- Email: [email protected]
15 Documentation of acute radiation effects in the urinary bladder during treatment for prostate cancer
Discussion of Proffered Papers
Sunday, l0 December 2000
SI3
14
The ICD-IO as a useful diagnosis code for recorded acute radiation morbidity p__Sch(Jller1, F. Bruns 2, O. Micke 1, U. Haverkamp2 1Dpt. of Radiooncology, University of, MDnster, Germany 2Dpt. of Radiology, Clemenshospital, MOnster, Germany Purpose: The obligatory documentation of radiation induced toxicities is usually done in uncoded text format, even if the patient chart is kept electronically. Data exchange between radiation oncology departments is often limited to multicentre studies; because a standardized code is missing, direct electronic data transmission is difficult even between study centres. The question arises how the assessment of acute treatment related toxicities can be utilized in national and international evaluations against the background that up to now side effects have been systematically assessed only within the scope of multicentre studies. For treatment related toxicities, various forms of encoding, differing in the intended amount of documentation, are imaginable; some are presented below. Methods: The most widely known internationally evaluated diagnosis code is the ICD-10 (Tenth Revision of the International Classification of Diseases), which was published in the current form in 1993 by the WHO and comprises the formerly independent ICD-O (International Classification of Diseases for Oncology). The purpose of the ICD-10 is to make relevant morbidity and mortality data available to electronic processing in an encoded form. The ICD-1O assigns a three-digit main code. In the case of radiation induced toxicities the code is extended by a fourth digit in the form of a sub-category (e.g. acute radiation pneumonitis = J7O.O). On the basis of this classification, a proposal is made to extend the existing diagnosis code by a fifth digit encoding the severity of acute toxicity by 1, 2, 3, 4, or X (if not evaluable). In the case of a moderate (grade 1) acute radiation pneumonitis this results in the code J70.01. For the definition of the toxicity grading, the internationally established classification of the RTOG toxicity criteria is used. An evaluation is being done in the context of a study on the treatment of head and neck tumours. Discussion: The ICD-10 has been available for years as an internationally renowned encoding instrument which allows the systematic assessment, analysis, and comparison of morbidity (and mortality) data collected in different countries over various periods of time.In the German health system, the ICD-10 has already been introduced as obligatory in some fields (i.e. in the assessment of mortality data). The ICD-10 offers two possibilities of supplementary encoding. The letter ,,U" has been left free for the encoding of additional diseases. A different code can be integrated using the ,,dagger and asterisk" system. However, as all radiation induced morbidities can in principle be encoded using the existing ICD-10 code, only a slight modification is proposed which includes a score for the severity of side effects (e.g. the EORTC/RTOG classification) by adding a fifth digit. At least the acute radiation morbidity recorded for treatment evaluation should be documented in every department as an electronic data base supplementing the ICD-10. The addition of the toxicity data to the ICD-10 code, which can be done automatically in the electronic network, is not only useful for internal quality control inside the department but also enables interested superior institutions to carry out therapy optimization studies and meta-analyses with limited human resources. The ICD-10 as an established diagnosis code can cover a large part of the encoding, so that the requirements for the establishment of a multi-institutional network for the exchange of toxicity related data can be easily met by the proposed slight modification of the ICD-10 by the severity of acute toxicity. A prospective computer based encoding can be done just as easily as a retrospective manual encoding. The relevant radiation induced acute toxicities (EORTC/RTOG) assessed during treatment should be submittable to a superior institution (e.g. a study centre) in adequate form (i.e. electronically). Conclusion: An extension of the ICD-10 for the encoding of acute radiation morbidity is proposed which is directly derived from the RTOG Toxicity Criteria. This diagnosis code permits simplified electronic data transmission, e.g. in the context of multi-centre studies. With knowledge of the RTOG Toxicity Criteria, the use of the proposed diagnosis code is simple and easily verifiable. References: ICD-10: International Statistical Classification of Diseases and Related Health Problems, 10th Revision. World Health Organization, Geneva, 1992. - Seegenschmiedt MH Nebenwirkungen in der Onkologie - Internationale Systematik und Dokumentation. Kap.8: RTOG- und RTOG/EORTC Toxicity Criteria. Springer, Berlin Heidelberg New York: 51 - 65, 1998. -
