Clinical Investigations
Normal tissue complication probabilities correlated with late effects in the rectum after prostate conformal radiotherapy

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Abstract

Purpose: Radiation therapy of deep-sited tumours will always result in normal tissue doses to some extent. The aim of this study was to calculate different risk estimates of late effects in the rectum for a group of cancer prostate patients treated with conformal radiation therapy (CRT) and correlate these estimates with the occurrences of late effects. Since the rectum is a hollow organ, several ways of generating dose-volume distributions over the organ are possible, and we wanted to investigate two of them.

Methods and Materials: A mathematical model, known as the Lyman-Kutcher model, conventionally used to estimate normal tissue complication probabilities (NTCP) associated with radiation therapy, was applied to a material of 52 cancer prostate patients. The patients were treated with a four field box technique, with the rectum as organ at risk. Dose-volume histograms (DVH) were generated for the whole rectum (including the cavity) and of the rectum wall. One to two years after the treatment, the patients completed a questionnaire concerning bowel (rectum) related morbidity quantifying the extent of late effects.

Results: A correlation analysis using Spearman’s rank correlation coefficient, for NTCP values calculated from the DVHs and the patients’ scores, gave correlation coefficients which were not statistically significant at the p < 0.01 level. The correlation coefficients based on histograms of the whole rectum were larger than those derived from histograms of the rectum wall. Also, simpler descriptive measures as Dmax, of the whole rectum, correlated better to observed late toxicity than Dmax derived from histograms of the rectum wall. Correlation coefficients from “high-dose” measures were larger than those calculated from the NTCP values. Accordingly, as the volume parameter of the Lyman-Kutcher model was reduced, raising the impact of small high-dose volumes on the NTCP values, the correlation between observed effects and NTCP values became significant at p < 0.01 level.

Conclusions: 1) High-dose levels corresponding to small volume fractions of the cumulative dose-volume histograms were best correlated with the occurrences of late effects in the rectum as measured with questionnaires. This is compatible with a more serial organisation of the rectal tissue architecture than previously reported. 2) Reducing the Lyman-Kutcher model’s volume parameter, thus allowing small high-dose regions to determine the NTCP, improved the correlation, but not beyond that of high-dose levels corresponding to small volume fractions of the cumulative dose-volume histograms.

Introduction

Carcinoma of the prostate is the most common cancer in men. External beam radiotherapy is an important treatment modality with curative aims (1). Predicting the irradiation-induced late adverse effects by calculating the normal tissue complication probability (NTCP), has been an issue of debate for many years. Reliable NTCP calculations allow choosing among different treatment plans, thereby optimising the treatment for each individual. The Lyman-Kutcher NTCP model 2, 3, 4, 5, 6, 7, 8, 9 has been widely used, mainly because of the studies of Emami et al. (10) and Burman et al. (2) where the model was fitted to tolerance doses for a wide range of organs and biological endpoints. The tolerance doses were estimated by a group of clinicians. In spite of the model’s widespread use, the large uncertainties of the parameters have several times been emphasised, and some effort has been made to improve its accuracy 11, 12. The severe endpoints that form the basis of the tolerance calculation may especially be an issue of debate. For the rectum the whole organ tolerance dose giving 50% of the patients (TD50(1)) severe proctitis/necrosis/fistula/stenosis, is set to 80 Gy (10). Many clinicians will claim that this endpoint is far beyond acceptability when considering the patients’ quality of life. Moreover, one should be aware that less severe endpoints may give rise to entirely different NTCP values, than commonly obtained.

The rectum is the organ at particularly high risk of late adverse effects when treating carcinoma of the prostate with radiotherapy 6, 13, 14. The most frequently used NTCP models incorporate the dose-volume histogram (DVH), the distribution of doses over the volume of an organ. Previously, NTCP calculations have been based on DVHs over the whole rectum including the cavity, neglecting the fact that the rectum is a hollow organ (2). Some authors have suggested to exclude the cavity from the DVH leading to the dose-wall histogram (DWH) (14), and more recently the concept of dose-surface histograms (DSH) has been introduced (6). The DSH represents a distribution of doses on the wall of a hollow organ. An important assumption is that the wall of the organ is thin enough so that the dose gradient over the wall may be neglected.

In this study, DVHs of the whole rectum including cavity, as well as DWHs of the rectum wall alone, were generated. The histograms were generated for a group of patients who had received conformal radiation therapy (CRT) for cancer of the prostate. The aims were:

  • 1.

    To calculate NTCP values with the Lyman-Kutcher model, and to study the model’s ability to predict late radiation side effects in the rectum. We aimed at measuring late side effects with less severe endpoints than those used previously.

  • 2.

    To compare the model’s predictive ability with that of simpler measures based on the dose-volume histograms.

  • 3.

    To identify the part of the dose-volume distribution which best represents the risk.

Section snippets

Radiotherapy of patients

Sixty-six cancer prostate patients were treated with external radiation therapy from August 1994 to December 1995 at the Norwegian Radium Hospital. The mean dose to the planning target volume (PTV) was 66 Gy for 60 patients while 6 patients treated for local recurrence after radical prostatectomy, received 60 Gy. The PTV comprised the prostate and the vesiculae seminalis including a 2.0 cm margin. The patients received 5 daily fractions of 2 Gy per week using a four field box technique with two

Patients’ scores, DVHs and DWHs

The question concerning “gas in the bowel” gave the largest scores (mean 2.2), while diarrhoea and mucous discharge gave the second largest scores (mean 1.6 for both) (Table 1). In total there were only 6 patients answering one or more questions with a score of 4 “Very much”, and 24 patients gave one or more of the questions score 3 “Quite a bit” (data not shown). In Table 2 descriptive data from the patients’ DVHs and DWHs are listed. Except for the rectum volume, there are no statistically

Discussion

In the present study six ad hoc questions were used for evaluation of late intestinal morbidity. The selection of endpoints and wording of the questions were based on clinical experience gained in the early 90ths. In an expanded study, the dimension of intestinal late toxicity built upon the six above questions, has shown acceptable reliability (Chronbach α = 0.73) (16). Regrettably the late side effect of faecal incontinence was not covered as it had not been observed at the time the study was

Conclusions

1. The high-dose levels corresponding to small volume fractions of the dose-volume histograms were best correlated with the occurrences of late effects in the rectum as assessed with questionnaires. This is compatible with a more serial organisation of the rectal tissue architecture than previously reported. 2. Reducing the Lyman-Kutcher model’s volume parameter, allowing small high-dose regions to determine the NTCP, would improve the correlation, but not beyond that of other predictive

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