Sarcopenia and excess visceral fat accumulation negatively affect early urinary function after I‐125 low‐dose‐rate brachytherapy for localized prostate cancer

To evaluate the effects of sarcopenia and excess visceral fat accumulation on early urinary function after I‐125 low‐dose‐rate brachytherapy for prostate cancer.


INTRODUCTION
Prostate cancer (PCA) is the second commonest cancer and the fifth commonest cause of cancer-specific deaths among men worldwide. 1 I-125 low-dose-rate brachytherapy (LDB) is a well-established treatment for clinically localized and low-, intermediate-, and high-risk localized PCA. 2 Treatment-related changes in quality of life (QOL) are important factors for determining the appropriate treatment. Lower urinary tract symptoms (LUTS) are major adverse events of LDB that can negatively impact QOL, especially in the early post-treatment period. LUTS deteriorates early post-LDB and returns to near baseline levels after 12-24 months. 3,4 Some patients quickly return to pre-treatment levels, while others take longer. LUTS prediction may lead to improved treatment selection and understanding of the post-treatment course.
Sarcopenia is the loss of skeletal muscle mass and strength that occurs with advancing age. 5 Sarcopenia adversely affects the oncologic outcome of PCA. 6 It also negatively impacts complications and QOL after surgery for localized PCA. 7,8 Excessive accumulation of abdominal visceral fat is associated with metabolic syndrome and LUTS, including an overactive bladder (OAB). 9,10 To our knowledge, no studies have investigated whether sarcopenia and excess visceral fat accumulation are associated with LUTS after LDB. Thus, we evaluated the effects of sarcopenia and excess visceral fat accumulation on the early urinary function post-LDB for localized PCA, focusing on longitudinal changes in QOL.

METHODS Patients
Between June 2012 and July 2019, 263 patients were treated with LDB for localized PCA at our hospital. Seventeen patients with follow-up periods <24 months, and those who could not be evaluated for longitudinal QOL indicators or sarcopenia or visceral fat accumulation using pre-treatment computed tomography (CT), were excluded; finally, 246 patients were enrolled.
This retrospective study was approved by our hospital's Institutional Review Board. The protocol conformed to the provisions of the Declaration of Helsinki and informed consent was obtained from all patients.

Treatment protocol
The LDB protocol 11 was based on the American Brachytherapy Society recommendations. 12 Patients were classified into risk groups according to the National Comprehensive Cancer Network risk criteria. 13 Patients in the low-and intermediaterisk groups with a Gleason score of 3 + 4 and a biopsypositive core rate <33% received LDB monotherapy. The intermediate-risk group received additional doses of external beam radiotherapy (EBRT), and the high-risk group received LDB, EBRT, and hormone therapy (androgen deprivation therapy and/or anti-androgens) for 9 months, from pre-to post-treatment.
A transrectal ultrasonography-based treatment plan was implemented 3 weeks before LDB. Neoadjuvant hormone therapy was administered for 3 months in patients with prostate volumes >40 ml, trimodality, or at the discretion of the attending urologist. The prescribed dose was 145 Gy for LDB monotherapy and 110 Gy for combination therapy followed by an additional EBRT of 45 Gy. All implantations were performed using I-125 loose seeds and a Mick applicator (Mick Radio-Nuclear Instruments Inc.) based on interactive planning and modified peripheral loading methods. Fiftysix patients were implanted with interplant software (CMS); the remaining 190 patients were implanted with VariSeed software (Varian Medical Systems). Dose-volume histograms for the prostate, urethra, and rectum were constructed to determine the minimal dose of 90% of the prostate volume (D90), volume of the prostate receiving 100% (V100) and 150% (V150) of the prescribed dose, minimal dose received by 5% (UD5) and 30% (UD30) of the urethra, and the volume of the rectum receiving 100% of the prescribed dose (RV100).
The intra-operative dosimetric parameters for LDB monotherapy and LDB and EBRT combination therapy were as follows: prostate V100 > 95%, prostate D90 > 100%, and <130% of the prescribed dose; prostate V150 < 60%, and rectal V100 < 1.0 ml. UD30 was set at <220 Gy and <160 Gy for LDB monotherapy and LDB and EBRT combination therapy, respectively. UD5 was set at <240 Gy for LDB monotherapy. Post-implant dosimetric analysis was performed using CT and magnetic resonance imaging 4-5 weeks post-LDB.
Patients were discharged 2 days post-implantation; most were prescribed alpha-blockers or a phosphodiesterase 5 inhibitor (PDE5i), while some did not receive any medication. The prescribed medication was continued for approximately 1 month until post-implant dosimetric analysis, after which they were continued, modified, or discontinued depending on the urinary symptoms. b-3 agonists or anticholinergic agents were administered when urinary symptoms did not improve with a-1 blockers or PDE5i. EBRT was performed 6-8 weeks post-implantation using intensity-modulated radiation therapy with a total dose of 45 Gy/25-fractions and the radiation field covering the prostate and seminal vesicles.

