Normal tissue complication probabilities: dependence on choice of biological model and dose-volume histogram reduction scheme

PURPOSE: To evaluate the impact of dose-volume histogram (DVH) reduction schemes and models of normal tissue complication probability (NTCP) on ranking of radiation treatment plans. METHODS AND MATERIALS: Data for liver complications in humans and for spinal cord in rats were used to derive input parameters of four different NTCP models. DVH reduction was performed using two schemes: "effective volume" and "preferred Lyman". DVHs for competing treatment plans were derived from a sample DVH by varying dose uniformity in a high dose region so that the obtained cumulative DVHs intersected. Treatment plans were ranked according to the calculated NTCP values. RESULTS: Whenever the preferred Lyman scheme was used to reduce the DVH, competing plans were indistinguishable as long as the mean dose was constant. The effective volume DVH reduction scheme did allow us to distinguish between these competing treatment plans. However, plan ranking depended on the radiobiological model used and its input parameters. CONCLUSIONS: Dose escalation will be a significant part of radiation treatment planning using new technologies, such as 3-D conformal radiotherapy and tomotherapy. Such dose escalation will depend on how the dose distributions in organs at risk are interpreted in terms of expected complication probabilities. The present study indicates considerable variability in predicted NTCP values because of the methods used for DVH reduction and radiobiological models and their input parameters. Animal studies and collection of standardized clinical data are needed to ascertain the effects of non-uniform dose distributions and to test the validity of the models currently in use.     

Prediction of radiation pneumonitis by dose - volume histogram parameters in lung cancer--a systematic review.

BACKGROUND AND PURPOSE: To perform a systematic review of the predictive ability of various dose-volume histogram (DVH) parameters (V(dose), mean lung dose (MLD), and normal tissue complication probability (NTCP)) in the incidence of radiation pneumonitis (RP) caused by external-beam radiation therapy. METHODS AND MATERIALS: Studies assessing the relationship between CT-based DVH reduction parameters and RP rate in radically treated lung cancer were eligible for the review. Synonyms for RP, lung cancer, DVH and its associated parameters (NTCP, V(20), V(30), MLD) were combined in a search strategy involving electronic databases, secondary reference searching, and consultation with experts. Individual or group data were abstracted from the various reports to calculate operating characteristics and odds ratios for the different DVH metrics. RESULTS: A total of 12 published studies and two abstracts were identified. Eleven studies assessed V(dose), seven assessed MLD, and eight assessed NTCP. Nine studies exclusively analyzed the association between various DVH metrics and RP risk. Five studies also analyzed other patient, tumor, and treatment variables in conjunction with standard DVH metrics. A direct comparison between studies and the generation of summary statistics (i.e. meta-analysis) could not be achieved due to significant predictive and outcome variable heterogeneity. Most studies did show an association between DVH parameters and RP risk. However, overall accuracy, sensitivity, specificity, and positive predictive value were generally poor to fair for all three classes of DVH metrics. CONCLUSIONS: An association between DVH parameters and RP risk has been demonstrated in the literature. However, the ideal DVH metric with excellent operating characteristics, either alone or in a model with other predictive variables, for RP risk prediction has not yet been identified. Several recommendations for reporting and conduct of future research into the association between DVH metrics and RP risk are provided.     

Dose-volume histograms

A plot of a cumulative dose-volume frequency distribution, commonly known as a dose-volume histogram (DVH), graphically summarizes the simulated radiation distribution within a volume of interest of a patient which would result from a proposed radiation treatment plan. DVHs show promise as tools for comparing rival treatment plans for a specific patient by clearly presenting the uniformity of dose in the target volume and any hot spots in adjacent normal organs or tissues. However, because of the loss of positional information in the volume(s) under consideration, it should not be the sole criterion for plan evaluation. DVHs can also be used as input data to estimate tumor control probability (TCP) and normal tissue complication probability (NTCP). The sensitivity of TCP and NTCP calculations to small changes in the DVH shape points to the need for an accurate method for computing DVHs. We present a discussion of the methodology for generating and plotting the DVHs, some caveats, limitations on their use and the general experience of four hospitals using DVHs.     

