Intravesical prostatic protrusion as a predictor of acute urinary retention following stereotactic body radiation therapy for localised prostate cancer: a retrospective study

Patients

We retrospectively reviewed the medical records of patients with non-metastatic prostate cancer (cT1–T3a, N0, and M0) who were treated between June 2017 and October 2023. We included patients aged≥20 years who underwent SBRT with radical intent. Of the 217 consecutive patients who underwent SBRT, 4 were excluded because the tumour was staged as T3b, 2 because of a short follow-up duration (<3 months), and 1 because of M1 staging. The remaining 210 patients were included in the final analysis. All patients underwent magnetic resonance imaging (MRI) of the pelvis and technetium-99m-methylene diphosphonate bone scan for staging. The patients were classified into risk groups according to the National Comprehensive Cancer Network guidelines [13]. Radiotherapy alone was offered to very low- or low-risk patients (clinical stage T1–T2a, prostate-specific antigen [PSA] level<10 ng/mL, and grade group 1). In contrast, intermediate- or higher-risk patients received neoadjuvant androgen-deprivation therapy (ADT) for 6 months. The patients underwent ultrasound-guided placement of three gold fiducial markers for daily imaging guidance. Only two patients were injected with periprostatic hydrogel spacers (SpaceOAR; Augmenix Inc., Waltham, MA, USA).

This retrospective study was approved by the Ethics Committee of Toyota Memorial Hospital (application No. R177). This study was conducted in accordance with the tenets of the Declaration of Helsinki and its subsequent amendments. Informed consent procedures were followed, and patients were given the opportunity to disclose and opt-out of this analysis prior to the study.

Radiotherapy

As we have already reported our radiotherapy methods in another publication [14], we briefly describe here the main points. Patients received 36.25 Gy in five fractions using the CyberKnife M6 system (Accuray Inc., Sunnyvale, CA, USA), delivered over five consecutive weekdays. Treatment duration was≤35 min, with the prostate’s position verified and corrected every 20–60 s. The targets were contoured by registering the T2-weighted MRI images with planning computed tomography (CT) scans. The gross tumour volume included the entire prostate for low-risk patients, and 1 cm of the proximal seminal vesicles was added for intermediate/high-risk cases. The clinical target volume incorporated 1-mm posterior and 3-mm isotropic margins, excluding the rectal/bladder mucosa overlap. A planning target volume (PTV) with 2-mm isotropic margins was added. Multiplan software (Accuray Inc.) was used for planning. The prescription dose was defined as PTV D₉₅, with the peak dose adjusted to 75–85 % and the minimum dose to>70 %. Dose constraints were the following: rectum, D_{0.5 cc}<37 Gy, D_{2 cc}<35 Gy, D_{5 cc}<28 Gy, V_50 % <25 %; bladder, D_{10 cc}<32 Gy, V_50 % <35 cc, V_100 % <5 cc; urethra, minimum dose>95 %, maximum dose<102 %; femoral heads, V_40 % <5 %.

Evaluation items

We quantified the mid-lobar enlargement of the prostate using several indices. All indices were calculated using Maestro (MIM Software, Inc., Cleveland, OH, USA) using treatment planning CT. IPP was defined as the distance from the apex of the prostate protruding towards the bladder to the plane connecting the bladder base, in accordance with a previous report [8] (Figure 1, black arrow). IPP was measured by a single radiographer (who is also a medical physicist) in the coronal and sagittal sections of the planning CT, and the larger value was defined as the maximum IPP. Agreement between coronal and sagittal measurements was assessed using Bland-Altman analysis. The intraclass correlation coefficient (ICC) was calculated to evaluate measurement reliability. In addition, the surface area of the bladder in contact with the prostate was defined as the protruding surface area (Figure 1, orange area), and the prostate volume cephalad to the plane connecting the bladder base as the protruding volume (Figure 1, blue volume). The bladder trigone was calculated by connecting the three points on the left and right ureteral orifices and the internal urethral orifice.

Figure 1:

Treatment planning computed tomography illustrating each parameter of the mid-lobar enlargement: (A) sagittal and (B) coronal sections. Note: Black arrow, distance from the apex of the prostatic protrusion towards the bladder to the plane connecting the bladder base (intravesical prostatic protrusion); orange area, surface area of the bladder in contact with the prostate (protruding surface area); blue volume, prostatic volume that is cephalad to the plane connecting the bladder base (protruding volume).

We measured the time to the event from the date of commencing the radiotherapy as well as the International Prostate Symptom Score (IPSS) and quality of life (QOL) based on patient reports. The IPSS obstructive subscore (IPSS-O) was calculated as the sum of items 1, 3, 5, and 6 of the questionnaire, based on previous reports [15]. Each score was measured before radiotherapy and 1 week, 4 weeks, 3 months, and 6 months later.

Treatment-related toxicities, including urinary retention, were graded according to the National Cancer Institute’s Common Terminology Criteria for Adverse Events, v5.0 [16]. Specifically, if the retention required urinary catheterisation, it was described as grade 2-C urinary retention; this category is not standard but was originally defined for this research. Acute toxicity was defined as symptoms observed during or less than 3 months after radiotherapy.

