Objective To quantify the effect of radiotherapy (RT) on urodynamic function 3 months after RT in patients with prostate cancer undergoing definitive external beam RT.
Patients and methods Seventeen patients with clinically localized prostate cancer were accrued into a single-arm prospective study. Sixteen of the patients completed a scheduled multichannel video-urodynamic study at baseline and again 3 months after RT; the urodynamic variables were then compared to assess the nature and extent of urodynamic change caused by RT. Correlations were assessed between these quantitative changes and those in self-assessed qualitative urinary function measured by International Prostate Symptom Score (IPSS), Quality of Life assessment index (QoL) and urinary functional enquiry.
Results There were significant changes detected by the urodynamic study 3 months after RT in bladder volume at capacity (mean decrease 70 mL) and bladder volume at first sensation when supine (mean decrease 85 mL), and a lower postvoid residual volume (mean 50 mL). There was no significant change in the remaining urodynamic variables (including maximum flow rate and voided volume), nor in bladder compliance, bladder instability or bladder outlet obstruction. The self-assessed qualitative urological function measured by the IPSS, QoL and median urinary frequency/24 h showed no significant change after RT.
Conclusions This is the first quantitative study to prospectively evaluate the effect of RT on urodynamics in patients with prostate cancer. Only a few urodynamic variables changed significantly 3 months after RT, while most, including self-assessed qualitative urinary function, did not. This finding corresponds well with the notion that most patients tolerate RT well and that acute RT-induced urinary symptoms resolve successfully, with the return of lower urinary tract function to baseline levels by 3 months after RT.
The optimal management of clinically localized prostate cancer remains unresolved. Curative management options for clinically localized prostate cancer include radical prostatectomy, and definitive radiotherapy (RT) with either EBRT or prostate brachytherapy. As there are no results from prospective randomized trials, radical prostatectomy and RT are usually offered to patients as equivalent curative strategies , although each of these options is associated with a risk of significant morbidity [2,3].
In recent years the radiation dose for treating clinically localized prostate cancer has increased steadily, as there has been increasing evidence for a dose–response relationship. With these dose-escalation regimens it is important to address acute and late RT-induced morbidity, as both could compromise the therapeutic benefit of the strategy. Acute RT-induced genitourinary symptoms are secondary to the acute inflammation of the lower urinary tract and consist of dysuria, frequency, urgency and diminished urinary flow. The severity of these symptoms can influence the tolerability of a protracted course of a dose-escalation regimen and cause treatment to be interrupted, which compromises the effectiveness of RT.
To date, all studies evaluating RT-related urinary morbidity in patients treated with RT for prostate cancer have been qualitative, with no clinical study using quantitative objective variables to assess the effect of RT on urodynamic function. To quantify the immediate effect of RT on the lower urinary tract and urodynamics, we conducted a prospective study using urodynamics as an objective tool. The nature and extent of urodynamic changes caused by RT 3 months after treatment were examined and quantified. Correlations were assessed between these urodynamic changes and those in self-assessed qualitative urinary function measured by the IPSS, Quality of Life assessment index (QoL) and urinary functional enquiry, to assess the significance of these urodynamic changes to subjective urological symptoms.
Patients and methods
A prospective single-arm study was conducted at the authors' institution between January 1998 and February 2001; patients were eligible if they had a histological diagnosis of adenocarcinoma of the prostate, clinical stage T1b-T3N0M0 and planned definitive EBRT. Patients with previous radical prostatectomy, previous RT to the pelvis, or failure to give informed consent were excluded. All patients underwent a multichannel video-urodynamic study before EBRT and again 3 months and 18 months afterward, carried out according to the recommendations of the ICS . The results were analysed and interpreted by one of the authors (S.H.), a urologist with expertise in this field.