15
Documentation of acute radiation effects in the urinary bladder during treatment for prostate cancer W. Doerr T. Herrmann Technica/ University Dresden, Medica/ Facu/ty Car/Gustav Carus, Dept. of Radiotherapy and Radiation Onco/ogy, Dresden, Germany Impairment of urinary bladder function is a frequent side effect of radiotherapy of tumours in the pelvis, i. e. malignancies of prostate, uterus/cervix uteri, rectum or bladder. The radiation response occurs in three distinct phases: The acute reaction develops during the treatment and usually lasts for some weeks post irradiation. The acute phase is followed by a dose-dependent latent time which, e.g. after treatment for prostate cancer, can last up to 10 years or longer (Perez et al. 1994). Hence, the radiation sensitivity of the urinary bladder, based on a follow-up of 5 years, is usually underestimated. Late sequelae, in contrast to the acute effects, are progressive and irreversible. Their incidence, after sufficient follow-up times, exceeds that of late radiation effects in the intestine. Clinical symptoms in the acute as well as in the late response phase comprise an increase in micturition frequency, including nocturia, dysuria and pollakiuria. These are caused by a reduction in bladder storage capacity. The detailed pathogenesis of this functional impairment still remains unclear. Recent experimental studies revealed that changes in prostaglandin levels are involved in the acute response (D6rr et al. 1998). Moreover, an impairment of the urothelial barrier and alterations of urothelial cell function have been demonstrated (Eckhardt/D6rr 1998, Eckhardt et al. 1997), while no acute urothelial denudation could be shown. In contrast, late functional sequelae correlated with morphological changes, such as denuded and hyperproliferative areas, in the urothelium (Kraft et al. 1996). Detailed analyses of clinical (Schultheiss et al. 1997) and experimental data (DSrr/Beck-Bornholdt 1999, D6rr et al. this issue) revealed a strong consequential component of the late radiation sequelae in the bladder: The intensity and/or duration of the acute reaction significantly influence the risk for manifestation of late functional effects. Detailed, objective monitoring and documentation of acute functional changes in the bladder are a prerequisite for clinical studies of side effects of radiotherapy in the pelvic region, which may, to some extent, allow for prediction of late sequelae. Objective endpoints, which may be used for routine a s s e s s ment of acute bladder reactions, should allow for easy and frequent data acquisition, and the methods applied should be non-invasive. Direct measurements of bladder capacity, e.g. by ultrasound, are time consuming and are not applicable as routine assays. Alternatively, micturition frequency or micturition volume may be assessed. Micturition frequency, however, is subject to major variations, and frequently is not properly and with sufficient precision reported by the patients. In contrast, direct measurements of micturition volumes can read@ performed, but require preparation and disposal or cleaning of the vessels provided for the patients. As an alternative, indirect method, determination of the body weight of the patients before and after micturition has been proposed (Hanfmann et al. 1998). The present study in prostate cancer patients was initiated to compare direct measurement of micturition volumes with the weighing method, and to check for the feasibility of the latter for routine documentation of bladder function during radiotherapy. Between November 1998 and August 2000, 24 patients have been included in this study. Radiotherapy consisted of a tumour dose of 5xl .8 Gy/week. The
SI4
Sunday, l0 December 2000
Discussion of Proffered Papers
