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Quantitative analysis of genitourinary toxicity after iodine-125 brachytherapy for localized prostate cancer: Followup of the International Prostate Symptom Score and Overactive Bladder Symptom Score
Brachytherapy
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Quantitative analysis of genitourinary toxicity after iodine-125 brachytherapy for localized prostate cancer: Followup of the International Prostate Symptom Score and Overactive Bladder Symptom Score Masanori Sakayori1, Toshio Ohashi1,2,*, Tetsuo Momma3, Tomoya Kaneda1, Shuichi Nishimura1, Shinya Sutani1, Shoji Yamashita2, Naoyuki Shigematsu1 2
1 Department of Radiology, Keio University School of Medicine, Tokyo, Japan Department of Radiology, National Hospital Organization Saitama Hospital, Saitama, Japan 3 Department of Urology, National Hospital Organization Saitama Hospital, Saitama, Japan
ABSTRACT
PURPOSE: To analyze genitourinary toxicity by followup of the International Prostate Symptom Score (IPSS) and Overactive Bladder Symptom Score (OABSS) after prostate brachytherapy. METHODS AND MATERIALS: Six hundred eighty patients were treated with iodine-125 brachytherapy for localized prostate cancer. IPSS, OABSS, and two categories of IPSS questions (storage symptom score [IPSS-S] and voiding symptom score [IPSS-V]) were evaluated. RESULTS: The median followup was 54 months (range, 24e108). All scales showed rapid increases followed by gradual decreases. The median times to IPSS peak and resolution were 1 and 6 months, respectively. The resolution rates of IPSS, IPSS-S, IPSS-V, and OABSS at the last followup were 84.2%, 86.3%, 89.5%, and 83.0%, respectively. The difference between IPSS baseline and peak was greater for larger preimplant prostate volumes ($25 mL, p 5 0.004). The time to resolution was longer for higher biologic effective dose (BED) ($210 Gy, p 5 0.019 [IPSS]), in those with larger prostate volumes ($25 mL, p 5 0.025 [OABSS]), in younger patients (younger than 70 years, p 5 0.043 [IPSS-S]), and in those with androgen deprivation therapy (ADT) use ( p 5 0.049 [IPSS-V]). Urge incontinence, included in the OABSS, was observed more commonly in older patients (75 years and older, p 5 0.018), with ADT use ( p ! 0.001), and for higher BED ($210 Gy, p 5 0.006). CONCLUSIONS: The IPSS and OABSS showed similar patterns of change. Urinary symptoms improved more rapidly in those with high baseline IPSS levels. The OABSS was useful for following urinary symptoms after prostate brachytherapy. Age, ADT use, preimplant prostate volume, and BED were significantly associated with urinary outcomes. Ó 2017 American Brachytherapy Society. Published by Elsevier Inc. All rights reserved.
Keywords:
Prostate cancer; Brachytherapy; Toxicity; IPSS; OABSS
Introduction Prostate cancer is one of the most frequently diagnosed cancers in developed countries. In Japanese men, it is the sixth leading cause of death (1). Its morbidity is surpassed Received 2 March 2017; received in revised form 18 April 2017; accepted 18 April 2017. Conflict of interest: The authors report no proprietary or commercial interest in any product mentioned or concept discussed in this article. Financial disclosure: This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors. * Corresponding author. Department of Radiology, Keio University School of Medicine, 35 Shinanomachi, Shinjuku-ku, Tokyo 160-8582, Japan. Tel.: þ81-3-3353-1211; fax: þ81-3-3359-7425. E-mail address: [email protected] (T. Ohashi).
only by that of gastric cancer, and it is expected to continue to increase in the future. In recent years, iodine-125 brachytherapy (permanent seed implantation [PI]) with or without external beam radiotherapy (EBRT) has been one of the standard definitive radiotherapies for localized prostate cancer. However, genitourinary (GU) toxicity is a frequent adverse event associated with prostate radiotherapy and can severely affect patients’ quality of life. Clinical factors related to late GU and gastrointestinal (GI) toxicities have been reported previously (2). Of all patients, 12.7% and 0.6% of patients developed late Grade 2 and Grade 3 GU toxicities, respectively. In addition, late Grade $2 GU toxicity was significantly more common in patients who underwent PI (PI alone and PI þ EBRT) than in those
1538-4721/$ - see front matter Ó 2017 American Brachytherapy Society. Published by Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.brachy.2017.04.241
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undergoing conventional radiotherapy or EBRT (intensitymodulated radiotherapy) alone. In subgroup analysis, a higher biologic effective dose (BED) was associated with greater late Grade $2 GU toxicity. Therefore, in the present study, we focused on the importance of PI-related GU toxicity and reviewed the urinary symptom scales after PI. The International Prostate Symptom Score (IPSS) is the most widely used scale to assess urinary symptoms, and several studies have reported IPSS followup after PI. In 1992, the IPSS was validated by the American Urological Association for the evaluation of the lower urinary tract symptoms of benign prostate hyperplasia (3). The IPSS includes seven questions that are subdivided into two categories, including the storage (IPSS-S: 2, frequency; 4, urgency; and 7, nocturia) and voiding (IPSS-V: 1, incomplete emptying; 3, intermittency; 5, weak stream; and 6, straining) symptom scores. All these symptoms might occur after prostate radiotherapy; however, voiding symptoms are relatively infrequent and clinically inconsequential in everyday clinical practice. The Overactive Bladder Symptom Score (OABSS) is a relatively new scale that, although validated in 2006, has not yet been used (4). Details of the OABSS are given in Table 1. The OABSS evaluates overactive bladder symptoms rather than their effects on daily life, which are evaluable using the previously reported scales, including the Patient Perception of Bladder Condition, Primary Overactive Bladder Symptom Questionnaire, Overactive Bladder Questionnaire, Urgency Questionnaire, and Indevus Urgency Severity Scale (5e8). The reliability and validity of the English version of the OABSS have been demonstrated previously (9). Table 1 Overactive Bladder Symptom Score Question
Frequency
Score
How many times do you typically urinate from waking in the morning until sleeping at night? How many times do you typically wake up to urinate from sleeping at night until waking in the morning? How often do you have a sudden desire to urinate, which is difficult to defer?
#7 8e14 $15
0 1 2
0 1 2 $3
0 1 2 3
How often do you leak urine because you cannot defer the sudden desire to urinate?
Not at all Less than once a week Once a week or more About once a day 2e4 times a day 5 times a day or more Not at all Less than once a week Once a week or more About once a day 2e4 times a day 5 times a day or more
0 1 2 3 4 5 0 1 2 3 4 5
Patients were instructed to circle the score that best applied to their urinary condition during the past week; the overall score was the sum of the four scores.
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Compared with the IPSS, the OABSS mainly focuses on urinary storage symptoms and does not exclusively require information concerning obstructive symptoms related to urinary voiding. Overactive bladder is defined by the International Continence Society as urgency, with or without urge incontinence, usually with frequency and nocturia (10). The OABSS consists of four questions related to storage symptoms, such as daytime voiding, nighttime voiding, urgency, and urge incontinence (Table 1). Furthermore, the recall duration of the OABSS is the past 7 days, whereas that of the IPSS is the past month. The Urgency Questionnaire queries patients’ symptoms and their effects on daily life, and it includes more than 15 questions, which the patient may find complicated. Focusing on these points, in addition to IPSS, we adopted the OABSS to assess urinary symptoms. We hypothesized that the OABSS would be more suitable for evaluating urinary symptoms after prostate radiotherapy and easier for patients to complete. To our knowledge, this is the first report concerning the use of the OABSS after PI, although a few reports have noted that the suitability of the OABSS to diagnose and evaluate urinary symptoms is equivalent to that of the IPSS (4, 11e13). The aim of the present study was to analyze PI-related GU toxicity using the IPSS and OABSS and evaluate the usefulness of the OABSS for this purpose.
Methods and materials Patient characteristics From March 2007 to January 2014, 734 patients underwent PI for localized prostate cancer at our hospital. Of these patients, 54 were excluded because of incomplete followup. Finally, 680 patients with a minimum followup of 24 months were included. No patients in the present study underwent transurethral prostate resections before PI. The institutional review board approved this study. Treatment and followup PI was performed with iodine-125 seeds using the ultrasonography-guided intraoperative transperineal technique (14). The prescribed minimum peripheral doses were 160 Gy for PI alone and 110 Gy for PI þ EBRT. EBRT was administered (45 Gy in 1.8 Gy fractions) to the prostate and seminal vesicles within ~1 month after PI, using conventional radiotherapy or intensity-modulated radiotherapy. Androgen deprivation therapy (ADT) consisted of a luteinizing hormoneereleasing hormone agonist with or without an antiandrogen. Neoadjuvant ADT was administered to 218 patients (32.2%), depending on the need to reduce prostate volume and/or for anticancer effects. Twenty-eight patients (4.1%) underwent adjuvant ADT for 6 months in addition to neoadjuvant ADT. Most patients were routinely initiated on alpha-1 blockers after PI.