Treatment margins and treatment fractionation in conformal radiotherapy of muscle-invading urinary bladder cancer.

BACKGROUND AND PURPOSE: Different treatment margins and fractionation schedules are used in conformal radiotherapy (CRT) of urinary bladder cancer. This study compared intestine and rectum dose-volume histogram (DVH) data and normal tissue complication probability (NTCP) estimates for various clinically applied margins and fractionation schedules in bladder irradiation. PATIENTS AND METHODS: Normal tissue dose distributions in fifteen bladder cancer patients treated with CRT were studied using standard three- and four-field configurations. The impact of margin width on intestine and rectum dose distributions was initially evaluated using DVH data. NTCP modelling with the probit model was used to compare the impact of choice of margin size and fractionation schedule. The analysis included margin combinations of 1.0 cm isotropic (narrow margins) and 1.2-2.0 cm non-isotropic (wide margins) and fractionation schedule alternatives of 52.5Gy/20, 55Gy/20, 57.5Gy/20 and 64Gy/32. RESULTS: Using wide as compared to narrow margins, the volumes of intestine and rectum receiving high doses increased by factors of approximately two and four, respectively. Similar differences between wide and narrow margins were found when calculating intestine and rectum NTCPs. The impact of margin size depended strongly on the volume effect expressed by the NTCP model parameters. With standard parameters, however, the choice of margins and fractionation schedule had a similar impact on intestine NTCPs, while for the rectum, the choice of margin had a greater impact than the choice of fractionation. For a given margin size, the intestine and rectum NTCPs for the 55Gy/20 and the 64Gy/32 schedules were comparable. For clinics using narrow margins and a fractionation of 52.5Gy/20, the NTCP modelling suggested that a change in fractionation schedule (to 55Gy/20 or 64Gy/32) or a change to wide margins would have a similar effect on the intestine NTCP predictions. CONCLUSIONS: This modelling study documented that the choice of margins was as important as the choice of fractionation in terms of intestine and rectum DVH data and NTCP predictions.     

Calculation of the uncertainty in complication probability for various dose-response models, applied to the parotid gland

PURPOSE: Usually, models that predict normal tissue complication probability (NTCP) are fitted to clinical data with the maximum likelihood (ML) method. This method inevitably causes a loss of information contained in the data. In this study, an alternative method is investigated that calculates the parameter probability distribution (PD), and, thus, conserves all information. The PD method also allows the calculation of the uncertainty in the NTCP, which is an (often-neglected) prerequisite for the intercomparison of both treatment plans and NTCP models. The PD and ML methods are applied to parotid gland data, and the results are compared. METHODS AND MATERIALS: The drop in salivary flow due to radiotherapy was measured in 25 parotid glands of 15 patients. Together with the parotid gland dose-volume histograms (DVH), this enabled the calculation of the parameter PDs for three different NTCP models (Lyman, relative seriality, and critical volume). From these PDs, the NTCP and its uncertainty could be calculated for arbitrary parotid gland DVHs. ML parameters and resulting NTCP values were calculated also. RESULTS: All models fitted equally well. The parameter PDs turned out to have nonnormal shapes and long tails. The NTCP predictions of the ML and PD method usually differed considerably, depending on the NTCP model and the nature of irradiation. NTCP curves and ML parameters suggested a highly parallel organization of the parotid gland. CONCLUSIONS: Considering the substantial differences between the NTCP predictions of the ML and PD method, the use of the PD method is preferred, because this is the only method that takes all information contained in the clinical data into account. Furthermore, PD method gives a true measure of the uncertainty in the NTCP.     

