased tolerance of rat spinal cord with decreasing fraction doses below 2 Gy. International Journal of Radiation Oncology, Biology and Physics, 11, 105—110. DEACON, J., PECKHAM, M. J. & STEEL, G. G., 1984. The radiore-
sponsiveness of human tumours and the initial slope of the cell survival curve. Radiotherapy and Oncology, 2, 317—323. FERTIL, B. & MALAISE, E.-P., 1981. Inherent cellular radiosensitivity as a basic concept for human tumor radiotherapy. International Journal ofRadiation Oncology, Biology and Physics, 7,621 -629. FOWLER, J. F., 1989. The linear-quadratic formula and progress in fractionated radiotherapy. British Journal of Radiology, 62, 679-694. PLOWMAN, P. N. & DOUGHTY, D., 1991. An innovative method for
neuraxis radiotherapy using partial transmission block technique. British Journal of Radiology, 64, 603-607. VAN DER KOGEL, A. J., 1986. Radiation-induced damage in the central nervous system: an interpretation of target cell responses.
Vol. 65, No. 773
British Journal of Cancer, 53 (Suppl. VII), 207-217. WILLIAMS, M. V., DENEKAMP. J. & FOWLER, J. F., 1985. A review
of alpha/beta ratios for experimental tumours: implications for clinical studies of altered fractionation. International Journal of Radiation Oncology, Biology and Physics, 11, 87-96. WITHERS, H. R., TAYLOR, J. M. G. & MACIEJEWSKI, B., 1988. The
hazard of accelerated tumor clonogen repopulation during radiotherapy. Acta Oncologica, 27, 131-146.
Authors' reply THE EDITOR—SIR,
The major morbidity of neuraxis radiotherapy in young children is late neuropsychological retardation, which may be severe (reviewed by Gamis et al, 1991). Two recent studies suggest that the total radiation dose to the neuraxis may not be lowered safely in (? any) group of these children (Deutsch et al, 1991, SIOP medulloblastoma second trial unpublished results), and this prevents the most certain method of reducing this morbidity. An alternative method of reducing this morbidity must be desirable, but carefully weighed against a possible loss of tumour control. Like a bumble-bee's flight capability necessitating modification of the laws of aerodynamics, so the clinical observation of paediatric tumour (including primary brain tumour) responses to low daily fraction sizes may indicate the need for caution in accepting "biologically effective dose models" that reach conclusions contrary to such clinical observations. Until the oc/p ratios for human tumours in vivo and the relevant proliferation factors are known, such models must be regarded critically. Contrary to the statement by Bates and Williams, our partial transmission block method does not extend overall treatment (by 21 days) and we would point out that the conventional dose per fraction is maintained to the posterior fossa (highest risk site) throughout. In his 1985 Leukaemia Research Fund Annual Guest Lecture, and in a radiobiological context, Professor Lazlo Lajtha stated ' i t is very dangerous to fall in love with models". We would suggest a Bart's amendment: "one may later regret...". We believe that the late neuropsychological damage in children surviving neuraxis irradiation by conventional shrinking field technique may be severe and that this justifies careful exploration of our published partial transmission block technique, for which we maintain the rationale remains intact (Plowman & Doughty, 1991). In an upcoming paper, we apply the a/P concept to our application of the partial transmission block technique to pineal tumour therapy (Sebag-Montefiore et al, 1992). Yours etc., P. N. PLOWMAN D. DOUGHTY D. SEBAG-MONTEFIORE
Department of Radiotherapy, St Bartholomew's Hospital, London EC1A7BE, UK (Received 2 January 1992, accepted 12 February 1992)
461
X-ray Department, Royal Children's Hospital, Brisbane, Australia (Received 6 January 1992, accepted 30 January 1992)
Altered radiotherapy fractionation in medulloblastoma THE EDITOR—SIR,
Plowman and Doughty have recently described a partial transmission block technique for the treatment of children with medulloblastoma or similar tumours, who require total neuraxis radiotherapy (Plowman & Doughty, 1991). In this technique, the neuraxis radiotherapy is given in a larger number of smaller fractions, and it is proposed that this will reduce the neurological morbidity associated with the treatment without reducing tumour control rates. While we agree that late side effects are likely to be less severe, we do not accept that tumour control will be unchanged; indeed we expect that it will be significantly impaired. Using the linear-quadratic model, a prediction of the biological effect of a fractionated course of radiotherapy can be obtained by rearranging the expression:
where SF((ii is the fraction of cells surviving after n radiation doses, each ofdby. The biologically effective dose (BED) (Fowler, 1989) is given by: BED = nd (1 +d
)
In Table I we have used this equation to compare possible neuraxis treatments for the child with high-risk disease described by Plowman and Doughty. Normally, 35 Gy in 20 fractions over 4 weeks would be given, and this is shown as Regimen A. The proposed new treatment, Regimen B, is 35 Gy in 35 fractions over 7 weeks. Regimen C also gives 35 fractions over 7 weeks, but the total dose is calculated to give the same predicted late nervous system toxicity as the standard, shorter course. The BED is shown for three values of alpha/beta. 3 Gy represents normal neural tissue, while 20 Gy and 50 Gy have been chosen as approximations of the medulloblastoma response. It is difficult to give precise values for the tumour alpha/beta ratio as there is little published data. Neuroblastoma is probably not analagous to medulloblastoma as its radiobiological behaviour is different (Deacon et al, 1984). The alpha/beta ratios for two medulloblastoma cell lines have been measured at 51 Gy and 82 Gy (Fertil & Malaise, 1981), but these values may be artefactually elevated (Williams et al, 1985), as sublethal damage is probably less effectively repaired
References ASHLEIGH, R. J., SPINKS, B. C. & BISSET, R., 1991. The use of a
disposable nasoduodenal feeding tube for the small bowel enema examination. British Journal of Radiology, 64, 869—870. HARTNELI, G. G., 1991. A sense of deja vu. British Journal of Radiology, 64, 976. HINWOOD, D. & MANHIRE, A. R., 1991. Percutaneous nephrostomy
to relieve renal tract obstruction in pregnancy. British Journal of Radiology, 64, 976. RATCLIFFE, J. F., 1983. The small bowel enema in children. A description of a technique. Clinical Radiology, 34, 287-289. RENNY, F. H., 1991. Percutaneous nephrostomy to relieve renal tract obstruction in pregnancy. British Journal of Radiology, 64, 976.
460
Table I. The biologically effective dose of various treatment regimens at different alpha/beta ratios. Regimen
Total dose (Gy)
A. 20 x 1.75 Gy 35.0 B. 35 x 1.0 Gy
35.0
C. 35 X 1.145 Gy 40.1
Biologically effective dose by alpha/beta ratio (Gy) 3Gy 20 Gy 50 Gy " 55.4 46.7 55.4
38.1 36.8 42.4
36.2 35.7 41.0
The British Journal of Radiology, May 1992
Correspondence in vitro than in vivo. Table I shows that Regimen B, as proposed by Plowman and Doughty, gives a lower BED than Regimen A for all values of alpha/beta. The difference is small when alpha/beta is high, but becomes significant at lower levels of alpha/beta. It is quite possible that the true alpha/beta ratio of medulloblastoma is low enough for Regimen B to represent an important reduction in BED. Regimen C illustrates the predicted reduction in neural toxicity obtained by using an increased number of fractions. Theoretically, 40.1 Gy could be given over 35 fractions with no more late nervous tissue damage than 35 Gy in 20 fractions. In practice, however, nervous tissue tolerance may not increase as predicted with reduced fraction size at these low fraction doses (Ang et al, 1985). A further effect of the new regimen is to extend overall treatment time by 21 days. This is unlikely to result in any sparing of neural tissue injury (Van der Kogel, 1986), but would permit tumour proliferation. There is evidence that squamous cell head and neck malignancies enter a phase of rapid proliferation 3 or 4 weeks after starting radiotherapy (Withers et al, 1988). It is certainly possible that proliferation may accelerate even earlier (Fowler, 1989). The proposed new treatment duration would not only allow more proliferation at pre-treatment rates, but would extend into the period in which accelerated proliferation may be expected. For both these reasons, the new regime proposed by Plowman and Doughty represents a reduction in the effective dose to the tumour, and we would expect this to worsen control rates. In the absence of cell kinetic data on medulloblastoma it is not possible to predict the increase in dose required to counteract proliferation. In view of this we would advocate caution before changing from a clinically tested treatment. Yours etc., N. P. BATES M. V. WILLIAMS
Department of Clinical Oncology, Addenbrooke's Hospital, Hills Road, Cambridge CB2 2QQ, UK (Received I November 1991, accepted 12 February 1992) References ANG, K. K., VAN DER KOGEL, A. J. & VAN DER SCHUEREN, E., 1985.