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Both IPSS and OABSS self-reporting scales were obtained from all patients routinely. The scales were assessed at pretreatment; at 0.5, 1, 3, 6, 9, 12, 18, 24, 30, and 36 months after radiotherapy; and annually thereafter. Outcome criteriaddefinition of events
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Statistical analyses were performed using SPSS software, version 22.0 (SPSS Inc., Chicago, IL). All analyses used two-sided statistical tests, and p-value of !0.05 was deemed statistically significant.
Results
The peak of each scale was defined as the maximum score recorded within 12 months after radiotherapy. Four definitions of the IPSS resolution were used: a return to the baseline score (0 point), within the baseline score þ1 point, þ2 points, and þ3 points. Resolutions of IPSS-V, IPSS-S, and OABSS were defined as a return to the baseline score (0 point).
Patient characteristics The patient characteristics and treatment parameters are listed in Table 2. The PI-alone group consisted of 384 patients (56.5%), and the PI þ EBRT group consisted of 296 patients (43.5%). The median followup duration was 54 months (range, 24e108), and 316 patients (46.5%) were followed for 5 years or more.
Statistical analyses The following covariates were analyzed: age, diabetes mellitus, ADT use, preimplant prostate volume, and BED. The ManneWhitney U test and multiple regression analysis were used to evaluate the difference between the peak and baseline of the IPSS and OABSS. Time-to-event (resolution) curves were described using the KaplaneMeier method and compared using the log-rank test. The effects of covariates were assessed using the Cox proportional hazards model. Logistic regression analysis was used to evaluate urge incontinence.
Outcomes of followup The actual questionnaire completion rates of IPSS and OABSS were both 95.4%. The median score and the changes from baseline of the IPSS, IPSS-S, IPSS-V, and OABSS are shown in Fig. 1. Scores increased significantly between 0.5 and 3 months after treatment. The median time to peak was 1 month for each scale, and the scores decreased gradually thereafter. Urinary symptoms improved more rapidly in those with high baseline IPSS levels.
Table 2 Patient characteristics Treatment modality Characteristics Age (y), median (range) Followup time (mo) Median (range) Preimplant prostate volume (mL) Median (range) Preimplant prostate volume, n (%) !25 mL #25 to !30 mL $30 mL Gleason score, n (%) !7 7 O7 Risk classification, n (%) Low Intermediate High Initial PSA (ng/mL) Median (range) Baseline IPSS, n (%) Mild (#7 points) Intermediate (8e19 points) Severe ($20 points) ADT, n (%) Diabetes mellitus, n (%) BED (Gy), median (range)
Overall (n 5 680)
Monotherapy (PI alone) (n 5 384)
Combined therapy (PI þ EBRT) (n 5 296)
70 (51e82)
69 (51e82)
72 (53e82)
54 (24e108)
54 (24e108)
54 (24e96)
23.0 (7.0e41.4)
24.1 (7.00e40.4)
21.4 (8.50e41.4)
410 (60.3) 160 (23.5) 109 (16.0)
206 (53.6) 101 (26.3) 76 (19.8)
204 (68.9) 59 (19.9) 33 (11.1)
561 (82.5) 57 (8.4) 62 (9.1)
383 (99.7) 1 (0.3) 0 (0.0)
178 (60.1) 56 (18.9) 62 (20.9)
330 (48.5) 254 (37.4) 96 (14.1)
294 (76.6) 88 (22.9) 2 (0.5)
36 (12.2) 166 (56.1) 94 (31.8)
6.90 (2.30e48.0)
6.00 (3.10e48.0)
10.2 (2.30e46.9)
381 250 42 218 68 213.9
(56.6) (37.1) (6.2) (32.2) (10.0) (152.0e259.4)
222 130 28 103 29 205.0
(57.8) (33.9) (7.3) (26.8) (7.6) (152.0e259.4)
159 120 14 115 39 220.7
(53.7) (40.5) (4.7) (38.9) (13.2) (188.8e244.5)
PI 5 permanent seed implantation; EBRT 5 external beam radiotherapy; PSA 5 prostate-specific antigen; IPSS 5 International Prostate Symptom Score; ADT 5 androgen deprivation therapy; BED 5 biologic effective dose.
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Fig. 1. Median score and change from baseline of urinary symptom scales. (a) International Prostate Symptom Score (IPSS), (b) IPSS change from baseline, (c) IPSS storage symptom score (IPSS-S), (d) IPSS-S change from baseline, (e) IPSS voiding symptom score (IPSS-V), (f) IPSS-V change from baseline, (g) Overactive Bladder Symptom Score (OABSS), and (h) OABSS change from baseline. All scales are shown in subgroups of baseline IPSS level (mild [0e7 points], intermediate [8e19 points], and severe group [$20 points]).
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Rates of IPSS resolution (within baseline 0, þ1, þ2, and þ3 points) were 74.9%, 79.1%, 82.1%, and 84.0%, respectively, at 12 months; 83.2%, 89.0%, 92.8%, and 94.4%, respectively, at 36 months; and 83.8%, 89.6%, 93.2%, and 95.1%, respectively, at the last followup. Rates of IPSS-S, IPSS-V, and OABSS resolutions were 66.5%, 66.6%, and 71.2%, respectively, at 12 months; 84.3%, 87.5%, and 81.0%, respectively, at 36 months; and 86.5%, 89.4%, and 83.1%, respectively, at the last followup. The median times to resolution were 6 months for IPSS and OABSS and 9 months for IPSS-S and IPSS-V. Differences between peak and baseline On multivariate analysis (MVA), differences between peak and baseline values were significantly greater in those with a larger prostate volume ($25 mL, p 5 0.004 [IPSS], 0.020 [IPSS-S], 0.008 [IPSS-V], and 0.023 [OABSS]). A subgroup analysis of the mild IPSS group revealed that the difference between peak and baseline levels was greater in those with a larger prostate volume ($25 mL, p 5 0.033 [IPSS], 0.017 [IPSS-S], and 0.045 [OABSS]) and in those who received ADT ( p 5 0.021 [IPSS-S] and 0.016 [OABSS]). Score resolution delay On MVA, the time to resolution was significantly longer in the higher BED group ($210 Gy, p 5 0.019 [IPSS baseline 0 point]; Fig. 2a), in those with larger prostate volumes ($25 mL, p 5 0.025 [OABSS]; Fig. 2b), in younger patients (younger than 70 years, p 5 0.043 [IPSS-S]), and in those using ADT ( p 5 0.049 [IPSS-V]) (Table 3). Concordance rates between the times to resolution of IPSS and OABSS In most cases, the peaks of IPSS and OABSS were both within 3 months of radiotherapy. In contrast, in some cases, the times to resolution of the two scales differed.
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The proportions of patients who achieved both IPSS and OABSS resolutions until the last followup were 75.8% (IPSS [baseline 0 point]), 80.0% (IPSS-S), and 76.7% (IPSS-V). Of these patients, the exact concordance rates (the same times to resolution of IPSS and OABSS) were 32.0%, 30.1%, and 23.6%. The nearly concordance rates (within a difference of 6 months) were 75.6%, 72.4%, and 64.2%. Analysis of urge incontinence In contrast to the IPSS, the OABSS includes a question about urge incontinence. Overall, urinary urgency, urge incontinence, and urge incontinence once a day or more were seen in 93.8%, 66.5%, and 28.8% of patients, respectively (Table 4). On MVA, older age (75 years and older, p 5 0.018), ADT use ( p ! 0.001), and a higher BED ($210 Gy, p 5 0.006) were significant risk factors for urge incontinence. ADT use ( p ! 0.001) and larger prostate volumes ($25 mL, p 5 0.031) were significant risk factors for urge incontinence once a day or more.