Practical considerations in using calculated healthy-tissue complication probabilities for treatment-plan optimization

PURPOSE: Healthy and neoplastic tissues are generally exposed nonuniformly to ionizing radiation. It is thus useful to develop algorithms that predict the probability of tumor control or normal tissue complication probability (NTCP) for any given spatial pattern of dose delivery. The questions addressed here concern: (a) the sensitivity of the NTCP predictions to the actual model used for extrapolation from uniform irradiation (where some clinical data exist) to nonuniform exposures, (b) its dependence on tissue type, and (c) consequences for treatment-plan optimization. METHODS AND MATERIALS: Two (of several possible) NTCP formulations are used here: the Lyman model and a binomial equation. The effective volume-reduction scheme of Kutcher and Burman is used to obtain the NTCP for an arbitrary distribution of dose. NTCP was calculated for seven organs by postulating a dose distribution of maximum nonuniformity. RESULTS: Both models fit available NTCP data well, but have very different extrapolations for exposures of small tissue volumes and very low values of NTCP (e.g., < 5%) where no data exist. Organs with pronounced volume effects (lung, kidneys) show substantial NTCP differences between the two models. Even in organs where the volume effect is small (e.g., spinal cord, brain), differences in NTCP due to the model selected may still have serious clinical consequences, as an actual example (for the spinal cord) indicates. CONCLUSIONS: NTCP calculations based on extrapolations to volume fractions and/or NTCP levels for which reliable data do not exist depend on the model used to fit the data and the degree of dose nonuniformity. If NTCP is to be used in treatment-plan optimization, the prudent approach is to design plans that reproduce the conditions under which available dose-volume data were taken (e. g., uniform dose distributions).     

非小细胞肺癌同期放化疗后重度急性放射性肺炎的预测模型研究

目的 利用剂量体积直方图(DVH)参数建立Logistic剂量反应及Lyman-Kutcher-Burman正常组织并发症概率(LKB-NTCP)模型,并评估其对非小细胞肺癌同期放化疗后重度急性放射性肺炎(SARP)的预测价值。方法 搜集2006—2010年间行三维适形放疗同期化疗的147例非小细胞肺癌患者资料。按美国RTOG毒性评价标准定义超过3级的ARP为SARP。根据DVH剂量学信息建立Logistic剂量反应模型和LKB-NTCP模型。结果 SARP 发生率为9.5%(14/147)。Logistic剂量反应模型参数:常数b₀=－6.66、b₁=0.252,TD₅₀=26.43 Gy,γ₅₀=1.67;模型曲线在17 Gy以下相对平坦,17~18 Gy处变为陡峭,SARP风险增大。LKB-NTCP模型参数:体积效应因子n=0.87±0.40,曲线斜率倒数m=0.27±0.10,TD₅₀₍₁₎=(29.5±8.0) Gy;Logistic回归及ROC分析均发现此参数下计算出NTCP值对SARP有良好预测价值(P=0.013、0.019)。结论 NTCP值对SARP的预测价值优于简单剂量参数,2个模型曲线均提示最大限制剂量在约17 Gy。     

基于EUD鼻咽癌调强放疗中NTCP和TCP的计算程序设计研究

目的 设计一个基于等效均一剂量（EUD）的计算程序来计算鼻咽癌调强放疗（IMRT）计划中正常组织并发症概率（NTCP）和肿瘤控制概率（TCP）。方法 采用具有较强数学特性及友好交互界面等优势的高效编程语言Matlab编写计算NTCP和TCP程序,其中NTCP 数学模型选用基于EUD的Lyman Kutcher Burman模型,而TCP模型则选用Schultheiss逻辑模型 。收集3例接受IMRT治疗的鼻咽癌患者的正常组织和靶区剂量体积直方图（DVH）,计划系统为医科达precise plan。结果编写计算机代码保存为Matlab可执行程序。3例鼻咽癌患者的4种正常组织（脑干、脊髓、左右侧腮腺）和肿瘤的EUD被编写程序算出,进而计算出NTCP和TCP。结论 编写的程序对正常组织耐受量的计算结果与理论值非常吻合,有助于临床选择更安全和高效的治疗方案,将来还可将程序用于其他肿瘤如前列腺癌和肺癌的放疗计划中。     

Partially wedged beams improve radiotherapy treatment of urinary bladder cancer.