Figure 1 shows a schematic illustration of the multi-channel video-urodynamic study; each patient was catheterized with two 8 F catheters, one for measuring the filling pressure and the other for intravesical pressure (Pves). A 10 F balloon-tipped rectal catheter was also introduced to measure intra-abdominal pressure (Pabd). Detrusor pressure (Pdet) was calculated as (Pves − Pabd). Contrast medium solution was instilled into the bladder at a mean filling rate of 50 mL/min and fluoroscopy used to image the urinary system. Several variables were measured during the filling and voiding phase of the bladder with the patients both supine and upright. With the patient supine and the bladder being filled, pressures and volumes at first sensation, at desire to void and at capacity were measured. Instability and decreased compliance were also assessed. The patient was then asked to cough and strain. If stress incontinence was detected, the Valsalva or cough-leak pressure was recorded. The bladder was then emptied and refilled with the patient upright, with the same variables measured; stress manoeuvres were again carried out. After these measurements the filling catheter was removed and the patient asked to void, to measure the voiding pressure and flow rates.
All patients completed the IPSS and QoL questionnaire  in conjunction with the urodynamic studies. The IPSS is an instrument designed to evaluate LUTS in men with BPH; scores of 7, 8–19 and 20 correspond to mild, intermediate and severe LUTS, respectively . The application of the IPSS has been validated for evaluating LUTS in patients treated with permanent-source interstitial brachytherapy  and EBRT  for clinically localized prostate cancer.
At the time of the urodynamic study all patients were examined physically and provided a detailed medical history, including previous urological or pelvic surgery, spinal cord injury, neurological illness, diabetes mellitus and concomitant medications that might have affect the urodynamic study. Urine was analysed and tested by culture and sensitivity to exclude UTI. Baseline biochemical tests included a blood count, urea, creatinine, serum PSA, prostate alkaline phosphatase, liver function profiles and random glucose levels.
All patients received conformal EBRT using a four-field box technique and high-energy photons (18 or 23 MV). Patients were treated while supine and advised to keep their bladder full before EBRT. The clinical target volume (CTV) was limited to the prostate and periprostatic tissue with known extent of tumour. Regional pelvic lymph nodes were not included in the CTV. A uniform 15 mm was added to the CTV to determine the planning target volume (PTV). All patients underwent CT planning to obtain the CTV and PTV. The bladder volume and the proportion of bladder volume within the 100%, 80% and 50% radiation isodoses were calculated with appropriate software. The EBRT dose and fractionation ranged from 66 Gy/33 fractions, to 70 Gy/35 fractions, with most receiving 66 Gy/33 fractions. EBRT was delivered 5 days/week in 2 Gy daily fractions; the dose was prescribed at the recommended reference point .
Because of the exploratory and invasive nature of the study, the accrual was limited to 17 patients. Moreover, this project was considered as a pilot study from which a future, more rigorous, study could be developed.
Seventeen patients were accrued for this pilot study; one patient was excluded from analysis as he had a syncopal episode during the baseline urodynamic study, resulting in an incomplete evaluation. The change in urodynamics at 18 months after EBRT, which reflects the late effects, will be addressed separately.
The median (range) age of the patients was 72 (56–77) years. All underwent CT of the abdomen and pelvis, and had a bone scan before EBRT; they had no evidence of metastatic disease. One patient had a history of diabetes mellitus and another had undergone TURP before the diagnosis of prostate cancer. None had pelvic or urological surgery, spinal cord injury, neurological illness, or other major medical illness between the baseline assessment and that 3 months after EBRT.
The median (range) pretreatment PSA level was 8.55 (1.1–49.7) ng/mL (Tandem-R assay, Hybritech Inc., USA). The median (range) Gleason score was 7 (6–8) and the clinical T stage distribution was three with T1c, 12 with T2 and one with T3.
The median percentage of bladder volume within the 100% radiation isodose was 0.9 (0–19.5)% with the median calculated volume of 4.1 (0–36.3) mL. The respective values for 80% and 50% of the prescribed dose was 30.6% and 60.6%, respectively.