patients were asked to present for irradiation with a maximally filled bladder. Before irradiation, patients performed weighing immediately before and after micturition. The body weight was recorded by the patients themselves on an individual form sheet provided by the hospital. The sensitivity of the scale was 10 g. The difference between post- and pre-micturition body weight is assumed to mirror the micturition volume. In addition, patients were asked to report their micturition frequencies, separately for days and nights, on the same form sheet. Two patients were excluded from the analysis, one because of cessation of radiotherapy in week 2, and one because of incompliance. In a pilot phase in the first 9 patients, direct measurements of micturition volumes were compared with the weight differences assessed. Regression analysis revealed a good correlation between weight differences and micturition volumes (p=0.001), with an overall correlation coefficient of 0.72. The correlation coefficients in the individual patients ranged from 0.40 to 0.90, with a significant correlation (p=0.001) in all patients. It has to be noted that major deviations from a one-to-one relationship in most of the cases were based on a reduced volume compared to the weight difference, indicating loss of urine during collection. Hence, the weighing method must be considered the more precise technique. Individual baseline data for the individual patients were calculated from the data documented during the first 6 days after onset of radiotherapy, and hence comprised the initial 5 measurements. Mean baseline values (ASD) were a weight difference of 150A83 g (range 23-398 g), a day-time micturition frequency of 7.2A3.0 (range 3.2-15.0) and a night-time micturition frequency of 2.3A1.1 (range 0-4.8). Based on these individual control values, relative changes in the parameters during radiotherapy were calculated. The measurements display a substantial day-to-day variation of the weight differences assessed. This may be due to variations in the grade of bladder filling with which the patients present. Therefore, for each patient, the weekly average value of the micturition volume has been calculated in order to illustrate the time course of the acute bladder response. The average micturition volume for all patients, as reflected by the weight difference, remained almost unchanged during the first 3 treatment weeks, and then gradually decreased to 87% (p=0.005), 85% (p=0.023), 80% (p=0.001), and 79% (p=0.0002) in weeks 4, 5, 6 and 7, respectively. Micturition frequencies increased to a maximum of 120%-125% in week 6-8 for day-time, and to 140%-150% in weeks 48 for the night frequency. However, a detailed analysis revealed no significant correlation between these micturition frequencies, reported by the patients, and weight differences or micturition volumes. This indicates that frequency assessment in patients is not sufficiently sensitive, or at least not reliable enough, to objectively quantitate the acute radiation response of the urinary bladder. The reduction in micturition volumes might be a result from an increase in residual, post-micturition urine volume. In order to test for this, one patient has been subjected to weekly ultrasound measurements of pre- and post-micturition bladder volume. This patient developed a significant acute reduction in micturition volumes as defined by the weight difference technique. No systematical fluctuations in the residual volume were found, and the micturition-associated volume changes assessed by ultrasound were in good accordance with the weight difference. Hence, the changes observed can be attributed to a reduction in bladder storage capacity. However, ultrasound examination in further patients is required. As mentioned above, the intensity and/or duration of the acute bladder response may be predictive for the risk to develop late sequelae because of the strong consequential component. As a measure for the combination of intensity and duration, the mean micturition volume over the entire treatment time in relation to the baseline value can be used. In combination with the minimum values for bladder capacity measured, 4 patterns of radiation response can readily be identified: (i) patients with only a minor reaction, (ii) patients with a minor to intermediate, but long-lasting functional impairment, (iii) patients with a substantial, but short response, and (iv) patients with a marked, long-lasting reduction in bladder capacity. In conclusion, acute side