BACKGROUND AND PURPOSE: Partially wedged beams (PWBs) having wedge in one part of the field only, can be shaped using dynamic jaw intensity modulation. The possible clinical benefit of PWBs was tested in treatment plans for muscle-infiltrating bladder cancer. MATERIAL AND METHODS: Three-dimensional treatment plans for 25 bladder cancer patients were analyzed. The originally prescribed standard conformal four-field box technique, which includes the use of lateral ordinary wedge beams, was compared to a modified conformal treatment using customized lateral PWBs. In these modified treatment plans, only the anterior parts of the two lateral beams had a wedge. To analyze the potential clinical benefit of treatment with PWBs, treatment plans were scored and compared using both physical parameters and biological dose response models. One tumour control probability model and two normal tissue complication probability (NTCP) models were applied. Different parameters for normal tissue radiation tolerance presented in the literature were used. RESULTS: By PWBs the dose homogeneity throughout the target volume was improved for all patients, reducing the average relative standard deviation of the target dose distribution from 2.3 to 1.8%. A consistent reduction in the maximum doses to surrounding normal tissue volumes was also found. The most notable improvement was demonstrated in the rectum where the volume receiving more than the prescribed tumour dose was halved. Treatment with PWBs would permit a target dose escalation of 2-6 Gy in several of the patients analyzed, without increasing the overall risk for complications. The number of patients suitable for dose escalation ranged from 3 to 15, depending on whether support from all or only one of the five applied NTCP model/parameter combinations were required in each case to recommend dose escalation. CONCLUSION: PWBs represent a simple dose conformation tool that may allow radiation dose escalation in the treatment of muscle-infiltrating urinary bladder tumours.     

Importance of accurate dose calculations outside segment edges in intensity modulated radiotherapy treatment planning.

BACKGROUND AND PURPOSE: To assess the effect of differences in the calculation of the dose outside segment edges on the overall dose distribution and the optimisation process of intensity modulated radiation therapy (IMRT) treatment plans. PATIENTS AND METHODS: Accuracy of dose calculations of two treatment planning systems (TPS1 and TPS2) was assessed, to ensure that they are both suitable for IMRT treatment planning according to published guidelines. Successively, 10 treatment plans for patients with prostate and head and neck tumours were calculated in both systems. The calculations were compared in selected points as well as in combination with volumetric parameters concerning the planning target volume (PTV) and organs at risk. RESULTS: For both planning systems, the calculations agree within 2.0% or 3 mm with the measurements in the high-dose region for single and multiple segment dose distributions. The accuracy of the dose calculation is within the tolerances proposed by recent recommendations. Below 35% of the prescribed dose, TPS1 overestimates and TPS2 underestimates the measured dose values, TPS2 being closer to the experimental data. The differences between TPS1 and TPS2 in the calculation of the dose outside segments explain the differences (up to 50% of the local value) found in point dose comparisons. For the prostate plans, the discrepancies between the TPS do not translate into differences in PTV coverage, normal tissue complication probability (NTCP) values and results of the plan optimisation process. The dose-volume histograms (DVH) of the rectal wall differ below 60 Gy, thus affecting the plan optimisation if a cost function would operate in this dose region. For the head and neck cases, the two systems give different evaluations of the DVH points for the PTV (up to 22% differences in target coverage) and the parotid mean dose (1.0-3.0 Gy). Also the results of the optimisation are influenced by the choice of the dose calculation algorithm. CONCLUSIONS: In IMRT, the accuracy of the dose calculation outside segment edges is important for the determination of the dose to both organs at risks and target volumes and for a correct outcome of the optimisation process. This aspect should therefore be of major concern in the commissioning of a TPS intended for use in IMRT. Fulfilment of the accuracy criteria valid for conformal radiotherapy is not sufficient. Three-dimensional evaluation of the dose distribution is needed in order to assess the impact of dose calculation accuracy outside the segment edges on the total dose delivered to patients treated with IMRT.     

