Despite the introduction of more advanced techniques such as IMRT, VMAT and IGRT in clinical practice, reductions in acute and late toxicity were observed only in rectal symptoms . On the other hand, results of phase 3 dose-escalation trials suggest that there were no significant differences with 3DCRT or IMRT for acute or late G2 + or G3 + UGT . In addition to the RT technique, other factors are involved in the occurrence of symptoms of UGT. Understanding the impact of dosimetric/clinical factors on urinary symptom after RT is crucial to decision-making process for a more tailored treatment and patient care .
In our prior publication we estimated the incidence of acute and late UGT after a median follow-up of 27 months and influence of individual/clinical factors on late UGT . Since we know that the influence of the follow-up length is important because some symptoms appear later, we decided to continue our investigation with update the results. After median follow-up of 66 months we have got new results: thirty-three of 94 patients (35.11%) showed no symptoms of late UGT.
To overcome the limitations in toxicity reporting by using incidence rates, other approaches were proposed in the literature.
Schmid et al. suggests that the combination of incidence and prevalence rates provides a more comprehensive view on the complex issue of late side effects because incidence rates may lead to misinterpretation or overestimation. Their study demonstrates that the majority of late GIT and UGT after primary external beam RT for PC are temporary .
In contrast, Olson et al.  found that the temporal pattern of symptom occurrence varied, but the prevalence generally changed moderately over time.
In our study the prevalence rate of late UGT grade ≥ 1 increase over time while the prevalence rate of late UGT grade ≥ 2 fluctuates.
The increase and decrease of prevalence rate at different time points during follow-up suggests that in some patients the symptoms may be diminished and/or be temporary, while in other patients, symptoms may be developed "de novo" or pre-existing symptoms may have worsened.
Therefore, we wanted to take into account all changes in the degree of late UGT at all-time points for each patient, in order to determine how the overall grade of late UGT changes over time.
Having in mind the fluctuation of the prevalence of late UGT symptoms, we expected a decrease in the degree of late UGT symptoms, which would mean that these symptoms are temporary and that they may heal over time.
Surprisingly, we found that there is a statistically significant positive trend for an increase in the overall degree of late UGT over time (b = 0.028; p < 001) (Fig. 2). Based on this result, we can conclude that if we follow these patients long enough (longer than 5 years), the degree of late UGT will be higher.
As far as we know, this is the first time in the literature that late toxicity is assessed taking into account all changes in the degree of late UGT at all -time points for each patient, in order to determine how the overall degree of late UGT changes over time.
The second goal of our study was to estimate the possible influence of individual and clinical characteristics on the occurrence of late UGT.
In RADAR study, several parameters affecting the development of specific urinary symptoms after prostate cancer radiotherapy were identified. Baseline symptoms and non-insulin-dependent diabetes mellitus (NIDDM) were found to have sustained impacts across all time point, while age and PC1 (PC1 has high correlation to the mean dose) were repeated in more than one time point. Other associations found to be significant are not repeated at different time points suggesting poorer or temporary impacts .
As this is a partially retrospective study, we did not have any pre-treatment symptoms recorded in the medical history so we could not examine the correlation between baseline symptoms and the occurrence of late UGT.
In the current study NIDDM in UVA was statistically significant (p = 0.043) but in MVA was not significant (p = 0.09). Similar results we got in our former study: in UVA, NIDDM was statistically significant (p = 0.028) but in MVA was border line significant (p = 0.056) .
In the literature, we found studies which reported a correlation between PAPS and the symptoms of late GIT , but we did not find any which reported correlations between PAPS and the advent of late UGT.
The authors who found a correlation between previous surgery and GIT symptoms assumed that the inflammatory response could increase due to surgery even though the surgical injury was outside the irradiated volume and therefore radiation sensitivity increases. It has also been observed that cytokine expression increases due to surgery, which could lead to a more pronounced inflammatory response of the gastrointestinal mucosa to radiation [21, 22].
Christensen et al.  observed that the expression of IL1 and IL6 was associated with an increased probability for acute UGT and GIT, respectively.
In contrast, Bedini et al.  in their study showed that IL-1b and IL-6 were fairly undetectable in most patients and presented with very low variability among patients. This preliminary study identified a correlation between CCL2 levels at the end of radiotherapy and basal CCL2, age, and previous abdominal/pelvic surgery (PAPS), suggesting a different response to RT in older patients and in patients with pretreatment abdominal surgery.
In our prior study PAPS was a statistically significant factor for grade ≥ 2 of acute UGT (p = 0.012) but not for late UGT (= 0.108) . Interestingly, in our current study PAPS was a statistically significant factor (p = 0.007) for late UGT grade ≥ 1. To our knowledge, we are so far the only one to report a statistically significant association between PAPS and acute and late UGT. The relationship between acute and late effects of RT remains controversial.
It was traditionally thought that there was no link between the acute reaction to radiation exposure and the late effects in other organs and tissues, and that acute and late toxicity were the consequences of different independent pathological mechanisms. It has been shown that the acute and late toxicity do not share a similar set of predictors [25, 26]. More aggressive RT protocols can result in aggravation, i.e. an increase in severity and duration, of acute radiation effects . The non-healing response can progress directly into a late effect. In other examples of consequential late effects, there is clinical healing of acute effects and a symptom-free period before the independent development of late effects in the same tissue .
In the Medical Research Council RT01 TRIAL , acute bladder symptoms correlated with the presence of all late bladder symptoms scores but only with a change in the score for the symptoms of urinary frequency and hematuria. This therefore suggests that patients with symptoms before treatment will probably suffer acute bladder toxicity during treatment and may develop late symptoms.
Pinkawa et al.  found a strong dependence of urinary/bowel QoL after radiotherapy on urinary/bowel QoL before radiotherapy. In contrast to absolute scores, QoL score changes (relative to baseline scores) did not correlate with pretreatment scores. They concluded that long-term changes could be well predicted by acute changes.
In our current study applying the multivariate multilevel ordinal regression model we found, apart from PAPS, acute UGT during radiotherapy to be statistically significantly associated with a higher degree of late UGT (p = 0.013). The conclusions coincide with the results from our previous study (p = 0.024).
Based on the obtained results, we can conclude that in the examined group the degree of late UGT increased with time. PAPS is a statistically significant predictive factor for the onset of late UGT symptoms. There is a statistically significant correlation between the frequency and the severity of symptoms of acute and late UGT.