Discussion The present study indicated that urinary symptoms worsened rapidly within 3 months and resolved gradually within ~12 months. Several studies have reported IPSS changes after PI (15e23). An initial Japanese study evaluating IPSS serial changes reported similar results (16). Neill et al. (24) found that IPSS resolution (two points above baseline) was achieved in 72.2% and 83.3% of patients by 12 and 24 months, respectively. In the present study, IPSS resolution was achieved in 82.1% and 91.9% of patients by 12 and 24 months, respectively. Stone et al. (15) reported the resolution rates at 24 months regarding the baseline IPSS as 39.4%, 59.5%, and 83.3% in the mild, intermediate, and severe groups, respectively. In the present study, the
Fig. 2. Cumulative incidence of score resolution. (a) International Prostate Symptom Score (IPSS). Open circles indicate the resolution time in the biologic effective dose (BED) !210 Gy group, whereas plus symbols indicate that of the $210 Gy group. (b) Overactive Bladder Symptom Score (OABSS). Open circles indicate the resolution time in the preimplant prostate volume !25 mL group, whereas plus symbols indicate that of the $25 mL group.
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Table 3 Factors predicting longer time to resolution, using log-rank test and Cox proportional hazards model Log-rank test
Factor Time to IPSS resolution (baseline 0 point) Age (younger than 70 y) Diabetes mellitus (yes vs. no) ADH (yes vs. no) Initial prostate volume ($25 mL) BED ($210 Gy) Time to IPSS-S resolution Age (younger than 70 y) Diabetes mellitus (yes vs. no) ADH (yes vs. no) Initial prostate volume ($25 mL) BED ($210 Gy) Time to IPSS-V resolution Age (younger than 70 y) Diabetes mellitus (yes vs. no) ADH (yes vs. no) Initial prostate volume ($25 mL) BED ($210 Gy) Time to OABSS resolution Age (younger than 70 y) Diabetes mellitus (yes vs. no) ADH (yes vs. no) Initial prostate volume ($25 mL) BED ($210 Gy)
Cox proportional hazards model Univariate analysis
MVA
p
p
Hazard ratio (95% CI)
p
Hazard ratio (95% CI)
0.46 0.723 0.722 0.918 0.009a
0.511 0.753 0.752 0.927 0.021a
0.946 1.045 0.972 0.992 0.822
(0.802e1.116) (0.796e1.371) (0.815e1.159) (0.840e1.172) (0.696e0.971)
0.682 0.555 0.585 0.723 0.019a
0.966 1.086 0.952 0.970 0.815
(0.817e1.142) (0.826e1.428) (0.797e1.137) (0.819e1.149) (0.688e0.966)
0.04a 0.766 0.872 0.223 0.168
0.063 0.787 0.884 0.188 0.212
1.169 1.038 1.013 0.895 0.901
(0.991e1.377) (0.793e1.358) (0.852e1.204) (0.758e1.056) (0.764e1.061)
0.043a 0.646 0.947 0.169 0.112
1.187 1.066 0.994 0.889 0.874
(1.006e1.401) (0.813e1.397) (0.834e1.184) (0.752e1.051) (0.740e1.032)
0.7 0.416 0.04a 0.702 0.061
0.728 0.464 0.065 0.872 0.092
0.972 1.105 0.850 1.013 0.870
(0.828e1.141) (0.846e1.443) (0.716e1.010) (0.862e1.192) (0.740e1.023)
0.853 0.287 0.049a 0.911 0.068
0.985 1.158 0.840 0.991 0.857
(0.837e1.159) (0.884e1.516) (0.707e0.999) (0.841e1.167) (0.726e1.011)
0.452 0.576 0.4 0.002a 0.409
0.497 0.614 0.447 0.02a 0.456
1.059 1.073 1.071 0.818 0.938
(0.897e1.252) (0.816e1.411) (0.898e1.277) (0.691e0.969) (0.794e1.109)
0.398 0.513 0.606 0.025a 0.285
1.075 1.096 1.048 0.823 0.912
(0.909e1.273) (0.832e1.445) (0.877e1.253) (0.694e0.976) (0.771e1.080)
MVA 5 multivariate analysis; CI 5 confidence interval; IPSS 5 International Prostate Symptom Score; ADT 5 androgen deprivation therapy; BED 5 biologic effective dose; IPSS-S 5 International Prostate Symptom Score (storage symptom score); IPSS-V 5 International Prostate Symptom Score (voiding symptom score); OABSS 5 Overactive Bladder Symptom Score. a Significant.
percentages of patients achieving resolution at 24 months were much greater, at 86.6%, 94.8%, and 100% in the mild, intermediate, and severe groups, respectively. Although the results of these studies cannot be compared directly because of the differences in PI conditions, the findings in the present study are similar to those reported previously. In the present study, a lower baseline IPSS and OABSS resulted in a longer time to resolution. It is notable that, in the higher baseline groups, urinary symptoms improved to levels below the baseline and improved earlier than those in the mild and intermediate baseline groups, which was congruent with several previous studies (21, 25, 26). In the present series, a higher BED resulted in score resolution delay and more frequent urge incontinence. This was concordant with a previous study that indicated that the late GU/GI toxicity risk could be explained by the total radiation dose to the GU/GI tract (2). Likewise, several other reports have indicated correlations between a greater prostate dose and poorer urinary symptoms (22, 27e30). The OABSS changes in the present study were similar to the changes seen with other scales. The OABSS resolution rates were 71.2% and 81.0% at 12 and 36 months, respectively. Of the patients who achieved both IPSS and OABSS resolutions, the concordance rates between the times to resolution of IPSS and OABSS (within a difference of
6 months) were 75.6%, 72.4%, and 64.2%. Initially, there was a concern that, because of its simplicity and lower total score, the OABSS might have differed significantly from the IPSS. However, the OABSS showed similar change patterns and relatively high concordance rates with the time to resolution of the IPSS. These findings indicate the usefulness of the OABSS and the possibility of the substitution of the OABSS for the IPSS. However, it remains doubtful whether the OABSS truly reflects the symptoms after PI. Hikita et al. (31) found significant differences between the OABSS and the score derived from a bladder diary. In the present study, a bladder diary was not assessed; therefore, there is a possibility of overestimation or underestimation of the OABSS in the present study. IPSS and OABSS are both patient-reported questionnaires rather than physician-reported scores, and it has been suggested that subjective toxicities are often underevaluated by physicians, even in prospective studies (32). Presently, we believe that both OABSS and IPSS reflect urinary symptoms directly. In the present study, OABSS was not inferior to IPSS in evaluating urinary symptoms after PI. Two previous studies have verified a correlation between OABSS and IPSS-S, and although the conclusions of these studies remain controversial, both reports included men and women and
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Table 4 Factors predicting urinary incontinence, using logistic regression analysis Urinary incontinence Univariate analysis Factor
p
Urinary incontinence once a day or more MVA
Univariate analysis
Odds ratio (95% CI) p a
Age (75 y and older) 0.003 Diabetes mellitus 0.199 (yes vs. no) ADH (yes vs. no) !0.001a Initial prostate 0.249 volume ($25 mL) BED ($210 Gy) 0.009a
1.869 (1.236e2.825) 1.447 (0.824e2.544)
Odds ratio (95% CI) p a
0.018 0.395
1.675 (1.093e2.566) 1.289 (0.718e2.313)
MVA
Odds ratio (95% CI) p 0.182 0.334
1.301 (0.884e1.914) 1.300 (0.763e2.214)
Odds ratio (95% CI) 0.389 0.433
1.192 (0.799e1.780) 1.246 (0.720e2.156)
2.613 (1.787e3.820) !0.001a 2.698 (1.832e3.973) !0.001a 2.407 (1.701e3.405) !0.001a 2.316 (1.633e3.285) 1.213 (0.873e1.685) 0.096 1.335 (0.950e1.877) 0.106 1.320 (0.943e1.848) 0.031a 1.466 (1.036e2.077) 1.542 (1.116e2.130)
0.006a 1.603 (1.147e2.242)
0.905
1.021 (0.727e1.432)
0.749
1.059 (0.745e1.506)
MVA 5 multivariate analysis; CI 5 confidence interval; ADT 5 androgen deprivation therapy; BED 5 biologic effective dose. a Significant.
