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NORMAL CELLULAR RADIOSENSITIVITY IN AN ADULT FANCONI ANAEMIA PATIENT WITH MARKED CLINICAL RADIOSENSITIVITY (1)
350
Letters to the Editor asymmetrical collimator for a cobalt unit. Int J Radiation Oncology Biol Phys 2001;49:265–271.
Sincerely, Piet-Hein van der Giessen (Received 18 September 2001; accepted 16 October 2001) Dr. Bernard Verbeeten Instituut, Brugstraat 10, 5042 SB Tilburg, The Netherlands
0167-8140/02/$ - see front matter q 2002 Elsevier Science Ireland Ltd. All rights reserved. PII: S01 67- 8140(01)0046 7-4
NORMAL CELLULAR RADIOSENSITIVITY IN AN ADULT FANCONI ANAEMIA PATIENT WITH MARKED CLINICAL RADIOSENSITIVITY (1) To the Editor, We were interested to read this report concerning an adult Fanconi anaemia (FA) patient who suffered a severe clinical radiation reaction after a rather small dose of conventional radiotherapy [6]. In particular we raise issue with the authors with their conclusions regarding the relative sensitivity of fibroblasts cultured from this individual (designated 425 BR). Cases of this sort are extremely important. A reaction of this severity is outside the normal range of reactions that should be expected with radiotherapy, and patients with clinical radiosensitivity of this degree are likely to suffer dangerous or fatal normal tissue complications from standard radiotherapy. They therefore represent a clinically rare but important group of patients. The second reason for their importance is that patients of this sort may contribute to an understanding of the factors that determine variation in normal cellular and normal tissue radiosensitivity. The authors make much of the clinical reactions observed in ataxia-telangiectasia (AT) and other genetic syndrome patients and the association with high fibroblast radiosensitivity. What they fail to state is that these syndromic individuals make up a small proportion of the large literature describing patients with abnormal reactions to radiotherapy in which fibroblast radiosensitivity is not so dramatically different from normal. These studies together with a series examining the direct relationship between fibroblast sensitivity and normal tissue response in ‘normal’ cancer patients stimulated the nomenclature proposed by a European group studying clinical and cellular radiation sensitivity [4]. The case described here fits the criteria to be classed as a severe over-reactor (OR). This contrasts with extreme ORs, a group which includes AT patients and also the non-syndromic case, designated 180 BR and described by the same group [8], who developed extreme acute, early delayed
and late effects which proved fatal after a dose of only 18 Gy in ten fractions. With regard to fibroblast sensitivity, the authors have defined 425 BR as normal, although only by comparison with a single normal fibroblast line. Whilst we agree that 425 BR fibroblasts are not as sensitive as AT cells, the alpha and beta values quoted result in estimations of SF2 and D0.01 which do indicate a sensitivity which is at the lower edge of the range of variation in cellular sensitivity from non-syndromic patients. The authors actually state this in the text. This is a similar conclusion to our own earlier study of fibroblasts from FA patients in which we compared their sensitivity with those from a group of patients who had exhibited a range of normal tissue reactions. FA cell lines fell at the lower end of the range of sensitivities of nonsyndromic cases [1]. This is illustrated in Fig. 1 where we compare both sets of Fanconi data to the full range of sensitivities of non-syndromic breast cancer patients studied by Peacock et al. [7]. This finding is in good agreement with data from Gluckman [5] who attempted sensitivity testing of patients prior to bone marrow transplantation, when the protocol included both chemotherapy and total body irradiation. The conclusion from the clinical experience in this group of FA patients is that they are slightly more sensitive to radiation than normal, but not in an extreme way. This case, 425 BR, certainly has a clinical sensitivity which is more extreme than previously reported FA cases, despite having relatively typical chromosomal fragility. We are also concerned that the measurement of fibroblast sensitivity, especially at high dose, appears to be modified by a feeder effect. The experimental techniques should be able to overcome this, and we believe it is not appropriate to alter the model to fit these perturbed data points. We have found that the parameter D0.01 (the dose required to reduce the surviving fraction to 0.01 or 1%) is useful in discrimi-
Fig. 1. Frequency distribution of D0.01 values for 130 non-syndromic patients (hatched) plus three FA patients (in black). The case 425 BR has a D0.01 of 4.5 Gy and is located on the left of the figure. The other FA strains (in black with white hatching), FAN 1 and FAN 2, have D0.01 values of 5.23 and 4.71 Gy, respectively [1].