Sarcopenia and visceral fat accumulation
CT scans were performed 3 weeks pre-LDB. The skeletal muscle index (SMI) was calculated by normalizing the L3 skeletal muscle areas by the square of the height (m 2 ) ( Figure 1a). For men, sarcopenia was defined as SMI <43 cm 2 /m 2 for body mass index (BMI) <25 kg/m 2 and SMI <53 cm 2 /m 2 for BMI ≥25 kg/m 2 . 7 Visceral fat area (VFA) and subcutaneous fat area (SFA) were measured at the umbilical level (Figure 1b) as continuous variables, with VFA in two groups with a cutoff of 100 cm 2 . 14 The analyses were performed using ImageJ (NIH).

Follow-up and outcomes
Baseline patient characteristics, treatment-related factors, and dosimetric factors were collected from medical records. Posttreatment follow-up was performed every 3 months for the first 2 years, every 6 months for the next 5 years, and every year for the next 10 years. Comorbidities were assessed by age-adjusted Charlson Comorbidity Index (ACCI). 15 The International Prostate Symptom Score (IPSS), calculated as the sum of the individual scores of seven symptomrelated questions, was used to assess LUTS. 16 Total IPSS was divided into IPSS voiding score (sum of questions 1, 3, 5, and 6) and IPSS storage score (sum of questions 2, 4, and 7). Higher scores indicated poorer conditions. Total IPSS, storage, and voiding scores were individually categorized into mild, moderate, and severe. Disease-specific health-related QOL (HRQOL) was assessed using the University of California Los Angeles Prostate Cancer Index (UCLA-PCI), which assesses urinary function, urinary bother, bowel function, bowel bother, sexual function, and sexual bother on a 0 to 100 point scale, with higher scores indicating better conditions. 17

Statistical analysis
Baseline characteristics, treatment parameters, dosimetric factors, and QOL questionnaire scores were compared between the two groups using Mann-Whitney U, Chi-squared, and Fisher exact tests as appropriate. Shapiro-Wilk test was used to evaluate the normality of the distribution of continuous variables. All QOL questionnaire scores are depicted as mean AE standard error. Dunnett's multiple comparisons were used to compare measurement scores at each time point to the baseline score. Two-way repeated measures analysis of variance was used to compare the longitudinal changes in questionnaire scores between groups (sarcopenia vs. nonsarcopenia groups or VFA ≥100 cm 2 vs. VFA <100 cm 2 groups). Multiple linear regression analysis was used to examine independent predictors associated with HRQOL score 12 months post-implantation. A clinically meaningful change was defined as a difference of at least half the standard deviation at baseline. 18 Multiple logistic regression analyses were used to examine independent predictors associated with clinically significant changes in the questionnaire scores 12 months post-implantation. To evaluate the effects of sarcopenia and visceral fat accumulation, baseline HRQOL score, age, neoadjuvant and adjuvant hormone therapy, EBRT, D90, UD30, prostate volume at implantation, and use of alpha-blockers or PDE5-i were selected as adjustment variables for the multivariate analysis. All statistical analyses were performed using JMP version 16 (SAS Institute Inc.). All tests were two-sided, and p < 0.05 was considered statistically significant.
The median duration of medication for LUTS after LDB was 12 (1-66) months, and 42 patients (17.1%) had medication changes. There were no significant differences in medication changes between the sarcopenia and non-sarcopenia groups or between the VFA ≥100 cm 2 and VFA <100 cm 2 groups. Anticholinergic agents or b-3 agonists were administered in 14 patients (5.7%). There were no significant differences in the administration of anticholinergic agents or b-3 agonists between the sarcopenia and non-sarcopenia groups or the VFA ≥100 cm 2 and VFA <100 cm 2 groups (Table 3).