were not limited to PI-related GU toxicity (11, 12). Further investigation would be needed for a thorough evaluation of the comparison of the scoring systems for PI-related GU toxicity. It is interesting that urge incontinence is evaluable when using the OABSS. However, because urge incontinence is not included in the Radiation Therapy Oncology Group urinary toxicity scales (33), there are limited data available. Zelefsky et al. (27) found incontinence requiring pad use in !1% of 367 patients, and Crook et al. (17) found urgency and/or urge incontinence in 6.4% of 484 patients. In the present study, the urinary urgency (93.8%), urge incontinence (66.5%), and urge incontinence once a day or more (28.8%) rates were much higher. These surprisingly high rates of incontinence might indicate the potential effectiveness of the OABSS in revealing the impairment of patients’ quality of life. However, the results cannot be compared directly because Zelefsky et al. (27) and Crook et al. (17) included PI-alone patients, and the BEDs were lower than those in the present study. This difference could also be because of a discrepancy in the understanding of the term incontinence between different patient groups. For example, patients might not be aware of the different types of incontinence (urge, stress, and overflow incontinence). In addition, different definitions might be used between studies; for example, the use of incontinence pads was not taken into consideration in the present study. Furthermore, in grading the severity of incontinence, Crook et al. (17) evaluated whether anticholinergics were prescribed, whereas the present study did not take this into consideration. One point from the present findings is worthy of further discussion. Keyes et al. (26) reported that ADT use was independently predictive for more acute and less late Radiation Therapy Oncology Group urinary toxicity and that patients who did not use ADT but who had acute toxicity showed the worst IPSS resolution. Stone et al. (15) reported that a lack of ADT use predicted a greater IPSS change from baseline. To some extent, their results are inconsistent with the findings of the present study regarding worse urinary toxicity when ADT was not prescribed. Although the
effect of ADT remains controversial, this inconsistency might be the result of differences in the pretreatment prostate volume between the present study and those of Keyes et al. (26) and Stone et al. (15). A larger prostate volume can increase the efficacy of ADT and result in greater improvements in urinary toxicities. The reasons for ADT use in these patients should also be noted, which would usually be to reduce the prostate size or to control the disease (34, 35). In the present study, 28 patients (4.1%) received adjuvant ADT in addition to neoadjuvant ADT. However, because the number of the patients was small, we did not use adjuvant ADT as a separate clinical factor. This point is a limitation to the present study. Further investigation will be needed with a larger number of patients. There are several additional limitations. First, the study design was retrospective and conducted at a single institution. Second, PI was performed with separate seeds using the Mick applicator (Mick Radio-Nuclear Instruments, Mount Vernon, NY). Recently, in Japan, linked seeds have been introduced and became more popular. Therefore, the present results might not be comparable with those using other seed types. Finally, the definition of IPSS resolution has not been clearly determined, and several definitions exist (16e18, 36). In the present study, IPSS resolution was defined as a return to the baseline (0 point) and being within þ1, þ2, or þ3 points of baseline. Using various definitions for the same score might make interpretation of the results more complicated. However, several definitions have been used in this field. For this reason, we adopted four definitions of IPSS resolution in our investigation. We found no major differences between the definitions. In contrast, IPSS-S, IPSS-V, and OABSS resolutions were defined as a return to baseline (0 point) alone. These points should be taken into consideration when comparing the data with those from previous reports.
Conclusion This study evaluated long-term IPSS and OABSS changes in Japanese patients with prostate cancer who
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underwent PI. Both scales showed similar patterns of change. In the higher baseline IPSS group, urinary symptoms were the first to improve below the baseline level. OABSS, a simple scale that includes only four questions, was useful for following urinary symptoms and allowed the evaluation of urge incontinence. Age, ADT use, preimplant prostate volume, and BED had a significant impact on urinary outcomes after PI. Acknowledgments We thank Editage (www.editage.jp) for English language editing. References [1] Cancer Registry and Statistics. Cancer Information Service, National Cancer Center, Japan. Available at: http://ganjoho.jp/en/index.html. Accessed March 2, 2017. [2] Sutani S, Ohashi T, Sakayori M, et al. Comparison of genitourinary and gastrointestinal toxicity among four radiotherapy modalities for prostate cancer: Conventional radiotherapy, intensity-modulated radiotherapy, and permanent iodine-125 implantation with or without external beam radiotherapy. Radiother Oncol 2015;117: 270e276. [3] Barry MJ, Fowler FJ Jr, O’Leary MP, et al. The American Urological Association Symptom Index for benign prostatic hyperplasia. The Measurement Committee of the American Urological Association. J Urol 1992;148:1549e1557. discussion 1564. [4] Homma Y, Yoshida M, Seki N, et al. Symptom assessment tool for overactive bladder syndromeeoveractive bladder symptom score. Urology 2006;68:318e323. [5] Coyne KS, Matza LS, Thompson CL. The responsiveness of the Overactive Bladder Questionnaire (OAB-q). Qual Life Res 2005;14: 849e855. [6] Matza LS, Thompson CL, Krasnow J, et al. Test-retest reliability of four questionnaires for patients with overactive bladder: The overactive bladder questionnaire (OAB-q), patient perception of bladder condition (PPBC), urgency questionnaire (UQ), and the primary OAB symptom questionnaire (POSQ). Neurourol Urodyn 2005;24: 215e225. [7] Zinner N, Harnett M, Sabounjian L, et al. The overactive bladdersymptom composite score: A composite symptom score of toilet voids, urgency severity and urge urinary incontinence in patients with overactive bladder. J Urol 2005;173:1639e1643. [8] Nixon A, Colman S, Sabounjian L, et al. A validated patient reported measure of urinary urgency severity in overactive bladder for use in clinical trials. J Urol 2005;174:604e607. [9] Homma Y, Fujimura T. Psychometric validation of the English version of the overactive bladder symptom score. Urology 2014;84: 46e50. [10] Abrams P, Cardozo L, Fall M, et al. The standardisation of terminology of lower urinary tract function: Report from the Standardisation Sub-committee of the International Continence Society. Neurourol Urodyn 2002;21:167e178. [11] Hsiao SM, Lin HH, Kuo HC. International Prostate Symptom Score for assessing lower urinary tract dysfunction in women. Int Urogynecol J 2013;24:263e267. [12] Shim JS, Kim JH, Choi H, et al. Diagnostic tool for assessing overactive bladder symptoms: Could the International Prostate Symptom Storage Subscore replace the Overactive Bladder Symptom Score? Int Neurourol J 2016;20:209e213.
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[13] Kubota Y, Kojima Y, Shibata Y, et al. Correlation between improvements in Overactive Bladder Symptom Score and healthrelated quality of life questionnaires in overactive bladder patients treated with an antimuscarinic drug. Neurourol Urodyn 2011;30: 1309e1314. [14] Ohashi T, Yorozu A, Toya K, et al. Comparison of intraoperative ultrasound with postimplant computed tomographyddosimetric values at Day 1 and Day 30 after prostate brachytherapy. Brachytherapy 2007;6:246e253. [15] Stone NN, Gerber NK, Blacksburg S, et al. Factors influencing urinary symptoms 10 years after permanent prostate seed implantation. J Urol 2012;187:117e123. [16] Ohashi T, Yorozu A, Toya K, et al. Serial changes of international prostate symptom score following I-125 prostate brachytherapy. Int J Clin Oncol 2006;11:320e325. [17] Crook J, Fleshner N, Roberts C, et al. Long-term urinary sequelae following 125iodine prostate brachytherapy. J Urol 2008;179:141e 145. discussion 146. [18] Williams SG, Millar JL, Duchesne GM, et al. Factors predicting for urinary morbidity following 125iodine transperineal prostate brachytherapy. Radiother Oncol 2004;73:33e38. [19] Tanaka N, Fujimoto K, Hirao Y, et al. Variations in international prostate symptom scores, uroflowmetric parameters, and prostate volume after (125)I permanent brachytherapy for localized prostate cancer. Urology 2009;74:407e411. [20] Merrick GS, Butler WM, Lief JH, et al. Temporal resolution of urinary morbidity following prostate brachytherapy. Int J Radiat Oncol Biol Phys 2000;47:121e128. [21] Aaltomaa SH, Kataja VV, Lahtinen T, et al. Eight years experience of local prostate cancer treatment with permanent I125 seed brachytherapydmorbidity and outcome results. Radiother Oncol 2009;91: 213e216. [22] Stone NN, Stock RG. Long-term urinary, sexual, and rectal morbidity in patients treated with iodine-125 prostate brachytherapy followed up for a minimum of 5 years. Urology 2007;69:338e342. [23] Li X, Fang D, Cooperberg MR, et al. Long-term follow-up of International Prostate Symptom Score (IPSS) in men following prostate brachytherapy. World J Urol 2014;32:1061e1066. [24] Neill M, Studer G, Le L, et al. The nature and extent of urinary morbidity in relation to prostate brachytherapy urethral dosimetry. Brachytherapy 2007;6:173e179. [25] Gutman S, Merrick GS, Butler WM, et al. Severity categories of the International Prostate Symptom Score before, and urinary morbidity after, permanent prostate brachytherapy. BJU Int 2006;97:62e68. [26] Keyes M, Miller S, Moravan V, et al. Predictive factors for acute and late urinary toxicity after permanent prostate brachytherapy: Longterm outcome in 712 consecutive patients. Int J Radiat Oncol Biol Phys 2009;73:1023e1032. [27] Zelefsky MJ, Yamada Y, Cohen GN, et al. Five-year outcome of intraoperative conformal permanent I-125 interstitial implantation for patients with clinically localized prostate cancer. Int J Radiat Oncol Biol Phys 2007;67:65e70. [28] Van Gellekom MP, Moerland MA, Van Vulpen M, et al. Quality of life of patients after permanent prostate brachytherapy in relation to dosimetry. Int J Radiat Oncol Biol Phys 2005;63: 772e780. [29] Salem N, Simonian-Sauve M, Rosello R, et al. Predictive factors of acute urinary morbidity after iodine-125 brachytherapy for localised prostate cancer: A phase 2 study. Radiother Oncol 2003; 66:159e165. [30] Stock RG, Stone NN, Dahlal M, et al. What is the optimal dose for 125I prostate implants? A dose-response analysis of biochemical control, posttreatment prostate biopsies, and long-term urinary symptoms. Brachytherapy 2002;1:83e89.