Clinical impact of the detector size effect in 3D-CRT.

OBJECTIVE: The detector size artificially increases the measured penumbra of radiotherapy fields. The aim of this work is to determine the influence of the detector size when planning three-dimensional conformal radiation therapy (3D-CRT) treatments. MATERIAL AND METHODS: Two anatomical sites of interest in 3D-CRT were studied: prostate and hypophysis chordoma. Conventional 3D-CRT treatments for two cases in these locations were planned with a FOCUS 4.0.0 (Computerized Medical Systems, USA) treatment planning system (TPS) equipped with Fast Fourier Transform Convolution (FFTC) and Multigrid Superposition (MGS) algorithms, making use of beams modelled from radiation profiles measured either with a 2.0 mm diameter detector (PFD(3G) diode) or with a 5.5 mm diameter detector (PTW-31002 ionisation chamber). These detectors cover up the range of detector sizes commonly used to measure radiation profiles for 3D-CRT. Dose-volume histograms (DVHs), radiobiological indexes, tumor control probability (TCP) and normal tissue complication probability (NTCP) were analysed and compared for planning target volumes (PTVs) and organs at risk (OAR) studied. RESULTS: Important differences in DVH were found. OAR received higher dose levels when a 5.5 mm detector was used to measure profiles compared to the case in which a 2.0 mm detector was used. A 2 Gy increment in the mean rectal dose was found when the larger detector was used. In the same way, NTCP of brain stem in hypophysis chordoma treatments was doubled when this detector was used. CONCLUSION: The current use of ionisation chambers of about 5 mm active diameter to get the necessary data to model treatment machines in radiotherapy treatment planning systems (TPS) implies a significant overirradiation of OAR close to the PTV in 3D-CRT treatments due to errors in the measured penumbra of beam profiles. To avoid this overirradiation, the measured profiles should either being acquired with a suitable detector size (2-3 mm active diameter) or being deconvoluted.     

Modeling normal tissue complication probability from repetitive computed tomography scans during fractionated high-dose-rate brachytherapy and external beam radiotherapy of the uterine cervix

PURPOSE: To calculate the normal tissue complication probability (NTCP) of late radiation effects on the rectum and bladder from repetitive CT scans during fractionated high-dose-rate brachytherapy (HDRB) and external beam radiotherapy (EBRT) of the uterine cervix and compare the NTCP with the clinical frequency of late effects. METHODS AND MATERIALS: Fourteen patients with cancer of the uterine cervix (Stage IIb-IVa) underwent 3-6 (mean, 4.9) CT scans in treatment position during their course of HDRB using a ring applicator with an Iridium stepping source. The rectal and bladder walls were delineated on the treatment-planning system, such that a constant wall volume independent of organ filling was achieved. Dose-volume histograms (DVH) of the rectal and bladder walls were acquired. A method of summing multiple DVHs accounting for variable dose per fraction were applied to the DVHs of HDRB and EBRT together with the Lyman-Kutcher NTCP model fitted to clinical dose-volume tolerance data from recent studies. RESULTS: The D(mean) of the DVH from EBRT was close to the D(max) for both the rectum and bladder, confirming that the DVH from EBRT corresponded with homogeneous whole-organ irradiation. The NTCP of the rectum was 19.7% (13.5%, 25. 9%) (mean and 95% confidence interval), whereas the clinical frequency of late rectal sequelae (Grade 3-4, RTOG/EORTC) was 13% based on material from 200 patients. For the bladder the NTCP was 61. 9% (46.8%, 76.9%) as compared to the clinical frequency of Grade 3-4 late effects of 14%. If only 1 CT scan from HDRB was assumed available, the relative uncertainty (standard deviation or SD) of the NTCP value for an arbitrary patient was 20-30%, whereas 4 CT scans provided an uncertainty of 12-13%. CONCLUSION: The NTCP for the rectum was almost consistent with the clinical frequency of late effects, whereas the NTCP for bladder was too high. To obtain reliable (SD of 12-13%) NTCP values, 3-4 CT scans are needed during 5-7 fractions of HDRB treatments.     