Letters to the Editor
nating between cell lines of similar sensitivity [3]. The value of D0.01 measured from the cell survival figure has a value of 4.5 Gy. By reading the data points off the graph, curvefitting using non-linear regression returns a value of 4.8 Gy. Both of these values place the cell line at the lower end of the distribution of high dose rate cellular sensitivity in our series and others, and similar to the two FA lines we studied [1,2,7,10]. However, using the alpha and beta values quoted in the paper gives a result of 3.8 Gy, which is extremely sensitive. On the other hand, by using the curious four parameter model quoted, this value becomes 6.9 Gy. By comparison, the D0.01 value for 180 BR is around 2.39 Gy (we are grateful to Dr Colin Arlett for access to the original 180 BR cellular sensitivity experimental data). The difference in these values for D0.01 illustrates some of the difficulty in using clonogenic assay to assess cellular sensitivity. However, it also demonstrates how important experimental methods are to remove possible bias such as from a feeder effect which should certainly not be treated as a characteristic of cellular sensitivity. Comparison of the sensitivity of 425 BR with other cell lines taken from clinically sensitive children is also relevant in locating the sensitivity of this patient and the cell line relative to other cases. Rogers et al. [9] reported data on four children treated at one radiotherapy centre, including the case designated as 180 BR, who suffered extreme or fatal complications from radiotherapy, which would classify them as extreme ORs in our schema [4]. Values for D0.01 can be read from the graphs presented and give values for three of the lines of 2.4, 3.3, and 4.0 Gy; the value for 180 BR is 2.39 Gy. The clinical details place the 425 BR patient as a severe OR, not an extreme OR. The cellular sensitivity with a D0.01 of 4.5 Gy places the cells at or just below the range for normally reacting patients, rather than in the category of extreme ORs [2]. Our interpretation of the data presented in this paper is contrary to that presented by the authors. We agree that this patient has had an abnormal normal tissue reaction from a low dose of radiotherapy, and we would classify this patient as a severe OR. However, we suggest that the cells from this patient are indeed more sensitive than average and represent evidence to support the hypothesis that normal cellular radiation sensitivity is linked to clinical radiotherapy response. This case may be important in the further study of determinants of radiation sensitivity and should encourage rather than discourage continued interest in both the mechanisms of variation in clinical response and also the possibility of developing predictive tests.
References [1] Burnet NG, Wurm R, Tait DM, Peacock JH. Cellular sensitivity and low dose-rate recovery in Fanconi anaemia fibroblasts. Br J Radiol 1994;67:579–583. [2] Burnet NG, Nyman J, Turesson I, Wurm R, Yarnold JR, Peacock JH. The relationship between cellular radiation sensitivity and tissue
[3]
[4]
[5]
[6]
[7]
[8]
[9]
[10]
351
response to radiotherapy may provide the basis for individualising radiotherapy schedules. Radiother Oncol 1994;33:228–238. Burnet NG, Wurm R, Peacock JH. Low dose-rate fibroblast response: the correct measure of fibroblast radiosensitivity for the prediction of patient response to radiotherapy?. Int J Radiat Biol 1996;70:289–300. Burnet NG, Johansen J, Turesson I, Nyman J, Peacock JH. Describing patients’ normal tissue reactions: concerning the possibility of individualising radiotherapy dose prescriptions based on potential predictive assays of normal tissue radiosensitivity. Steering Committee of the BioMed2 European Union Concerted Action Programme on the Development of Predictive Tests of Normal Tissue Response to Radiation Therapy. Int J Cancer 1998;79:606–613. Gluckman E. Radiosensitivity in Fanconi anaemia: application to the conditioning for bone marrow transplantation. Radiother Oncol 1990;1(Suppl):88–93. Marcou Y, D’Andrea A, Jeggo PA, Plowman PN. Normal cellular radiosensitivity in an adult Fanconi anaemia patient with marked clinical radiosensitivity. Radiother Oncol 2001;60(1):75–79. Peacock J, Ashton A, Bliss J, et al. Cellular radiosensitivity and complication risk after curative radiotherapy. Radiother Oncol 2000;55(2):173–178. Plowman PN, Bridges BA, Arlett CF, et al. An instance of clinical morbidity and cellular radiosensitivity, not associated with ataxiatelangiectasia. Br J Radiol 1990;63:624–628. Rogers PB, Plowman PN, Harris SJ, Arlett CF. Four radiation hypersensitivity cases and their implications for clinical radiotherapy. Radiother Oncol 2000;57(2):143–154. Russell NS, Grummels A, Hart AA, et al. Low predictive value of intrinsic fibroblast radiosensitivity for fibrosis development following radiotherapy for breast cancer. Int J Radiat Biol 1998;73(6):661–670.