M. Sakayori et al. / Brachytherapy [31] Hikita KS, Honda M, Hirano S, et al. Comparison of the overactive bladder symptom score and the overactive bladder symptom score derived from the bladder diaries. Neurourol Urodyn 2016;35: 349e353. [32] Di Maio M, Gallo C, Leighl NB, et al. Symptomatic toxicities experienced during anticancer treatment: Agreement between patient and physician reporting in three randomized trials. J Clin Oncol 2015;33: 910e915. [33] Lawton CA, Won M, Pilepich MV, et al. Long-term treatment sequelae following external beam irradiation for adenocarcinoma of the prostate: Analysis of RTOG studies 7506 and 7706. Int J Radiat Oncol Biol Phys 1991;21:935e939.
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[34] Niehaus A, Merrick GS, Butler WM, et al. The influence of isotope and prostate volume on urinary morbidity after prostate brachytherapy. Int J Radiat Oncol Biol Phys 2006;64:136e143. [35] Hinerman-Mulroy A, Merrick GS, Butler WM, et al. Androgen deprivation-induced changes in prostate anatomy predict urinary morbidity after permanent interstitial brachytherapy. Int J Radiat Oncol Biol Phys 2004;59:1367e1382. [36] Keyes M, Miller S, Pickles T, et al. Late urinary side effects 10 years after low-dose-rate prostate brachytherapy: Population-based results from a multiphysician practice treating with a standardized protocol and uniform dosimetric goals. Int J Radiat Oncol Biol Phys 2014;90: 570e578.
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Quantitative analysis of genitourinary toxicity after iodine-125 brachytherapy for localized prostate cancer: Followup of the International Prostate Symptom Score and Overactive Bladder Symptom Score Masanori Sakayori1, Toshio Ohashi1,2,*, Tetsuo Momma3, Tomoya Kaneda1, Shuichi Nishimura1, Shinya Sutani1, Shoji Yamashita2, Naoyuki Shigematsu1 2
1 Department of Radiology, Keio University School of Medicine, Tokyo, Japan Department of Radiology, National Hospital Organization Saitama Hospital, Saitama, Japan 3 Department of Urology, National Hospital Organization Saitama Hospital, Saitama, Japan
ABSTRACT
PURPOSE: To analyze genitourinary toxicity by followup of the International Prostate Symptom Score (IPSS) and Overactive Bladder Symptom Score (OABSS) after prostate brachytherapy. METHODS AND MATERIALS: Six hundred eighty patients were treated with iodine-125 brachytherapy for localized prostate cancer. IPSS, OABSS, and two categories of IPSS questions (storage symptom score [IPSS-S] and voiding symptom score [IPSS-V]) were evaluated. RESULTS: The median followup was 54 months (range, 24e108). All scales showed rapid increases followed by gradual decreases. The median times to IPSS peak and resolution were 1 and 6 months, respectively. The resolution rates of IPSS, IPSS-S, IPSS-V, and OABSS at the last followup were 84.2%, 86.3%, 89.5%, and 83.0%, respectively. The difference between IPSS baseline and peak was greater for larger preimplant prostate volumes ($25 mL, p 5 0.004). The time to resolution was longer for higher biologic effective dose (BED) ($210 Gy, p 5 0.019 [IPSS]), in those with larger prostate volumes ($25 mL, p 5 0.025 [OABSS]), in younger patients (younger than 70 years, p 5 0.043 [IPSS-S]), and in those with androgen deprivation therapy (ADT) use ( p 5 0.049 [IPSS-V]). Urge incontinence, included in the OABSS, was observed more commonly in older patients (75 years and older, p 5 0.018), with ADT use ( p ! 0.001), and for higher BED ($210 Gy, p 5 0.006). CONCLUSIONS: The IPSS and OABSS showed similar patterns of change. Urinary symptoms improved more rapidly in those with high baseline IPSS levels. The OABSS was useful for following urinary symptoms after prostate brachytherapy. Age, ADT use, preimplant prostate volume, and BED were significantly associated with urinary outcomes. Ó 2017 American Brachytherapy Society. Published by Elsevier Inc. All rights reserved.
Keywords:
Prostate cancer; Brachytherapy; Toxicity; IPSS; OABSS
Introduction Prostate cancer is one of the most frequently diagnosed cancers in developed countries. In Japanese men, it is the sixth leading cause of death (1). Its morbidity is surpassed Received 2 March 2017; received in revised form 18 April 2017; accepted 18 April 2017. Conflict of interest: The authors report no proprietary or commercial interest in any product mentioned or concept discussed in this article. Financial disclosure: This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors. * Corresponding author. Department of Radiology, Keio University School of Medicine, 35 Shinanomachi, Shinjuku-ku, Tokyo 160-8582, Japan. Tel.: þ81-3-3353-1211; fax: þ81-3-3359-7425. E-mail address: [email protected] (T. Ohashi).
only by that of gastric cancer, and it is expected to continue to increase in the future. In recent years, iodine-125 brachytherapy (permanent seed implantation [PI]) with or without external beam radiotherapy (EBRT) has been one of the standard definitive radiotherapies for localized prostate cancer. However, genitourinary (GU) toxicity is a frequent adverse event associated with prostate radiotherapy and can severely affect patients’ quality of life. Clinical factors related to late GU and gastrointestinal (GI) toxicities have been reported previously (2). Of all patients, 12.7% and 0.6% of patients developed late Grade 2 and Grade 3 GU toxicities, respectively. In addition, late Grade $2 GU toxicity was significantly more common in patients who underwent PI (PI alone and PI þ EBRT) than in those
1538-4721/$ - see front matter Ó 2017 American Brachytherapy Society. Published by Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.brachy.2017.04.241
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undergoing conventional radiotherapy or EBRT (intensitymodulated radiotherapy) alone. In subgroup analysis, a higher biologic effective dose (BED) was associated with greater late Grade $2 GU toxicity. Therefore, in the present study, we focused on the importance of PI-related GU toxicity and reviewed the urinary symptom scales after PI. The International Prostate Symptom Score (IPSS) is the most widely used scale to assess urinary symptoms, and several studies have reported IPSS followup after PI. In 1992, the IPSS was validated by the American Urological Association for the evaluation of the lower urinary tract symptoms of benign prostate hyperplasia (3). The IPSS includes seven questions that are subdivided into two categories, including the storage (IPSS-S: 2, frequency; 4, urgency; and 7, nocturia) and voiding (IPSS-V: 1, incomplete emptying; 3, intermittency; 5, weak stream; and 6, straining) symptom scores. All these symptoms might occur after prostate radiotherapy; however, voiding symptoms are relatively infrequent and clinically inconsequential in everyday clinical practice. The Overactive Bladder Symptom Score (OABSS) is a relatively new scale that, although validated in 2006, has not yet been used (4). Details of the OABSS are given in Table 1. The OABSS evaluates overactive bladder symptoms rather than their effects on daily life, which are evaluable using the previously reported scales, including the Patient Perception of Bladder Condition, Primary Overactive Bladder Symptom Questionnaire, Overactive Bladder Questionnaire, Urgency Questionnaire, and Indevus Urgency Severity Scale (5e8). The reliability and validity of the English version of the OABSS have been demonstrated previously (9). Table 1 Overactive Bladder Symptom Score Question
Frequency
Score
How many times do you typically urinate from waking in the morning until sleeping at night? How many times do you typically wake up to urinate from sleeping at night until waking in the morning? How often do you have a sudden desire to urinate, which is difficult to defer?
