Radiation therapy (RT) is one of the treatment strategies for localized prostate cancer. However, radiation-induced urinary toxicity of the bladder and urethra can occur during or after the RT, which adversely impact patients’ quality of life. Decreasing high bladder dose volume may reduce the incidence of acute urinary toxicity [1]. Carbon-ion radiation therapy (CIRT) offers biological and physical advantages over conventional RT with X-rays. Carbon-ion beams have an estimated three-fold higher relative biological effectiveness than X-rays, and favorable clinical outcomes of CIRT for prostate cancer have been reported [2]. It has been reported that previous transurethral resection of the prostate or diabetes mellitus is associated with late urinary toxicities of intensity-modulated radiotherapy (IMRT), but the predictors of urinary toxicities of CIRT are not elucidated. In terms of prostate morphology, it has been reported that prostate volume (PV), transitional zone volume (TZV) and intravesical prostatic protrusion (IPP) are associated with lower urinary tract symptoms or bladder outlet obstruction. The purpose of this study is to predict the urinary toxicities in patients with prostate cancer treated with CIRT in terms of prostate morphology.

In total, 293 consecutive patients with prostate cancer treated with CIRT between December 2015 and March 2018 were analyzed in this study. The eligibility criteria for this study were as follows: (i) histological diagnosis of prostate adenocarcinoma, (ii) cT1bN0M0 to T3bN0M0 according to the 7th UICC classification, (iii) performance status of 0–2, and (iv) no previous treatment for prostate cancer excluding androgen deprivation therapy (ADT). The patients were classified using the D’Amico risk group classification. ADT was not administered to low-risk patients. Neoadjuvant ADT was administered for 6 months to intermediate-risk patients, and high-risk patients received a total of 24 months of neoadjuvant plus adjuvant ADT. CIRT was administered once daily for 4 days a week over 3 weeks and the total dose was set at 51.6 Gy. Toxicities were assessed according to the Common Terminology Criteria for Adverse Events version 4.0. Acute toxicity was defined as events occurring up to three months after the initiation of CIRT, and late toxicity was defined as events occurring after three months. The worst toxicity grade was considered the final grade of toxicity. Prostate morphological parameters were measured by MRI or CT before CIRT. IPP was measured on sagittal view, and defined by the distance from the tip of the prostatic protrusion into the vesical lumen to the bladder neck. Fifteen patients who could not undergo MRI were only evaluated PV and IPP by CT. Fisher's exact test was used for statistical analysis.

Patient characteristics are summarized in Table 1. The median age was 69 (range, 47–86) years. The median follow-up duration was 41.8 (range, 14.1–59.9) months. Among 293 patients, 9, 101, and 183 patients were classified as having low, intermediate, and high risks, respectively. The Median PV and IPP were 26.2 (range, 8.1–101.3) mL and 0 (range 0–12) mm in 293 patients, and the median TZV was 9.2 (range, 1.6–48.4) mL in 278 patients. Table 2 shows the maximal acute and late urinary toxicities in this study. Among acute urinary toxicities, urinary frequency was the major symptom observed. Grades 1 and 2 urinary frequency were observed in 36 (12.3%) and 11 (3.8%) patients, respectively. The number of patients with any acute urinary toxicities was 54 (18.4%) for grade 1, 14 (4.8%) for grade 2, and 0 for grade 3. Similarly, the number of patients with any late urinary toxicities, except for hematuria, was 46 (15.7%) for grade 1, 42 (14.3%) for grade 2, and 0 for grade 3. Grade 1, 2 and 3 hematuria were observed in 17, 1 and 3 patients, respectively. The presence or absence of IPP was significantly different between Grade 0 and Grade 1 and 2 for acute urinary toxicities, with odds ratios and relative risk of 2.364 and 1.866, respectively (P < 0.01). Additionally, IPP was significantly different between Grade 0 and 1 and Grade 2 for late urinary toxicities, with odds ratios and relative risk of 2.350 and 2.028, respectively (P < 0.05). PV or TZV was not significantly associated with urinary toxicities and none of these parameters were associated with hematuria.

Using the spot scanning method, CIRT is a 3D scanning beam delivery method that uses a thin pencil beam of carbon ions to cover the entire target volume. By gradually reducing the energy and repeating irradiation for each slice, the tumor can be irradiated from the most distal end to the proximal end of the target according to its shape. However, intravesical prostate protrusion can be a potential risk of radiation therapy complications due to its morphological characteristics. The limitation of this study is that the incidence of urinary toxicities is based on self-reported interviews and lacks objective data (eg, parameters obtained from uroflowmetry). However, more than 80% of late toxicities occurred within 2 years after CIRT [3]; therefore, toxicities were evaluated for a sufficient period in the present study. Further observation with a large patient cohort will be necessary to confirm our clinical outcome.

IPP can be useful parameter for predicting acute or late urinary toxicities in patients with prostate cancer treated with CIRT. This is the first study to examine urinary toxicities of CIRT in terms of prostate morphology.

Radiother Oncol 156: 69-79, 2021
Radiother Oncol 121: 288-293, 2016
Clin Oncol (R Coll Radiol) 29: 617-625, 2017