放射生物模型在乳腺癌放疗计划评价中的比较

目的 比较分析不同放射生物模型的特性,以寻求评价乳腺癌放疗计划合理的放射生物模型.方法 比较预测放射性肺炎发生率和放射性心脏病死亡率的NTCP两种模型和TCP四种模型,计算相同DVH数据所得结果的差异;并分析同一模型中,输入DVH数据的形式、参数的选择等对结果的影响.结果 假设全肺平均照射30 Gy剂量时,NTCP-RSM模型预测的放射性肺炎发生率为32%,NTCP-Lyman模型预测的为54%.以发生放射性心脏病死亡率1%为例,NTCP-RSM模型对应的心脏平均照射剂量为28 Gy,而NTCP-Lyman模型对应的为40 Cy.应用LQ-Poisson-TCP模型、Poisson-TCP模型、Logit-TCP模型和Zaider-TCP模型,计算相同DVH数据库的平均TCP分别为21.1%、38.4%、41.0%和80.8%(P=0.000).采用不同栅格大小计算的NTCP/TCP结果差别较小.计算时采用物理剂量或LQED2剂量对NTCP/TCP结果有一定影响,采用物理剂量时的结果稍大.ft.和p值、肿瘤细胞密度、D50值和DVH简化方法对TCP的影响显著(P=0.000).结论 评价和优化乳腺癌放疗计划选择放射生物模型时,以NTCP-Lyman模型计算放射性肺炎和以NTCP-RSM模型计算放射性心脏病死亡率比较合理.TCP模型以LQ-Poisson-TCP模型比较符合临床实际.影响预测结果最大的是模型参数值的选取,选择时需要加以注意.这些模型目前有助于对不同治疗模式进行研究和比较,而不是给出对临床实际结果的精确预测.     

A method of computerized evaluation of CT based treatment plants in external radiotherapy

Selection of an optimal treatment plan requires the comparison of dose distributions and dose-volume histograms (DVH) of all plan variants calculated for the patient. Each treatment plan consists generally of 30 to 40 CT slices, making the comparison difficult and time consuming. The present study proposes an objective index that takes into account both physical and biological criteria for the evaluation of the dose distribution. The DHV-based evaluation index can be calculated according to the following four criteria: ICRU conformity (review of the differences between the dose in the planning target volume and the ICRU recommendations); mean dose and dose homogeneity of the planning target volume; the product of tumour complication probability (TCP) and normal tissue complication probability (NTCP); and finally a criterion that takes into account the dose load of non-segmented tissue portions within the CT slice. The application of the objective index is demonstrated for two different clinical cases (esophagus and breast carcinoma). During the evaluation period, the objective index showed a good correlation between the doctor's decision and the proposed objective index. Thus, the objective index is suitable for a computer-based evaluation of treatment plans.     

Fraction Size and Dose Parameters Related to the Incidence of Pericardial Effusions