Sincerely, Neil G. Burnet a,*, John H. Peacock b (Received 4 September 2001; accepted 24 September 2001) a Department of Oncology, University of Cambridge, Addenbrooke’s Hospital, Cambridge, UK, bRadiotherapy Research Unit, The Institute of Cancer Research, Sutton, UK
*Corresponding author. Addenbrooke’s Hospital, Oncology Centre, Box 193, Hills Road, Cambridge CB2 2QQ, UK 0167-8140/02/$ - see front matter q 2002 Elsevier Science Ireland Ltd. All rights reserved. PII: S0167 -8 140(01)00454 -6
NORMAL CELLULAR RADIOSENSITIVITY IN AN ADULT FANCONI ANAEMIA PATIENT WITH MARKED CLINICAL RADIOSENSITIVITY (2) To the Editor, Dr Alter’s observations [1] are of great interest and enhance the literature and Dr Burnet and Peacock’s data [2] endorse, from their own studies, the fact that standard in vitro radiobiological assays do not find extremely abnormal results in Fanconi Anaemia. Since our publication was submitted, the paradox of clinical sensitivity and relatively normal in vitro cellular radiosensitivity assay results has taken a new step forward with a
Letters to the Editor asymmetrical collimator for a cobalt unit. Int J Radiation Oncology Biol Phys 2001;49:265–271.
Sincerely, Piet-Hein van der Giessen (Received 18 September 2001; accepted 16 October 2001) Dr. Bernard Verbeeten Instituut, Brugstraat 10, 5042 SB Tilburg, The Netherlands
0167-8140/02/$ - see front matter q 2002 Elsevier Science Ireland Ltd. All rights reserved. PII: S01 67- 8140(01)0046 7-4
NORMAL CELLULAR RADIOSENSITIVITY IN AN ADULT FANCONI ANAEMIA PATIENT WITH MARKED CLINICAL RADIOSENSITIVITY (1) To the Editor, We were interested to read this report concerning an adult Fanconi anaemia (FA) patient who suffered a severe clinical radiation reaction after a rather small dose of conventional radiotherapy [6]. In particular we raise issue with the authors with their conclusions regarding the relative sensitivity of fibroblasts cultured from this individual (designated 425 BR). Cases of this sort are extremely important. A reaction of this severity is outside the normal range of reactions that should be expected with radiotherapy, and patients with clinical radiosensitivity of this degree are likely to suffer dangerous or fatal normal tissue complications from standard radiotherapy. They therefore represent a clinically rare but important group of patients. The second reason for their importance is that patients of this sort may contribute to an understanding of the factors that determine variation in normal cellular and normal tissue radiosensitivity. The authors make much of the clinical reactions observed in ataxia-telangiectasia (AT) and other genetic syndrome patients and the association with high fibroblast radiosensitivity. What they fail to state is that these syndromic individuals make up a small proportion of the large literature describing patients with abnormal reactions to radiotherapy in which fibroblast radiosensitivity is not so dramatically different from normal. These studies together with a series examining the direct relationship between fibroblast sensitivity and normal tissue response in ‘normal’ cancer patients stimulated the nomenclature proposed by a European group studying clinical and cellular radiation sensitivity [4]. The case described here fits the criteria to be classed as a severe over-reactor (OR). This contrasts with extreme ORs, a group which includes AT patients and also the non-syndromic case, designated 180 BR and described by the same group [8], who developed extreme acute, early delayed
and late effects which proved fatal after a dose of only 18 Gy in ten fractions. With regard to fibroblast sensitivity, the authors have defined 425 BR as normal, although only by comparison with a single normal fibroblast line. Whilst we agree that 425 BR fibroblasts are not as sensitive as AT cells, the alpha and beta values quoted result in estimations of SF2 and D0.01 which do indicate a sensitivity which is at the lower edge of the range of variation in cellular sensitivity from non-syndromic patients. The authors actually state this in the text. This is a similar conclusion to our own earlier study of fibroblasts from FA patients in which we compared their sensitivity with those from a group of patients who had exhibited a range of normal tissue reactions. FA cell lines fell at the