The clinical outcomes were assessed in terms of biochemical recurrence-free and overall survival. Biochemical recurrence was defined according to the Phoenix definition, with an increase of 2 ng/mL in the absolute nadir PSA level [17].

Statistical analyses

All statistical analyses were performed using EZR version 1.62 (Saitama Medical Centre, Jichi Medical University, Saitama, Japan) based on R version 4.3.2 and R Commander version 2.9-1 [18].

Logistic regression was used for the univariate and multivariate analyses to determine the factors contributing to IPP and grade 2 retention. Statistical significance was set at p<0.05. Factors demonstrating p<0.1 in the univariate analysis were included in the multivariate analysis. For covariates with sparse events and evidence of separation, we additionally performed Firth’s penalised logistic regression to obtain bias-reduced estimates. This analysis was applied only to the univariable models for grade 2-C urinary retention, specifically for low risk, neoadjuvant ADT, previous TURP, and IPP_max.

Receiver operating characteristic (ROC) curves were used to evaluate the relationship between IPP and grade 2 retention. The cut-off point was determined based on the Youden index, and well-balanced sensitivity and specificity values were obtained [19].

Patient characteristics and treatment feasibility

Table 1 summarises the patient and dosimetric characteristics. A total of 210 patients were included in this study. One low-risk patient underwent short-term neoadjuvant ADT to delay SBRT because of personal reasons. One intermediate-risk patient did not undergo neoadjuvant ADT because of age or an underlying disease. There were 70, 127, and 13 patients with IPSS≤7, 8–19, and ≥20, respectively. The median IPP was 0.6 cm regardless of the measured cross section. Bland-Altman analysis showed excellent agreement between measurements (mean difference=0.012; 95 % limits of agreement, −0.227 to 0.251; ICC=0.975).

All patients completed the treatment and were followed up for at least 3 months. In 7 patients, there was an unexpected interruption of treatment, three of which were due to balloon insertion because of urinary retention; the remaining 4 were due to poor reproducibility of the gastrointestinal tract position (2 cases), emergency maintenance of the treatment system (1 case), and personal reasons for the patient (1 case).

Urinary retention

Grade 2 acute genitourinary toxicity was observed in 69 patients (33 %), of whom 43 (20 %) had urinary retention. Five patients (2 %) with urinary retention required urgent urinary catheterisation. The details are presented in Table 2. In common in the 5 cases, the prostate volume and indices of mid-lobe enlargement were greater than the overall median. Of the five patients, three developed urinary retention during the irradiation period, requiring up to 19 days to complete radiotherapy. However, no biological recurrence was observed during the observation period.

The results of the univariate and multivariate analyses of urinary retention for grades 2 and 2-C are presented in Table 3. The univariate analysis showed that pre-radiotherapy QOL scores and indices of mid-lobar hypertrophy, such as IPP, prostate volume, bladder V_50 %, and bladder trigone D_mean, contributed to grade 2 urinary retention. The multivariate analysis showed that IPP was the only independent contributor to grade 2 urinary retention (odds ratio [OR]=7.25; 95 % confidence interval [CI] 2.86–18.4; p<0 0.001). IPP also significantly contributed to the occurrence of grade 2-C urinary retention, which is, requiring urgent urinary catheterisation (p=0.004).

The predictive sensitivity and specificity for grade 2 acute retention were 77.2% and 55.8 %, respectively, at a cut-off value of 0.8 cm for IPP. The area under the curve (AUC) was 0.70 (95 % CI 0.61–0.79). At the 1.4-cm cut-off point, the sensitivity and specificity of IPP for grade 2-C retention were 98.0% and 100.0 %, respectively, with an AUC of 0.99 (95 % CI 0.98–1.00). The duration of catheter use was relatively short, and none of the patients became catheter-dependent.

Transitions in the IPSS-O based on patient reports are presented in Figure 2 together with the IPSS and QOL scores. Symptoms of retention worsened significantly after irradiation (p<0.001) and peaked at 4 weeks. The same was true for IPSS and QOL scores.

Figure 2:

Changes in the (A) IPSS/IPSS-O and (B) QOL score following radiotherapy. Note: IPSS, international Prostate Symptom Score; QOL, quality of life.

Other toxicities and clinical outcomes

The other acute-phase toxicities are summarised in Table 4. Grade 2 acute gastrointestinal toxicity was observed in 14 patients (7 %). We did not observe grade≥3 acute toxicities in any category.

The 2-year biochemical recurrence-free and overall survival rates were 99.0 % (95 % CI, 96.0–99.7 %) and 99.1 % (95 % CI, 93.5–99.9 %), respectively. Biochemical recurrence was observed in 6 patients during the observation period, one of whom showed distant metastases on imaging studies. The risk classification was low in 2 patients and high in 4 patients. Five patients died of causes other than prostate cancer. Two of the five patients developed myelodysplastic syndrome, and the others developed gastric cancer, subarachnoid haemorrhage, and fatal arrhythmia (one each) after treatment.