#7 8e14 $15
0 1 2
0 1 2 $3
0 1 2 3
How often do you leak urine because you cannot defer the sudden desire to urinate?
Not at all Less than once a week Once a week or more About once a day 2e4 times a day 5 times a day or more Not at all Less than once a week Once a week or more About once a day 2e4 times a day 5 times a day or more
0 1 2 3 4 5 0 1 2 3 4 5
Patients were instructed to circle the score that best applied to their urinary condition during the past week; the overall score was the sum of the four scores.
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Compared with the IPSS, the OABSS mainly focuses on urinary storage symptoms and does not exclusively require information concerning obstructive symptoms related to urinary voiding. Overactive bladder is defined by the International Continence Society as urgency, with or without urge incontinence, usually with frequency and nocturia (10). The OABSS consists of four questions related to storage symptoms, such as daytime voiding, nighttime voiding, urgency, and urge incontinence (Table 1). Furthermore, the recall duration of the OABSS is the past 7 days, whereas that of the IPSS is the past month. The Urgency Questionnaire queries patients’ symptoms and their effects on daily life, and it includes more than 15 questions, which the patient may find complicated. Focusing on these points, in addition to IPSS, we adopted the OABSS to assess urinary symptoms. We hypothesized that the OABSS would be more suitable for evaluating urinary symptoms after prostate radiotherapy and easier for patients to complete. To our knowledge, this is the first report concerning the use of the OABSS after PI, although a few reports have noted that the suitability of the OABSS to diagnose and evaluate urinary symptoms is equivalent to that of the IPSS (4, 11e13). The aim of the present study was to analyze PI-related GU toxicity using the IPSS and OABSS and evaluate the usefulness of the OABSS for this purpose.
Methods and materials Patient characteristics From March 2007 to January 2014, 734 patients underwent PI for localized prostate cancer at our hospital. Of these patients, 54 were excluded because of incomplete followup. Finally, 680 patients with a minimum followup of 24 months were included. No patients in the present study underwent transurethral prostate resections before PI. The institutional review board approved this study. Treatment and followup PI was performed with iodine-125 seeds using the ultrasonography-guided intraoperative transperineal technique (14). The prescribed minimum peripheral doses were 160 Gy for PI alone and 110 Gy for PI þ EBRT. EBRT was administered (45 Gy in 1.8 Gy fractions) to the prostate and seminal vesicles within ~1 month after PI, using conventional radiotherapy or intensity-modulated radiotherapy. Androgen deprivation therapy (ADT) consisted of a luteinizing hormoneereleasing hormone agonist with or without an antiandrogen. Neoadjuvant ADT was administered to 218 patients (32.2%), depending on the need to reduce prostate volume and/or for anticancer effects. Twenty-eight patients (4.1%) underwent adjuvant ADT for 6 months in addition to neoadjuvant ADT. Most patients were routinely initiated on alpha-1 blockers after PI.
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Both IPSS and OABSS self-reporting scales were obtained from all patients routinely. The scales were assessed at pretreatment; at 0.5, 1, 3, 6, 9, 12, 18, 24, 30, and 36 months after radiotherapy; and annually thereafter. Outcome criteriaddefinition of events
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Statistical analyses were performed using SPSS software, version 22.0 (SPSS Inc., Chicago, IL). All analyses used two-sided statistical tests, and p-value of !0.05 was deemed statistically significant.
Results
The peak of each scale was defined as the maximum score recorded within 12 months after radiotherapy. Four definitions of the IPSS resolution were used: a return to the baseline score (0 point), within the baseline score þ1 point, þ2 points, and þ3 points. Resolutions of IPSS-V, IPSS-S, and OABSS were defined as a return to the baseline score (0 point).
Patient characteristics The patient characteristics and treatment parameters are listed in Table 2. The PI-alone group consisted of 384 patients (56.5%), and the PI þ EBRT group consisted of 296 patients (43.5%). The median followup duration was 54 months (range, 24e108), and 316 patients (46.5%) were followed for 5 years or more.
Statistical analyses The following covariates were analyzed: age, diabetes mellitus, ADT use, preimplant prostate volume, and BED. The ManneWhitney U test and multiple regression analysis were used to evaluate the difference between the peak and baseline of the IPSS and OABSS. Time-to-event (resolution) curves were described using the KaplaneMeier method and compared using the log-rank test. The effects of covariates were assessed using the Cox proportional hazards model. Logistic regression analysis was used to evaluate urge incontinence.
Outcomes of followup The actual questionnaire completion rates of IPSS and OABSS were both 95.4%. The median score and the changes from baseline of the IPSS, IPSS-S, IPSS-V, and OABSS are shown in Fig. 1. Scores increased significantly between 0.5 and 3 months after treatment. The median time to peak was 1 month for each scale, and the scores decreased gradually thereafter. Urinary symptoms improved more rapidly in those with high baseline IPSS levels.
Table 2 Patient characteristics Treatment modality Characteristics Age (y), median (range) Followup time (mo) Median (range) Preimplant prostate volume (mL) Median (range) Preimplant prostate volume, n (%) !25 mL #25 to !30 mL $30 mL Gleason score, n (%) !7 7 O7 Risk classification, n (%) Low Intermediate High Initial PSA (ng/mL) Median (range) Baseline IPSS, n (%) Mild (#7 points) Intermediate (8e19 points) Severe ($20 points) ADT, n (%) Diabetes mellitus, n (%) BED (Gy), median (range)
Overall (n 5 680)
Monotherapy (PI alone) (n 5 384)
Combined therapy (PI þ EBRT) (n 5 296)
70 (51e82)
69 (51e82)
72 (53e82)
54 (24e108)
54 (24e108)
54 (24e96)
23.0 (7.0e41.4)
24.1 (7.00e40.4)
21.4 (8.50e41.4)
410 (60.3) 160 (23.5) 109 (16.0)
206 (53.6) 101 (26.3) 76 (19.8)
204 (68.9) 59 (19.9) 33 (11.1)
561 (82.5) 57 (8.4) 62 (9.1)
383 (99.7) 1 (0.3) 0 (0.0)
178 (60.1) 56 (18.9) 62 (20.9)
330 (48.5) 254 (37.4) 96 (14.1)
294 (76.6) 88 (22.9) 2 (0.5)
36 (12.2) 166 (56.1) 94 (31.8)
6.90 (2.30e48.0)
6.00 (3.10e48.0)
10.2 (2.30e46.9)
381 250 42 218 68 213.9
(56.6) (37.1) (6.2) (32.2) (10.0) (152.0e259.4)
222 130 28 103 29 205.0
(57.8) (33.9) (7.3) (26.8) (7.6) (152.0e259.4)
159 120 14 115 39 220.7
(53.7) (40.5) (4.7) (38.9) (13.2) (188.8e244.5)
PI 5 permanent seed implantation; EBRT 5 external beam radiotherapy; PSA 5 prostate-specific antigen; IPSS 5 International Prostate Symptom Score; ADT 5 androgen deprivation therapy; BED 5 biologic effective dose.
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Fig. 1. Median score and change from baseline of urinary symptom scales. (a) International Prostate Symptom Score (IPSS), (b) IPSS change from baseline, (c) IPSS storage symptom score (IPSS-S), (d) IPSS-S change from baseline, (e) IPSS voiding symptom score (IPSS-V), (f) IPSS-V change from baseline, (g) Overactive Bladder Symptom Score (OABSS), and (h) OABSS change from baseline. All scales are shown in subgroups of baseline IPSS level (mild [0e7 points], intermediate [8e19 points], and severe group [$20 points]).