lower end of the range of sensitivities of nonsyndromic cases [1]. This is illustrated in Fig. 1 where we compare both sets of Fanconi data to the full range of sensitivities of non-syndromic breast cancer patients studied by Peacock et al. [7]. This finding is in good agreement with data from Gluckman [5] who attempted sensitivity testing of patients prior to bone marrow transplantation, when the protocol included both chemotherapy and total body irradiation. The conclusion from the clinical experience in this group of FA patients is that they are slightly more sensitive to radiation than normal, but not in an extreme way. This case, 425 BR, certainly has a clinical sensitivity which is more extreme than previously reported FA cases, despite having relatively typical chromosomal fragility. We are also concerned that the measurement of fibroblast sensitivity, especially at high dose, appears to be modified by a feeder effect. The experimental techniques should be able to overcome this, and we believe it is not appropriate to alter the model to fit these perturbed data points. We have found that the parameter D0.01 (the dose required to reduce the surviving fraction to 0.01 or 1%) is useful in discrimi-
Fig. 1. Frequency distribution of D0.01 values for 130 non-syndromic patients (hatched) plus three FA patients (in black). The case 425 BR has a D0.01 of 4.5 Gy and is located on the left of the figure. The other FA strains (in black with white hatching), FAN 1 and FAN 2, have D0.01 values of 5.23 and 4.71 Gy, respectively [1].
Letters to the Editor
nating between cell lines of similar sensitivity [3]. The value of D0.01 measured from the cell survival figure has a value of 4.5 Gy. By reading the data points off the graph, curvefitting using non-linear regression returns a value of 4.8 Gy. Both of these values place the cell line at the lower end of the distribution of high dose rate cellular sensitivity in our series and others, and similar to the two FA lines we studied [1,2,7,10]. However, using the alpha and beta values quoted in the paper gives a result of 3.8 Gy, which is extremely sensitive. On the other hand, by using the curious four parameter model quoted, this value becomes 6.9 Gy. By comparison, the D0.01 value for 180 BR is around 2.39 Gy (we are grateful to Dr Colin Arlett for access to the original 180 BR cellular sensitivity experimental data). The difference in these values for D0.01 illustrates some of the difficulty in using clonogenic assay to assess cellular sensitivity. However, it also demonstrates how important experimental methods are to remove possible bias such as from a feeder effect which should certainly not be treated as a characteristic of cellular sensitivity. Comparison of the sensitivity of 425 BR with other cell lines taken from clinically sensitive children is also relevant in locating the sensitivity of this patient and the cell line relative to other cases. Rogers et al. [9] reported data on four children treated at one radiotherapy centre, including the case designated as 180 BR, who suffered extreme or fatal complications from radiotherapy, which would classify them as extreme ORs in our schema [4]. Values for D0.01 can be read from the graphs presented and give values for three of the lines of 2.4, 3.3, and 4.0 Gy; the value for 180 BR is 2.39 Gy. The clinical details place the 425 BR patient as a severe OR, not an extreme OR. The cellular sensitivity with a D0.01 of 4.5 Gy places the cells at or just below the range for normally reacting patients, rather than in the category of extreme ORs [2]. Our interpretation of the data presented in this paper is contrary to that presented by the authors. We agree that this patient has had an abnormal normal tissue reaction from a low dose of radiotherapy, and we would classify this patient as a severe OR. However, we suggest that the cells from this patient are indeed more sensitive than average and represent evidence to support the hypothesis that normal cellular radiation sensitivity is linked to clinical radiotherapy response. This case may be important in the further study of determinants of radiation sensitivity and should encourage rather than discourage continued interest in both the mechanisms of variation in clinical response and also the possibility of developing predictive tests.