effects of radiotherapy on urinary bladder function can easily be monitored on a routine bases by identification of pre- and postmicturition body weight. Further studies with this technique will be initiated to identity factors influencing the intensity of the acute response. These may include additional treatments, e. g. trans-urethral resection(s) of the prostate or additional surgery, but also radiotherapy related factors, like the mean bladder dose. Moreover, further follow-up will allow to assess late treatment effects in the patients included in this study, and to identity a possible correlation between the manifestation of the late reaction and the pattern of the acute response. References DSrr, W., Beck-Bornholdt, H.-P. Radiation-induced impairment of urinary bladder function in mice: fine structure of the acute response and consequences on late effects Radiat. Res., 151, 1999, 461-467 DSrr, W., Eckhardt, M., Ehme, A., Koi, S. Pathogenesis of acute radiation effects in the urinary bladder. Experimental results Strahlenther. Oncol. 174, Suppl. III, 1998, 93-95 Eckhardt, M., D6rr, W. Ver&nderungen der extrazellul&ren Matrix des Urothels w~.hrend der akuten Strahlenreaktion der Harn-blase tier Maus Exp. Strahlenther. Kiln. Strahlenbiol. 7, 1998, 84-87 (ISSN 1432-864-X) Eckhardt, M., Kasper, M., D6rr, W. Die Bedeutung der urothelialen Barrierefunktion fQr die Entwicklung von Strahlensch&den an der Harnblase Exp. Strahlenther. Kiln. Strahlenbiol. 6, 1997, 17-20 (ISSN 1432-864X) Hanfmann, B., Engels, B., DSrr, W. Radiation-induced impairment of urinary bladder fucntion. Assessment of micturition volumes Strahlenther. Oncol. 174, Suppl. III, 1998, 96-98 Kraft, M., Oussouren, Y., Stewart, F. A., D6rr, W., Schultz-Hector, S. Radiation-induced changes in TGFB and collagen expression in murine bladder wall and its correlation with bladder function Radiat. Res. 146, 1996, 619-627 Perez, C. A., Lee, H. K., Georgiou, A., Lockett, M. A. Technical factors affecting morbidity in definitive irradiation for localized carcinoma of the prostate Int. J. Radiat. Oncol. Biol. Phys. 28, 1994, 811-819 Schultheiss, T. E., Lee, W. R., Hunt, M. A., Hanlon, A. L., Peter, R. S., Hanks, G. E. Late GI and GU complications in the treatment of prostate cancer. Int. J. Radiat. Oncol. Biol. Phys. 37, 1997, 3-11
Sunday, l0 December 2000
SI3
14
The ICD-IO as a useful diagnosis code for recorded acute radiation morbidity p__Sch(Jller1, F. Bruns 2, O. Micke 1, U. Haverkamp2 1Dpt. of Radiooncology, University of, MDnster, Germany 2Dpt. of Radiology, Clemenshospital, MOnster, Germany Purpose: The obligatory documentation of radiation induced toxicities is usually done in uncoded text format, even if the patient chart is kept electronically. Data exchange between radiation oncology departments is often limited to multicentre studies; because a standardized code is missing, direct electronic data transmission is difficult even between study centres. The question arises how the assessment of acute treatment related toxicities can be utilized in national and international evaluations against the background that up to now side effects have been systematically assessed only within the scope of multicentre studies. For treatment related toxicities, various forms of encoding, differing in the intended amount of documentation, are imaginable; some are presented below. Methods: The most widely known internationally evaluated diagnosis code is the ICD-10 (Tenth Revision of the International Classification of Diseases), which was published in the current form in 1993 by the WHO and comprises the formerly independent ICD-O (International Classification of Diseases for Oncology). The purpose of the ICD-10 is to make relevant morbidity and mortality data available to electronic processing in an encoded form. The ICD-1O assigns a three-digit main code. In the case of radiation induced toxicities the code is extended by a fourth digit in the form of a sub-category (e.g. acute radiation pneumonitis = J7O.O). On the basis of this classification, a proposal is made to extend the existing diagnosis code by a fifth digit encoding the severity of acute toxicity by 1, 2, 3, 4, or X (if not evaluable). In the case of a moderate (grade 1) acute radiation pneumonitis this results in the code J70.01. For the definition of the toxicity grading, the internationally established classification of the RTOG toxicity criteria is used. An evaluation is being done in the