Purpose: The influence of treatment parameters, such as (a) fraction size and (b) average and maximum dose (as derived from three-dimensional (3D) distributions), on the incidence of pericarditis was analyzed. To understand and predict the dose and volume effect on the pericardium, a normal tissue-complication probability model was tested with these complication data.Methods and Materials: Patients (n = 57) entered in 3 consecutive University of Michigan protocols of combined modality for treatment of localized esophageal carcinoma, and having 3D treatment planning for radiation therapy were the subject of this study. Univariate and multivariate analyses were performed to determine the significance of the effect of fraction size and dose parameters on the development of any grade of pericarditis. Dose distributions were corrected for the biological effect of fraction size using the linear-quadratic method. Normal tissue complication probability (NTCP) was calculated with the Lyman model.Results: Nonmalignant pericardial effusions occurred in 5 of the 57 patients; all effusions were in patients who received treatment with 3.5 Gy daily fractions. On multivariate analysis, no dose factor except fraction size predicted pericarditis, until the dose distributions were corrected for the effect of fraction size (“bio”-dose). Then, both “bio-average” and “bio-maximum” dose were significant predictive factors (p = 0.014). NTCPs for the patients with pericarditis range from 62% to 99% for the calculations with the “bio”-dose distributions vs. 0.5% to 27% for the uncorrected distributions.Discussion: A normal tissue complication probability (NTCP) model predicts a trend towards a high incidence of radiation pericarditis for patients who have high complication probabilities. It is important to correct the dose distribution for the effects of fractionation, particularly when the fraction size deviates greatly from standard (2.0 Gy) fractionation.     

Fitting late rectal bleeding data using different NTCP models: results from an Italian multi-centric study (AIROPROS0101).

BACKGROUND AND PURPOSE: Recent investigations demonstrated a significant correlation between rectal dose-volume patterns and late rectal toxicity. The reduction of the DVH to a value expressing the probability of complication would be suitable. To fit different normal tissue complication probability (NTCP) models to clinical outcome on late rectal bleeding after external beam radiotherapy (RT) for prostate cancer. PATIENTS AND METHODS: Rectal dose-volume histograms of the rectum (DVH) and clinical records of 547 prostate cancer patients (pts) pooled from five institutions previously collected and analyzed were considered. All patients were treated in supine position with 3 or 4-field techniques: 123 patients received an ICRU dose between 64 and 70 Gy, 255 patients between 70 and 74 Gy and 169 patients between 74 and 79.2 Gy; 457/547 patients were treated with conformal RT and 203/547 underwent radical prostatectomy before RT. Minimum follow-up was 18 months. Patients were considered as bleeders if showing grade 2/3 late bleeding (slightly modified RTOG/EORTC scoring system) within 18 months after the end of RT. Four NTCP models were considered: (a) the Lyman model with DVH reduced to the equivalent uniform dose (LEUD, coincident with the classical Lyman-Kutcher-Burman, LKB, model), (b) logistic with DVH reduced to EUD (LOGEUD), (c) Poisson coupled to EUD reduction scheme and (d) relative seriality (RS). The parameters for the different models were fit to the patient data using a maximum likelihood analysis. The 68% confidence intervals (CI) of each parameter were also derived. RESULTS: Forty six out of five hundred and forty seven patients experienced grade 2/3 late bleeding: 38/46 developed rectal bleeding within 18 months and were then considered as bleeders The risk of rectal bleeding can be well calculated with a 'smooth' function of EUD (with a seriality parameter n equal to 0.23 (CI 0.05), best fit result). Using LEUD the relationship between EUD and NTCP can be described with a TD50 of 81.9 Gy (CI 1.8 Gy) and a steepness parameter m of 0.19 (CI 0.01); when using LOGEUD, TD50 is 82.2 Gy and k is 7.85. Best fit parameters for RS are s=0.49, gamma=1.69, TD50=83.1 Gy. Qualitative as well as quantitative comparisons (chi-squared statistics, P=0.005) show that the models fit the observed complication rates very well. The results found in the overall population were substantially confirmed in the subgroup of radically treated patients (LEUD: n=0.24 m=0.14 TD50=75.8 Gy). If considering just the grade 3 bleeders (n=9) the best fit is found in correspondence of a n-value around 0.06, suggesting that for severe bleeding the rectum is more serial. CONCLUSIONS: Different NTCP models fit quite accurately the considered clinical data. The results are consistent with a rectum 'less serial' than previously reported investigations when considering grade 2 bleeding while a more serial behaviour was found for severe bleeding. EUD may be considered as a robust and simple parameter correlated with the risk of late rectal bleeding.