References [1] Burnet NG, Wurm R, Tait DM, Peacock JH. Cellular sensitivity and low dose-rate recovery in Fanconi anaemia fibroblasts. Br J Radiol 1994;67:579–583. [2] Burnet NG, Nyman J, Turesson I, Wurm R, Yarnold JR, Peacock JH. The relationship between cellular radiation sensitivity and tissue
[3]
[4]
[5]
[6]
[7]
[8]
[9]
[10]
351
response to radiotherapy may provide the basis for individualising radiotherapy schedules. Radiother Oncol 1994;33:228–238. Burnet NG, Wurm R, Peacock JH. Low dose-rate fibroblast response: the correct measure of fibroblast radiosensitivity for the prediction of patient response to radiotherapy?. Int J Radiat Biol 1996;70:289–300. Burnet NG, Johansen J, Turesson I, Nyman J, Peacock JH. Describing patients’ normal tissue reactions: concerning the possibility of individualising radiotherapy dose prescriptions based on potential predictive assays of normal tissue radiosensitivity. Steering Committee of the BioMed2 European Union Concerted Action Programme on the Development of Predictive Tests of Normal Tissue Response to Radiation Therapy. Int J Cancer 1998;79:606–613. Gluckman E. Radiosensitivity in Fanconi anaemia: application to the conditioning for bone marrow transplantation. Radiother Oncol 1990;1(Suppl):88–93. Marcou Y, D’Andrea A, Jeggo PA, Plowman PN. Normal cellular radiosensitivity in an adult Fanconi anaemia patient with marked clinical radiosensitivity. Radiother Oncol 2001;60(1):75–79. Peacock J, Ashton A, Bliss J, et al. Cellular radiosensitivity and complication risk after curative radiotherapy. Radiother Oncol 2000;55(2):173–178. Plowman PN, Bridges BA, Arlett CF, et al. An instance of clinical morbidity and cellular radiosensitivity, not associated with ataxiatelangiectasia. Br J Radiol 1990;63:624–628. Rogers PB, Plowman PN, Harris SJ, Arlett CF. Four radiation hypersensitivity cases and their implications for clinical radiotherapy. Radiother Oncol 2000;57(2):143–154. Russell NS, Grummels A, Hart AA, et al. Low predictive value of intrinsic fibroblast radiosensitivity for fibrosis development following radiotherapy for breast cancer. Int J Radiat Biol 1998;73(6):661–670.
Sincerely, Neil G. Burnet a,*, John H. Peacock b (Received 4 September 2001; accepted 24 September 2001) a Department of Oncology, University of Cambridge, Addenbrooke’s Hospital, Cambridge, UK, bRadiotherapy Research Unit, The Institute of Cancer Research, Sutton, UK
*Corresponding author. Addenbrooke’s Hospital, Oncology Centre, Box 193, Hills Road, Cambridge CB2 2QQ, UK 0167-8140/02/$ - see front matter q 2002 Elsevier Science Ireland Ltd. All rights reserved. PII: S0167 -8 140(01)00454 -6
NORMAL CELLULAR RADIOSENSITIVITY IN AN ADULT FANCONI ANAEMIA PATIENT WITH MARKED CLINICAL RADIOSENSITIVITY (2) To the Editor, Dr Alter’s observations [1] are of great interest and enhance the literature and Dr Burnet and Peacock’s data [2] endorse, from their own studies, the fact that standard in vitro radiobiological assays do not find extremely abnormal results in Fanconi Anaemia. Since our publication was submitted, the paradox of clinical sensitivity and relatively normal in vitro cellular radiosensitivity assay results has taken a new step forward with a