Lack of evidence for increased tolerance of rat spinal cord with decreasing fraction doses below 2 Gy. International Journal of Radiation Oncology, Biology and Physics, 11, 105—110. DEACON, J., PECKHAM, M. J. & STEEL, G. G., 1984. The radiore-
sponsiveness of human tumours and the initial slope of the cell survival curve. Radiotherapy and Oncology, 2, 317—323. FERTIL, B. & MALAISE, E.-P., 1981. Inherent cellular radiosensitivity as a basic concept for human tumor radiotherapy. International Journal ofRadiation Oncology, Biology and Physics, 7,621 -629. FOWLER, J. F., 1989. The linear-quadratic formula and progress in fractionated radiotherapy. British Journal of Radiology, 62, 679-694. PLOWMAN, P. N. & DOUGHTY, D., 1991. An innovative method for
neuraxis radiotherapy using partial transmission block technique. British Journal of Radiology, 64, 603-607. VAN DER KOGEL, A. J., 1986. Radiation-induced damage in the central nervous system: an interpretation of target cell responses.
Vol. 65, No. 773
British Journal of Cancer, 53 (Suppl. VII), 207-217. WILLIAMS, M. V., DENEKAMP. J. & FOWLER, J. F., 1985. A review
of alpha/beta ratios for experimental tumours: implications for clinical studies of altered fractionation. International Journal of Radiation Oncology, Biology and Physics, 11, 87-96. WITHERS, H. R., TAYLOR, J. M. G. & MACIEJEWSKI, B., 1988. The
hazard of accelerated tumor clonogen repopulation during radiotherapy. Acta Oncologica, 27, 131-146.
Authors' reply THE EDITOR—SIR,
The major morbidity of neuraxis radiotherapy in young children is late neuropsychological retardation, which may be severe (reviewed by Gamis et al, 1991). Two recent studies suggest that the total radiation dose to the neuraxis may not be lowered safely in (? any) group of these children (Deutsch et al, 1991, SIOP medulloblastoma second trial unpublished results), and this prevents the most certain method of reducing this morbidity. An alternative method of reducing this morbidity must be desirable, but carefully weighed against a possible loss of tumour control. Like a bumble-bee's flight capability necessitating modification of the laws of aerodynamics, so the clinical observation of paediatric tumour (including primary brain tumour) responses to low daily fraction sizes may indicate the need for caution in accepting "biologically effective dose models" that reach conclusions contrary to such clinical observations. Until the oc/p ratios for human tumours in vivo and the relevant proliferation factors are known, such models must be regarded critically. Contrary to the statement by Bates and Williams, our partial transmission block method does not extend overall treatment (by 21 days) and we would point out that the conventional dose per fraction is maintained to the posterior fossa (highest risk site) throughout. In his 1985 Leukaemia Research Fund Annual Guest Lecture, and in a radiobiological context, Professor Lazlo Lajtha stated ' i t is very dangerous to fall in love with models". We would suggest a Bart's amendment: "one may later regret...". We believe that the late neuropsychological damage in children surviving neuraxis irradiation by conventional shrinking field technique may be severe and that this justifies careful exploration of our published partial transmission block technique, for which we maintain the rationale remains intact (Plowman & Doughty, 1991). In an upcoming paper, we apply the a/P concept to our application of the partial transmission block technique to pineal tumour therapy (Sebag-Montefiore et al, 1992). Yours etc., P. N. PLOWMAN D. DOUGHTY D. SEBAG-MONTEFIORE
Department of Radiotherapy, St Bartholomew's Hospital, London EC1A7BE, UK (Received 2 January 1992, accepted 12 February 1992)
461