Longitudinal changes
The UCLA-PCI urinary function score decreased early postimplantation, was the least at 3 months, and did not return to baseline even 24 months after implantation ( Figure 2a). The urinary function score was significantly lower from baseline 24 months post-treatment in the sarcopenia group than in the non-sarcopenia group with a non-significant interaction (p = 0.042, interaction p = 0.052) (Figure 2b). There was no significant difference in the urinary function score between the VFA ≥100 cm 2 and VFA <100 cm 2 groups (Figure 2c).
Total IPSS, voiding, and storage scores increased early post-implantation and peaked at 3 months. The total IPSS score returned to baseline more slowly than the voiding score post-implantation. The IPSS storage score did not return to baseline until 24 months post-implantation (Figure 3a-c). Total IPSS, storage, and voiding scores were not significantly different between the sarcopenia and non- The total IPSS score showed an interaction from baseline until 24 months post-implantation in the VFA ≥100 cm 2 and VFA <100 cm 2 groups (interaction p = 0.023). Meanwhile, the total IPSS score was significantly poorer from baseline until 12 months post-implantation in the VFA ≥100 cm 2 group than in the VFA <100 cm 2 group (p = 0.032 interaction p = 0.538) (Figure 3g).
The storage score showed an interaction from baseline until 24 months after implantation for the VFA ≥100 cm 2 and VFA <100 cm 2 groups (interaction p = 0.046).
Meanwhile, the storage score was significantly poorer from baseline until 12 months after implantation in the VFA ≥100 cm 2 than in the VFA <100 cm 2 group (p = 0.045 interaction p = 0.551) (Figure 3h).
There was no significant difference in the voiding score between the VFA ≥100 cm 2 and VFA <100 cm 2 groups from baseline until 24 months post-implantation, with the interaction being non-significant. Meanwhile, the voiding score was significantly poorer from baseline until 12 months postimplantation in the VFA ≥100 cm 2 group than in the VFA <100 cm 2 group (p = 0.049, interaction p = 0.620) (Figure 3i).      ≥100 cm 2 ) on QOL at 12 months. Statistically, sarcopenia significantly negatively impacted UCLA-PCI urinary function (Table 4); VFA ≥100 cm 2 significantly negatively impacted UCLA-PCI urinary function and total IPSS, storage, and voiding scores ( Table 5). The sarcopenia group had a higher proportion of clinically significant deterioration in UCLA-PCI than the nonsarcopenia group. The VFA ≥100 cm 2 group had a higher proportion of clinically significant deterioration in IPSS storage score than the VFA <100 cm 2 group (Table 6). Clinically, sarcopenia significantly negatively affected UCLA-PCI urinary function (Table 7); VFA ≥100 cm 2 significantly negatively impacted the storage and voiding scores (Table 8).