The median urinary frequency/24 h, IPSS and QoL at baseline were 8.5 (4–14), 7 (1–22) and 1.5 (0–5), respectively, compared with 8.5 (4–20), 8 (0–30) and 2 (0–5) at 3 months after EBRT. There was no statistically significant change in these self-assessed urological symptoms at 3 months after EBRT, the mean (sem) changes being 1.38 (1.81) for IPSS, 0.06 (0.39) for QoL and 1.56 (1.04) for urinary frequency. There was no statistically significant change in the distribution of urgency, urge incontinence and other bladder characteristics between baseline and 3 months after EBRT (Table 1).
Table 1. The number of patients with reduced bladder compliance, bladder instability, BOO, urge and urge incontinence at baseline and 3 months after EBRT
Status at baseline and 3 months after EBRT
All variables showed no significant change (McNemar's test); Y-Y, presence of condition at baseline and at follow-up; Y-N, presence of condition at baseline and normal at follow-up; N-N, absence of condition at baseline and absent at follow-up; N-Y, absence of condition at baseline but abnormal at follow-up.
Decreased bladder compliance
Figure 2 presents each patient's changes in bladder volume at capacity while supine, before and 3 months after EBRT. At 3 months after EBRT the mean (range) bladder capacity decreased from 422.6 (104–650) to 352.9 (103–665) mL while supine, and the mean bladder volume at first sensation from 229.8 (50–399) to 144.9 (1–342) mL. Table 2 summarizes the results of the urodynamic studies. There was a statistically significant reduction in bladder capacity (while supine) at 3 months, in bladder volume at first sensation and in the postvoid residual volume (PVR) ( Table 2 ), but no significant change in the other variables, including volumes while upright and pressures at capacity, at first sensation and at desire to void, maximum flow rate, voiding pressure and voided volume.
Table 2. Urodynamic studies at baseline and 3 months after RT
Table 1 also summarizes the changes after EBRT in patients with or without pre-existing low bladder compliance, bladder instability and BOO. Overall, there was no statistically significant change in these factors with EBRT.
Because there were few patients in the study a detailed evaluation of the relationship between the proportion of bladder volume receiving 100%, 80% and 50% of the prescribed dose and the magnitude of the reduction in bladder capacity was not feasible. However, the potential correlation was assessed of these proportions with the changes in urodynamic variables that were statistically significant at 3 months after EBRT (i.e. bladder capacity, bladder volume at first sensation and PVR) and the magnitude of change in IPSS, QoL and change in 24-h urinary frequency; there were no statistically significant correlations.
With dose-escalation for treating clinically localized prostate cancer, the potential morbidity of RT has become an increasingly important element to be included in management decisions. Although the acute morbidity of RT is often self-limiting and not as critical as late toxicity, it is nevertheless important as it influences the patients' ability to complete RT schedules without interruption.
There have been three randomized trials evaluating acute toxicity associated with conformal EBRT [9–11]. When a traditional total dose of 64–66 Gy with a conventional dose-fractionation schedule was applied, conformal EBRT resulted in no significant reduction in urological toxicity, although it improved bladder dose-volume histograms, sparing a greater proportion of the bladder a high radiation dose [9,10]. However, when a dose-escalation strategy was used the benefit of conformal EBRT was evident in acute urinary morbidity. Pollack et al. reported, in a phase III study comparing 70 Gy in 35 fractions using conventional RT with 78 Gy in 39 fractions and delivered by conformal EBRT, that there was no significant difference in acute urinary toxicity between the treatments. The conformal technique allowed a significant reduction in the percentage of bladder volume receiving 60 Gy, and probably explains why there was no significant increase in acute urological toxicity despite dose-escalation in the conformal arm. These findings suggest that a traditional total dose of 64–66 Gy is generally well tolerated, regardless of the use of the conformal technique, and that the benefit of conformal EBRT would be evident only in a dose-escalation regimen in which a much higher total dose is applied.