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Rates of IPSS resolution (within baseline 0, þ1, þ2, and þ3 points) were 74.9%, 79.1%, 82.1%, and 84.0%, respectively, at 12 months; 83.2%, 89.0%, 92.8%, and 94.4%, respectively, at 36 months; and 83.8%, 89.6%, 93.2%, and 95.1%, respectively, at the last followup. Rates of IPSS-S, IPSS-V, and OABSS resolutions were 66.5%, 66.6%, and 71.2%, respectively, at 12 months; 84.3%, 87.5%, and 81.0%, respectively, at 36 months; and 86.5%, 89.4%, and 83.1%, respectively, at the last followup. The median times to resolution were 6 months for IPSS and OABSS and 9 months for IPSS-S and IPSS-V. Differences between peak and baseline On multivariate analysis (MVA), differences between peak and baseline values were significantly greater in those with a larger prostate volume ($25 mL, p 5 0.004 [IPSS], 0.020 [IPSS-S], 0.008 [IPSS-V], and 0.023 [OABSS]). A subgroup analysis of the mild IPSS group revealed that the difference between peak and baseline levels was greater in those with a larger prostate volume ($25 mL, p 5 0.033 [IPSS], 0.017 [IPSS-S], and 0.045 [OABSS]) and in those who received ADT ( p 5 0.021 [IPSS-S] and 0.016 [OABSS]). Score resolution delay On MVA, the time to resolution was significantly longer in the higher BED group ($210 Gy, p 5 0.019 [IPSS baseline 0 point]; Fig. 2a), in those with larger prostate volumes ($25 mL, p 5 0.025 [OABSS]; Fig. 2b), in younger patients (younger than 70 years, p 5 0.043 [IPSS-S]), and in those using ADT ( p 5 0.049 [IPSS-V]) (Table 3). Concordance rates between the times to resolution of IPSS and OABSS In most cases, the peaks of IPSS and OABSS were both within 3 months of radiotherapy. In contrast, in some cases, the times to resolution of the two scales differed.
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The proportions of patients who achieved both IPSS and OABSS resolutions until the last followup were 75.8% (IPSS [baseline 0 point]), 80.0% (IPSS-S), and 76.7% (IPSS-V). Of these patients, the exact concordance rates (the same times to resolution of IPSS and OABSS) were 32.0%, 30.1%, and 23.6%. The nearly concordance rates (within a difference of 6 months) were 75.6%, 72.4%, and 64.2%. Analysis of urge incontinence In contrast to the IPSS, the OABSS includes a question about urge incontinence. Overall, urinary urgency, urge incontinence, and urge incontinence once a day or more were seen in 93.8%, 66.5%, and 28.8% of patients, respectively (Table 4). On MVA, older age (75 years and older, p 5 0.018), ADT use ( p ! 0.001), and a higher BED ($210 Gy, p 5 0.006) were significant risk factors for urge incontinence. ADT use ( p ! 0.001) and larger prostate volumes ($25 mL, p 5 0.031) were significant risk factors for urge incontinence once a day or more.
Discussion The present study indicated that urinary symptoms worsened rapidly within 3 months and resolved gradually within ~12 months. Several studies have reported IPSS changes after PI (15e23). An initial Japanese study evaluating IPSS serial changes reported similar results (16). Neill et al. (24) found that IPSS resolution (two points above baseline) was achieved in 72.2% and 83.3% of patients by 12 and 24 months, respectively. In the present study, IPSS resolution was achieved in 82.1% and 91.9% of patients by 12 and 24 months, respectively. Stone et al. (15) reported the resolution rates at 24 months regarding the baseline IPSS as 39.4%, 59.5%, and 83.3% in the mild, intermediate, and severe groups, respectively. In the present study, the
Fig. 2. Cumulative incidence of score resolution. (a) International Prostate Symptom Score (IPSS). Open circles indicate the resolution time in the biologic effective dose (BED) !210 Gy group, whereas plus symbols indicate that of the $210 Gy group. (b) Overactive Bladder Symptom Score (OABSS). Open circles indicate the resolution time in the preimplant prostate volume !25 mL group, whereas plus symbols indicate that of the $25 mL group.
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Table 3 Factors predicting longer time to resolution, using log-rank test and Cox proportional hazards model Log-rank test
Factor Time to IPSS resolution (baseline 0 point) Age (younger than 70 y) Diabetes mellitus (yes vs. no) ADH (yes vs. no) Initial prostate volume ($25 mL) BED ($210 Gy) Time to IPSS-S resolution Age (younger than 70 y) Diabetes mellitus (yes vs. no) ADH (yes vs. no) Initial prostate volume ($25 mL) BED ($210 Gy) Time to IPSS-V resolution Age (younger than 70 y) Diabetes mellitus (yes vs. no) ADH (yes vs. no) Initial prostate volume ($25 mL) BED ($210 Gy) Time to OABSS resolution Age (younger than 70 y) Diabetes mellitus (yes vs. no) ADH (yes vs. no) Initial prostate volume ($25 mL) BED ($210 Gy)
Cox proportional hazards model Univariate analysis
MVA
p
p
Hazard ratio (95% CI)
p
Hazard ratio (95% CI)
0.46 0.723 0.722 0.918 0.009a
0.511 0.753 0.752 0.927 0.021a
0.946 1.045 0.972 0.992 0.822
(0.802e1.116) (0.796e1.371) (0.815e1.159) (0.840e1.172) (0.696e0.971)
0.682 0.555 0.585 0.723 0.019a
0.966 1.086 0.952 0.970 0.815
(0.817e1.142) (0.826e1.428) (0.797e1.137) (0.819e1.149) (0.688e0.966)
0.04a 0.766 0.872 0.223 0.168
0.063 0.787 0.884 0.188 0.212
1.169 1.038 1.013 0.895 0.901
(0.991e1.377) (0.793e1.358) (0.852e1.204) (0.758e1.056) (0.764e1.061)
0.043a 0.646 0.947 0.169 0.112
1.187 1.066 0.994 0.889 0.874
(1.006e1.401) (0.813e1.397) (0.834e1.184) (0.752e1.051) (0.740e1.032)
0.7 0.416 0.04a 0.702 0.061
0.728 0.464 0.065 0.872 0.092
0.972 1.105 0.850 1.013 0.870
(0.828e1.141) (0.846e1.443) (0.716e1.010) (0.862e1.192) (0.740e1.023)
0.853 0.287 0.049a 0.911 0.068
0.985 1.158 0.840 0.991 0.857
(0.837e1.159) (0.884e1.516) (0.707e0.999) (0.841e1.167) (0.726e1.011)
0.452 0.576 0.4 0.002a 0.409
0.497 0.614 0.447 0.02a 0.456
1.059 1.073 1.071 0.818 0.938
(0.897e1.252) (0.816e1.411) (0.898e1.277) (0.691e0.969) (0.794e1.109)
0.398 0.513 0.606 0.025a 0.285
1.075 1.096 1.048 0.823 0.912
(0.909e1.273) (0.832e1.445) (0.877e1.253) (0.694e0.976) (0.771e1.080)
MVA 5 multivariate analysis; CI 5 confidence interval; IPSS 5 International Prostate Symptom Score; ADT 5 androgen deprivation therapy; BED 5 biologic effective dose; IPSS-S 5 International Prostate Symptom Score (storage symptom score); IPSS-V 5 International Prostate Symptom Score (voiding symptom score); OABSS 5 Overactive Bladder Symptom Score. a Significant.