context of a study on the treatment of head and neck tumours. Discussion: The ICD-10 has been available for years as an internationally renowned encoding instrument which allows the systematic assessment, analysis, and comparison of morbidity (and mortality) data collected in different countries over various periods of time.In the German health system, the ICD-10 has already been introduced as obligatory in some fields (i.e. in the assessment of mortality data). The ICD-10 offers two possibilities of supplementary encoding. The letter ,,U" has been left free for the encoding of additional diseases. A different code can be integrated using the ,,dagger and asterisk" system. However, as all radiation induced morbidities can in principle be encoded using the existing ICD-10 code, only a slight modification is proposed which includes a score for the severity of side effects (e.g. the EORTC/RTOG classification) by adding a fifth digit. At least the acute radiation morbidity recorded for treatment evaluation should be documented in every department as an electronic data base supplementing the ICD-10. The addition of the toxicity data to the ICD-10 code, which can be done automatically in the electronic network, is not only useful for internal quality control inside the department but also enables interested superior institutions to carry out therapy optimization studies and meta-analyses with limited human resources. The ICD-10 as an established diagnosis code can cover a large part of the encoding, so that the requirements for the establishment of a multi-institutional network for the exchange of toxicity related data can be easily met by the proposed slight modification of the ICD-10 by the severity of acute toxicity. A prospective computer based encoding can be done just as easily as a retrospective manual encoding. The relevant radiation induced acute toxicities (EORTC/RTOG) assessed during treatment should be submittable to a superior institution (e.g. a study centre) in adequate form (i.e. electronically). Conclusion: An extension of the ICD-10 for the encoding of acute radiation morbidity is proposed which is directly derived from the RTOG Toxicity Criteria. This diagnosis code permits simplified electronic data transmission, e.g. in the context of multi-centre studies. With knowledge of the RTOG Toxicity Criteria, the use of the proposed diagnosis code is simple and easily verifiable. References: ICD-10: International Statistical Classification of Diseases and Related Health Problems, 10th Revision. World Health Organization, Geneva, 1992. - Seegenschmiedt MH Nebenwirkungen in der Onkologie - Internationale Systematik und Dokumentation. Kap.8: RTOG- und RTOG/EORTC Toxicity Criteria. Springer, Berlin Heidelberg New York: 51 - 65, 1998. -
15
Documentation of acute radiation effects in the urinary bladder during treatment for prostate cancer W. Doerr T. Herrmann Technica/ University Dresden, Medica/ Facu/ty Car/Gustav Carus, Dept. of Radiotherapy and Radiation Onco/ogy, Dresden, Germany Impairment of urinary bladder function is a frequent side effect of radiotherapy of tumours in the pelvis, i. e. malignancies of prostate, uterus/cervix uteri, rectum or bladder. The radiation response occurs in three distinct phases: The acute reaction develops during the treatment and usually lasts for some weeks post irradiation. The acute phase is followed by a dose-dependent latent time which, e.g. after treatment for prostate cancer, can last up to 10 years or longer (Perez et al. 1994). Hence, the radiation sensitivity of the urinary bladder, based on a follow-up of 5 years, is usually underestimated. Late sequelae, in contrast to the acute effects, are progressive and irreversible. Their incidence, after sufficient follow-up times, exceeds that of late radiation effects in the intestine. Clinical symptoms in the acute as well as in the late response phase comprise an increase in micturition frequency, including nocturia, dysuria and pollakiuria. These are caused by a reduction in bladder storage capacity. The detailed pathogenesis of this functional impairment still remains unclear. Recent experimental studies revealed that changes in prostaglandin levels are involved in the acute response (D6rr et al. 1998). Moreover, an impairment of the urothelial barrier and alterations of urothelial cell function have been demonstrated (Eckhardt/D6rr 1998, Eckhardt et al. 1997), while no acute urothelial denudation could be