This study reports in detail bowel quality of life changes after 3DCRT, patient-related and dose-volume-related predisposing factors. In contrast to most other studies [1–3, 11–13, 25], patients were treated with a homogeneous dose and the same radiotherapy technique. Different dose levels usually coincide with changing treatment margins and radiotherapy techniques, implying possibly confounding variables. Patients after a radical prostatectomy, with a different anatomic situation, have not been included. Previous surgery can be predisposing for greater toxicity . The factors irritation, incontinence and bleeding defined separate quality of life subscales. Usually reported RTOG/EORTC toxicity grades do not allow this perspective. Rectal urgency or incontinence is not considered in these studies .
Significant correlations have been found between acute and late quality of life changes, particularly considering the irritative and incontinence domains. As shown by Heemsbergen et al.  recently, consequential late damage (non-healing acute response progressing directly into a late effect) is a significant independent factor in the development of late gastrointestinal toxicity.
Rectal bleeding is usually the mostly feared toxicity and in focus of toxicity studies. It is considered a key dose-limiting end point in prostate radiotherapy . In contrast to most other reports, this study does not evaluate a cumulative incidence of rectal bleeding since the end of treatment. The questionnaire asks about a specific period of four weeks. This study demonstrated that rectal bleeding is a subordinated problem in comparison to other problems from the patients' perspective. Especially in the acute phase (time B and C), irritative symptoms (urgency, frequency, pain) play the major role.
Incontinence was shown to be strongly associated with irritative symptoms. Nearly without exception, a daily incontinence was only reported with a simultaneously present rectal urgency at time D. Anorectal manometry pressures have not been documented in this patient population. Yeoh et al reported significantly reduced anorectal manometry pressures 4 to 6 weeks after radiotherapy for patients with fecal incontinence. However, patients with incontinence were found to have normal basal and squeeze pressures one year after radiotherapy . In a recently published study concerning anorectal function after radiotherapy for prostate cancer, a progressive deterioration of anorectal motor and sensory function has been shown. Rectal compliance progressively decreased and fecal sensitivity to distension increased after treatment .
These results focused on a median period of 16 months after treatment. Chronic effects several years after treatment might have additional effects on quality of life. In contrast to rectal bleeding, the cumulative incidence of fecal incontinence has been shown to increase even after more than five years . The percentage of patients with fecal incontinence has been shown to be higher than the incidence of rectal bleeding requiring laser or transfusion in the Dutch dose-escalation trial in both treatment arms (68 Gy and 78 Gy total doses) , confirming the findings of our study.
Significant predisposing factors for both rectal bleeding subscale score changes and the symptom "rectal bleeding" in multivariate analysis were the PTV, haemorrhoids and stroke in the past history. A volume-effect is already very well known [9, 10, 36]. Patients with a stroke in the past history always take anticoagulative drugs - this is the most probable reason for the considerably increased tendency for bleeding. Other agents (clopidrogel/ticlopidine) or a higher aspirin dose is used in comparison with patients with coronary artery disease of peripheral artery disease. The association of anticoagulants with acute and late rectal bleeding has been shown in other studies before [37, 38].
Haemorrhoids have been reported to be predictive for acute tenesmus and rectal bleeding after 3DCRT before . Our study very well demonstrates the predisposition for irritative symptoms already before 3DCRT, so that quality of life changes did not differ significantly. However, the effect on rectal bleeding became only evident after 3DCRT.
Higher volumes within higher isodose levels were associated with smaller quality of life changes in the irritative and incontinence subscales after 3DCRT. The multivariate analysis demonstrates the independence concerning irritative symptoms. This result may be associated with the specific dose constellation and treatment technique in our patient group. Yeoh et al reported a significantly lower incidence of rectal urgency for patients after 2DCRT vs. 3DCRT in spite of a considerably larger PTV - these patients have likewise been treated with a four-field technique and doses not exceeding 72 Gy.
The reduction of irritative symptoms (urgency, frequency, pain) can be the consequence of a radiation effect on peripheral nerves. In the case of all nervous tissues, a dose of 60 Gy is associated with a less than 5% probability of injury, but this rises steeply with increased radiation dose. The pathogenesis involves progressive vascular degeneration, fibrosis and demyelination with loss of nerve fibres. The latency period ranges from 6 months to several years . Comparably to an earlier development of erectile dysfunction , also usually considered as a chronic effect, differences have already been detected a few weeks after 3DCRT. Higher total doses, exceeding 72 Gy, can be expected to be associated with an increased risk of rectal ulcerations .
The association of larger rectum volumes within specific isodose levels with a paradoxically improved quality of life in the bowel domain was already found in a preliminary analysis of the first eighty patients . This association was also found in an independent group of patients after permanent brachytherapy with I-125 as monotherapy for prostate cancer . Quality of life scores have not been correlated with dose-volume histogram parameters for the rectum in the literature before. However, a validation of this association by other centres is needed.
Chronic renal failure is a rare comorbidity in a population of prostate cancer patients, with only 3% affected in our patient population. It has not been considered as a predisposing factor for toxicity before. This study has shown a dramatically increase risk of toxicity (specifically irritative symptoms), proven to be highly significant only more than one year after radiotherapy in spite of a low disease incidence. Metabolic effects must be postulated as the reason for this finding, but the actual mechanism is not clear (possibly slightly higher blood levels of toxic agents). This finding has to be taken into account in the treatment decision process for these patients.