percentages of patients achieving resolution at 24 months were much greater, at 86.6%, 94.8%, and 100% in the mild, intermediate, and severe groups, respectively. Although the results of these studies cannot be compared directly because of the differences in PI conditions, the findings in the present study are similar to those reported previously. In the present study, a lower baseline IPSS and OABSS resulted in a longer time to resolution. It is notable that, in the higher baseline groups, urinary symptoms improved to levels below the baseline and improved earlier than those in the mild and intermediate baseline groups, which was congruent with several previous studies (21, 25, 26). In the present series, a higher BED resulted in score resolution delay and more frequent urge incontinence. This was concordant with a previous study that indicated that the late GU/GI toxicity risk could be explained by the total radiation dose to the GU/GI tract (2). Likewise, several other reports have indicated correlations between a greater prostate dose and poorer urinary symptoms (22, 27e30). The OABSS changes in the present study were similar to the changes seen with other scales. The OABSS resolution rates were 71.2% and 81.0% at 12 and 36 months, respectively. Of the patients who achieved both IPSS and OABSS resolutions, the concordance rates between the times to resolution of IPSS and OABSS (within a difference of
6 months) were 75.6%, 72.4%, and 64.2%. Initially, there was a concern that, because of its simplicity and lower total score, the OABSS might have differed significantly from the IPSS. However, the OABSS showed similar change patterns and relatively high concordance rates with the time to resolution of the IPSS. These findings indicate the usefulness of the OABSS and the possibility of the substitution of the OABSS for the IPSS. However, it remains doubtful whether the OABSS truly reflects the symptoms after PI. Hikita et al. (31) found significant differences between the OABSS and the score derived from a bladder diary. In the present study, a bladder diary was not assessed; therefore, there is a possibility of overestimation or underestimation of the OABSS in the present study. IPSS and OABSS are both patient-reported questionnaires rather than physician-reported scores, and it has been suggested that subjective toxicities are often underevaluated by physicians, even in prospective studies (32). Presently, we believe that both OABSS and IPSS reflect urinary symptoms directly. In the present study, OABSS was not inferior to IPSS in evaluating urinary symptoms after PI. Two previous studies have verified a correlation between OABSS and IPSS-S, and although the conclusions of these studies remain controversial, both reports included men and women and
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Table 4 Factors predicting urinary incontinence, using logistic regression analysis Urinary incontinence Univariate analysis Factor
p
Urinary incontinence once a day or more MVA
Univariate analysis
Odds ratio (95% CI) p a
Age (75 y and older) 0.003 Diabetes mellitus 0.199 (yes vs. no) ADH (yes vs. no) !0.001a Initial prostate 0.249 volume ($25 mL) BED ($210 Gy) 0.009a
1.869 (1.236e2.825) 1.447 (0.824e2.544)
Odds ratio (95% CI) p a
0.018 0.395
1.675 (1.093e2.566) 1.289 (0.718e2.313)
MVA
Odds ratio (95% CI) p 0.182 0.334
1.301 (0.884e1.914) 1.300 (0.763e2.214)
Odds ratio (95% CI) 0.389 0.433
1.192 (0.799e1.780) 1.246 (0.720e2.156)
2.613 (1.787e3.820) !0.001a 2.698 (1.832e3.973) !0.001a 2.407 (1.701e3.405) !0.001a 2.316 (1.633e3.285) 1.213 (0.873e1.685) 0.096 1.335 (0.950e1.877) 0.106 1.320 (0.943e1.848) 0.031a 1.466 (1.036e2.077) 1.542 (1.116e2.130)
0.006a 1.603 (1.147e2.242)
0.905
1.021 (0.727e1.432)
0.749
1.059 (0.745e1.506)
MVA 5 multivariate analysis; CI 5 confidence interval; ADT 5 androgen deprivation therapy; BED 5 biologic effective dose. a Significant.
were not limited to PI-related GU toxicity (11, 12). Further investigation would be needed for a thorough evaluation of the comparison of the scoring systems for PI-related GU toxicity. It is interesting that urge incontinence is evaluable when using the OABSS. However, because urge incontinence is not included in the Radiation Therapy Oncology Group urinary toxicity scales (33), there are limited data available. Zelefsky et al. (27) found incontinence requiring pad use in !1% of 367 patients, and Crook et al. (17) found urgency and/or urge incontinence in 6.4% of 484 patients. In the present study, the urinary urgency (93.8%), urge incontinence (66.5%), and urge incontinence once a day or more (28.8%) rates were much higher. These surprisingly high rates of incontinence might indicate the potential effectiveness of the OABSS in revealing the impairment of patients’ quality of life. However, the results cannot be compared directly because Zelefsky et al. (27) and Crook et al. (17) included PI-alone patients, and the BEDs were lower than those in the present study. This difference could also be because of a discrepancy in the understanding of the term incontinence between different patient groups. For example, patients might not be aware of the different types of incontinence (urge, stress, and overflow incontinence). In addition, different definitions might be used between studies; for example, the use of incontinence pads was not taken into consideration in the present study. Furthermore, in grading the severity of incontinence, Crook et al. (17) evaluated whether anticholinergics were prescribed, whereas the present study did not take this into consideration. One point from the present findings is worthy of further discussion. Keyes et al. (26) reported that ADT use was independently predictive for more acute and less late Radiation Therapy Oncology Group urinary toxicity and that patients who did not use ADT but who had acute toxicity showed the worst IPSS resolution. Stone et al. (15) reported that a lack of ADT use predicted a greater IPSS change from baseline. To some extent, their results are inconsistent with the findings of the present study regarding worse urinary toxicity when ADT was not prescribed. Although the
effect of ADT remains controversial, this inconsistency might be the result of differences in the pretreatment prostate volume between the present study and those of Keyes et al. (26) and Stone et al. (15). A larger prostate volume can increase the efficacy of ADT and result in greater improvements in urinary toxicities. The reasons for ADT use in these patients should also be noted, which would usually be to reduce the prostate size or to control the disease (34, 35). In the present study, 28 patients (4.1%) received adjuvant ADT in addition to neoadjuvant ADT. However, because the number of the patients was small, we did not use adjuvant ADT as a separate clinical factor. This point is a limitation to the present study. Further investigation will be needed with a larger number of patients. There are several additional limitations. First, the study design was retrospective and conducted at a single institution. Second, PI was performed with separate seeds using the Mick applicator (Mick Radio-Nuclear Instruments, Mount Vernon, NY). Recently, in Japan, linked seeds have been introduced and became more popular. Therefore, the present results might not be comparable with those using other seed types. Finally, the definition of IPSS resolution has not been clearly determined, and several definitions exist (16e18, 36). In the present study, IPSS resolution was defined as a return to the baseline (0 point) and being within þ1, þ2, or þ3 points of baseline. Using various definitions for the same score might make interpretation of the results more complicated. However, several definitions have been used in this field. For this reason, we adopted four definitions of IPSS resolution in our investigation. We found no major differences between the definitions. In contrast, IPSS-S, IPSS-V, and OABSS resolutions were defined as a return to baseline (0 point) alone. These points should be taken into consideration when comparing the data with those from previous reports.
Conclusion This study evaluated long-term IPSS and OABSS changes in Japanese patients with prostate cancer who
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underwent PI. Both scales showed similar patterns of change. In the higher baseline IPSS group, urinary symptoms were the first to improve below the baseline level. OABSS, a simple scale that includes only four questions, was useful for following urinary symptoms and allowed the evaluation of urge incontinence. Age, ADT use, preimplant prostate volume, and BED had a significant impact on urinary outcomes after PI. Acknowledgments We thank Editage (www.editage.jp) for English language editing. References [1] Cancer Registry and Statistics. Cancer Information Service, National Cancer Center, Japan. Available at: http://ganjoho.jp/en/index.html. Accessed March 2, 2017. [2] Sutani S, Ohashi T, Sakayori M, et al. Comparison of genitourinary and gastrointestinal toxicity among four radiotherapy modalities for prostate cancer: Conventional radiotherapy, intensity-modulated radiotherapy, and permanent iodine-125 implantation with or without external beam radiotherapy. Radiother Oncol 2015;117: 270e276. [3] Barry MJ, Fowler FJ Jr, O’Leary MP, et al. The American Urological Association Symptom Index for benign prostatic hyperplasia. The Measurement Committee of the American Urological Association. J Urol 1992;148:1549e1557. discussion 1564. [4] Homma Y, Yoshida M, Seki N, et al. Symptom assessment tool for overactive bladder syndromeeoveractive bladder symptom score. Urology 2006;68:318e323. [5] Coyne KS, Matza LS, Thompson CL. The responsiveness of the Overactive Bladder Questionnaire (OAB-q). Qual Life Res 2005;14: 849e855. [6] Matza LS, Thompson CL, Krasnow J, et al. Test-retest reliability of four questionnaires for patients with overactive bladder: The overactive bladder questionnaire (OAB-q), patient perception of bladder condition (PPBC), urgency questionnaire (UQ), and the primary OAB symptom questionnaire (POSQ). Neurourol Urodyn 2005;24: 215e225. [7] Zinner N, Harnett M, Sabounjian L, et al. The overactive bladdersymptom composite score: A composite symptom score of toilet voids, urgency severity and urge urinary incontinence in patients with overactive bladder. J Urol 2005;173:1639e1643. [8] Nixon A, Colman S, Sabounjian L, et al. A validated patient reported measure of urinary urgency severity in overactive bladder for use in clinical trials. J Urol 2005;174:604e607. [9] Homma Y, Fujimura T. Psychometric validation of the English version of the overactive bladder symptom score. Urology 2014;84: 46e50. [10] Abrams P, Cardozo L, Fall M, et al. The standardisation of terminology of lower urinary tract function: Report from the Standardisation Sub-committee of the International Continence Society. Neurourol Urodyn 2002;21:167e178. [11] Hsiao SM, Lin HH, Kuo HC. International Prostate Symptom Score for assessing lower urinary tract dysfunction in women. Int Urogynecol J 2013;24:263e267. [12] Shim JS, Kim JH, Choi H, et al. Diagnostic tool for assessing overactive bladder symptoms: Could the International Prostate Symptom Storage Subscore replace the Overactive Bladder Symptom Score? Int Neurourol J 2016;20:209e213.
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