shown. In contrast, late functional sequelae correlated with morphological changes, such as denuded and hyperproliferative areas, in the urothelium (Kraft et al. 1996). Detailed analyses of clinical (Schultheiss et al. 1997) and experimental data (DSrr/Beck-Bornholdt 1999, D6rr et al. this issue) revealed a strong consequential component of the late radiation sequelae in the bladder: The intensity and/or duration of the acute reaction significantly influence the risk for manifestation of late functional effects. Detailed, objective monitoring and documentation of acute functional changes in the bladder are a prerequisite for clinical studies of side effects of radiotherapy in the pelvic region, which may, to some extent, allow for prediction of late sequelae. Objective endpoints, which may be used for routine a s s e s s ment of acute bladder reactions, should allow for easy and frequent data acquisition, and the methods applied should be non-invasive. Direct measurements of bladder capacity, e.g. by ultrasound, are time consuming and are not applicable as routine assays. Alternatively, micturition frequency or micturition volume may be assessed. Micturition frequency, however, is subject to major variations, and frequently is not properly and with sufficient precision reported by the patients. In contrast, direct measurements of micturition volumes can read@ performed, but require preparation and disposal or cleaning of the vessels provided for the patients. As an alternative, indirect method, determination of the body weight of the patients before and after micturition has been proposed (Hanfmann et al. 1998). The present study in prostate cancer patients was initiated to compare direct measurement of micturition volumes with the weighing method, and to check for the feasibility of the latter for routine documentation of bladder function during radiotherapy. Between November 1998 and August 2000, 24 patients have been included in this study. Radiotherapy consisted of a tumour dose of 5xl .8 Gy/week. The
SI4
Sunday, l0 December 2000
Discussion of Proffered Papers
patients were asked to present for irradiation with a maximally filled bladder. Before irradiation, patients performed weighing immediately before and after micturition. The body weight was recorded by the patients themselves on an individual form sheet provided by the hospital. The sensitivity of the scale was 10 g. The difference between post- and pre-micturition body weight is assumed to mirror the micturition volume. In addition, patients were asked to report their micturition frequencies, separately for days and nights, on the same form sheet. Two patients were excluded from the analysis, one because of cessation of radiotherapy in week 2, and one because of incompliance. In a pilot phase in the first 9 patients, direct measurements of micturition volumes were compared with the weight differences assessed. Regression analysis revealed a good correlation between weight differences and micturition volumes (p=0.001), with an overall correlation coefficient of 0.72. The correlation coefficients in the individual patients ranged from 0.40 to 0.90, with a significant correlation (p=0.001) in all patients. It has to be noted that major deviations from a one-to-one relationship in most of the cases were based on a reduced volume compared to the weight difference, indicating loss of urine during collection. Hence, the weighing method must be considered the more precise technique. Individual baseline data for the individual patients were calculated from the data documented during the first 6 days after onset of radiotherapy, and hence comprised the initial 5 measurements. Mean baseline values (ASD) were a weight difference of 150A83 g (range 23-398 g), a day-time micturition frequency of 7.2A3.0 (range 3.2-15.0) and a night-time micturition frequency of 2.3A1.1 (range 0-4.8). Based on these individual control values, relative changes in the parameters during radiotherapy were calculated. The measurements display a substantial day-to-day variation of the weight differences assessed. This may be due to variations in the grade of bladder filling with which the patients present. Therefore, for each patient, the weekly average value of the micturition volume has been calculated in order to illustrate the time course of the acute bladder response. The average micturition volume for all patients, as reflected by the weight difference, remained almost unchanged