These phase III studies also showed the prevalence of acute urological side-effects associated with EBRT for prostate cancer. Koper et al. reported, in a phase III study comparing conventional RT with three-dimensional conformal RT for the delivery of 66 Gy in 33 fractions, that the incidences of grade 1, 2 and 3 acute genitourinary toxicity were 47%, 17% and 2%, respectively. Similarly, Pollack et al. reported that 97% of patients receiving 78 Gy in 39 fractions using the conformal technique had grade 2 bladder reactions and one of 29 patients had grade 3 urinary toxicity.
In the present series, the 3-month follow-up was chosen as a surrogate endpoint, reflecting the acute effect of EBRT on the lower urinary tract. Although it is desirable to conduct the urodynamic study during and immediately after the course of RT, to accurately reflect the acute effect of RT, this would not be practical and, to some extent, unethical because of the invasiveness of the urodynamic study. As the urodynamic study requires repeated catheterization, then conducting it during or immediately after the course of RT may cause further trauma to the lower urinary tract already affected by acute inflammation from RT. This would probably in turn result in the aggravation of acute RT-induced urinary symptoms.
There are several limitations to the present study, mainly that few patients were included, giving large CIs for the variables estimated; this could lead to false-positive or false-negative conclusions. Another is that the urodynamic changes at 3 months after EBRT do not necessarily reflect the short-term urological effects, which are usually maximal during or immediately after EBRT. Furthermore, the evaluation of bladder compliance, bladder instability and the absence or presence of obstruction depends to some extent on a subjective interpretation of the urodynamic study. Despite these limitations the present study is, to the best of our knowledge, the first prospective quantitative study to evaluate the acute effects of EBRT on urodynamics in patients with prostate cancer receiving definitive EBRT.
Interestingly, the PVR was decreased 3 months after EBRT; this improvement may be associated with some resolution of BOO secondary to a reduction in tumour burden after EBRT. Despite significant change in some of the urodynamic variables at 3 months there was no significant change in self-assessed urological function, nor any significant adverse effects on bladder compliance, bladder instability or BOO. These findings correspond well with the notion that most patients tolerate EBRT well and that the acute radiation-induced urinary symptoms resolve, with the return of lower urinary tract function to baseline values by 3 months.
Urinary symptoms and urodynamic studies have been used to evaluate bladder function in women undergoing RT for gynaecological malignancies. In a prospective study of 33 patients, Farquharson et al. reported significant reductions in peak urinary flow, volume at first desire to void, cystometric capacity and bladder compliance during and immediately after RT. In addition, bladder compliance was significantly lower in those patients receiving >30 Gy to the entire bladder. The change in voided volume has also been used to assess the acute change in bladder function in patients undergoing RT for pelvic malignancy ; in 11 patients undergoing RT for prostate cancer, voided volumes were reduced, starting at 2 weeks after RT, and reached a minimum by 5–6 weeks, at ≈70% of the baseline volumes.
There are reports on the use of medication to ameliorate acute bladder toxicity. Selective α-blockers, e.g. terazosin, were better for improving acute urinary symptoms (frequency, nocturia and urgency) during RT for localized prostate cancer than were NSAIDs . Αβ2-agonist (mabuterol) also improved compliance, bladder capacity and flow rate in women with urinary disturbance after RT for cervical cancer . Further studies are required to determine whether this early intervention in the sequence of pathogenic processes can improve urodynamic function and subsequently reduce the incidence of late sequelae.
In summary, there are few studies addressing the relationship between RT-induced symptoms and pathophysiological, functional and anatomical changes caused by RT. Additional studies are needed to verify the present findings; furthermore, with dose-escalation regimens for prostate cancer in which the RT dose usually exceeds 76 Gy, it is desirable to repeat a similar study to evaluate the effect on urodynamic function secondary to dose escalation.
R. Choo, Department of Radiation Oncology, Toronto-Sunnybrook Regional Cancer Centre, 2075 Bayview Avenue, Toronto, ON M4N 3M5, Canada. e-mail: email@example.com