DISCUSSION
In this study, sarcopenia and excess visceral fat accumulation pre-LDB negatively affected urinary functional QOL early post-implantation. To the best of our knowledge, this is the first report on the clinical significance of sarcopenia and excess accumulation of visceral fat adversely affecting LUTS after LDB for PCA.
LUTS are one of the main adverse events for LDB, which are primarily evaluated by IPSS. 3,4,19 In these reports, IPSS was maximal at 1-3 months and returned to near baseline levels after 12-24 months. In this study, the storage score recovered more slowly than the voiding score. These results are consistent with those of a previous study. 19 Previous studies have described factors associated with the incidence and resolution of LUTS after LDB, such as baseline score, 20  IPSS voiding score (f) 16   Longitudinal changes in quality of life. The International Prostate Symptom Score (IPSS) total, storage, and voiding score (all cohorts) (a-c). All scores: mean scores, error bars: standard errors. *p < 0.05; **p < 0.01 (compared to baseline using Dunnett's multiple comparisons in all cohorts). IPSS total, storage, and voiding score (sarcopenia vs. non-sarcopenia) (d-f). IPSS total, storage, and voiding scores (visceral fat area [VFA] ≥100 cm 2 vs. VFA <100 cm 2 ) (g-i). All scores: mean scores, error bars: standard errors; standard errors were symmetric, but error bars are shown as one-sided to avoid overlap with mean scores. Two-way repeated measures analysis of variance (ANOVA) was used to compare longitudinal changes in the questionnaire scores between groups (sarcopenia vs. non-sarcopenia groups or VFA ≥100 cm 2 vs. VFA <100 cm 2 groups). The p-values for the group, time, and group-time interactions analyzed by two-way repeated measures ANOVA are shown. which may be useful because they can be evaluated in routine practice. In this study, sarcopenia was associated with the severity of baseline urinary function. Clinically, sarcopenia significantly negatively affected UCLA-PCI urinary function early post-LDB. UCLA-PCI urinary function score focuses primarily on urinary incontinence. In a cross-sectional study of elderly women, sarcopenia was associated with urinary incontinence, 23 and in a report on robot-assisted radical prostatectomy for PCA, reduced skeletal muscle size was reported to be related to postoperative urinary incontinence. 7 There are no reports on the association between sarcopenia and urinary incontinence in men treated with radiation therapy, including LDB, for PCA. All participants in this study were nonprostatectomized men, and prostate volume at the time of LDB was included as an adjustment factor in the multivariate analysis. Nevertheless, sarcopenia was significantly associated with worse UCLA-PCI urinary scores, indicating urinary    incontinence. To understand the association between sarcopenia and urinary incontinence, it may be helpful to note that skeletal muscle is a secretory organ. Cytokines, called myokines, are secreted by skeletal muscle after exercise and are believed to affect a variety of organs, including adipose tissue, the brain, liver, bones, and the immune system. 24 However, at present, there are no reports of myokine-mediated crosstalk between skeletal muscle and the bladder/prostate, and further studies are needed. Clinically, excess visceral fat accumulation significantly negatively affected IPSS storage and voiding scores early post-LDB. A cross-sectional study on men reported an association between OAB and VFA. 25 Other cross-sectional studies reported that abdominal circumference and BMI were not associated with the prevalence of OAB; however, excessive VFA was an independent risk factor for OAB. 26 Excessive visceral fat accumulation induces oxidative stress and organ ischemia, leading to LUTS. 27 Insulin resistance resulting from excessive accumulation of visceral fat is also reported to cause chronic sympathetic overactivity and ischemia of the lower urinary tract. 28 These studies on the relationship between excessive accumulation of visceral fat and LUTS support the results of this study.
The UCLA-PCI urinary function score after LDB had statistically significant adverse effects from both sarcopenia and excess accumulation of visceral fat. Inflammatory cytokines produced by the accumulation of visceral fat, such as tumor necrosis factor-a and leptin, are implicated in the development and progression of sarcopenia. Excessive accumulation of visceral fat exacerbates sarcopenia, leading to decreased physical activity and, therefore, decreased energy expenditure, increased insulin resistance, and further accumulation of visceral fat. Thus, excessive accumulation of visceral fat and sarcopenia can synergistically exacerbate the disease state. 29 Simultaneous assessment of sarcopenia and excess accumulation of visceral fat may lead to a better understanding of QOL changes after LDB. However, no QOL questionnaire results in the present study showed clinically significant adverse effects of both sarcopenia and excess visceral fat accumulation in the multivariate analysis, and further investigation is needed.
This study has several limitations. First, this was a singlecenter retrospective study with a small number of subjects. Second, not all medications that may affect urinary function after LDB were strictly monitored. Third, we assessed sarcopenia of the muscle mass using CT imaging. However, muscle mass may not correlate with muscle strength, leading to possible inadequate assessment of the effect of muscle strength on LUTS. 30 For more precise identification of sarcopenic patients, assessment methods such as grip strength tests and walking speed measurements are needed. Fourth, this study only evaluated pre-treatment body composition data. Excessive accumulation of visceral fat and sarcopenia are progressive diseases that interact with each other and are influenced by internal and external factors.
Despite these limitations, this is significant as it is the first report to suggest that sarcopenia and excess visceral fat accumulation may adversely affect LUTS after LDB. Additionally, these indicators can be evaluated in routine practice.
Although most studies are cross-sectional, this study is meaningful because it employs a longitudinal evaluation. Our results may lead to a better understanding of the post-LDB processes. Subsequently, we plan to objectively analyze this using uroflowmetry. In conclusion, sarcopenia and excess visceral fat accumulation pre-LDB negatively affected urinary function early post-implantation, especially at 12 months.