during the first 3 treatment weeks, and then gradually decreased to 87% (p=0.005), 85% (p=0.023), 80% (p=0.001), and 79% (p=0.0002) in weeks 4, 5, 6 and 7, respectively. Micturition frequencies increased to a maximum of 120%-125% in week 6-8 for day-time, and to 140%-150% in weeks 48 for the night frequency. However, a detailed analysis revealed no significant correlation between these micturition frequencies, reported by the patients, and weight differences or micturition volumes. This indicates that frequency assessment in patients is not sufficiently sensitive, or at least not reliable enough, to objectively quantitate the acute radiation response of the urinary bladder. The reduction in micturition volumes might be a result from an increase in residual, post-micturition urine volume. In order to test for this, one patient has been subjected to weekly ultrasound measurements of pre- and post-micturition bladder volume. This patient developed a significant acute reduction in micturition volumes as defined by the weight difference technique. No systematical fluctuations in the residual volume were found, and the micturition-associated volume changes assessed by ultrasound were in good accordance with the weight difference. Hence, the changes observed can be attributed to a reduction in bladder storage capacity. However, ultrasound examination in further patients is required. As mentioned above, the intensity and/or duration of the acute bladder response may be predictive for the risk to develop late sequelae because of the strong consequential component. As a measure for the combination of intensity and duration, the mean micturition volume over the entire treatment time in relation to the baseline value can be used. In combination with the minimum values for bladder capacity measured, 4 patterns of radiation response can readily be identified: (i) patients with only a minor reaction, (ii) patients with a minor to intermediate, but long-lasting functional impairment, (iii) patients with a substantial, but short response, and (iv) patients with a marked, long-lasting reduction in bladder capacity. In conclusion, acute side effects of radiotherapy on urinary bladder function can easily be monitored on a routine bases by identification of pre- and postmicturition body weight. Further studies with this technique will be initiated to identity factors influencing the intensity of the acute response. These may include additional treatments, e. g. trans-urethral resection(s) of the prostate or additional surgery, but also radiotherapy related factors, like the mean bladder dose. Moreover, further follow-up will allow to assess late treatment effects in the patients included in this study, and to identity a possible correlation between the manifestation of the late reaction and the pattern of the acute response. References DSrr, W., Beck-Bornholdt, H.-P. Radiation-induced impairment of urinary bladder function in mice: fine structure of the acute response and consequences on late effects Radiat. Res., 151, 1999, 461-467 DSrr, W., Eckhardt, M., Ehme, A., Koi, S. Pathogenesis of acute radiation effects in the urinary bladder. Experimental results Strahlenther. Oncol. 174, Suppl. III, 1998, 93-95 Eckhardt, M., D6rr, W. Ver&nderungen der extrazellul&ren Matrix des Urothels w~.hrend der akuten Strahlenreaktion der Harn-blase tier Maus Exp. Strahlenther. Kiln. Strahlenbiol. 7, 1998, 84-87 (ISSN 1432-864-X) Eckhardt, M., Kasper, M., D6rr, W. Die Bedeutung der urothelialen Barrierefunktion fQr die Entwicklung von Strahlensch&den an der Harnblase Exp. Strahlenther. Kiln. Strahlenbiol. 6, 1997, 17-20 (ISSN 1432-864X) Hanfmann, B., Engels, B., DSrr, W. Radiation-induced impairment of urinary bladder fucntion. Assessment of micturition volumes Strahlenther. Oncol. 174, Suppl. III, 1998, 96-98 Kraft, M., Oussouren, Y., Stewart, F. A., D6rr, W., Schultz-Hector, S. Radiation-induced changes in TGFB and collagen expression in murine bladder wall and its correlation with bladder function Radiat. Res. 146, 1996, 619-627 Perez, C. A., Lee, H. K., Georgiou, A., Lockett, M. A. Technical factors affecting morbidity in definitive irradiation for localized carcinoma of the prostate Int. J. Radiat. Oncol. Biol. Phys. 28, 1994, 811-819 Schultheiss, T. E., Lee, W. R., Hunt, M. A., Hanlon, A. L., Peter, R. S., Hanks, G. E. Late GI and GU complications in the treatment of prostate cancer. Int. J. Radiat. Oncol. Biol. Phys. 37, 1997, 3-11