Following IRB approval, twenty women signed consent and were prospectively enrolled over the 10 month study period (May 2019 to February 2020). There were a total of 40 unique patient encounters and 38 questionnaire sets completed (AUASS, ICIQ-FLUTS, SF12). Mean age was 59.1 ± 14.8 years (Table 1). Mean body mass index was 30.1 ± 8.5 kg/m2. Women previously had a median number of 2 (IQR 0–3) pregnancies and 2 (IQR 0–2) deliveries. Cancer diagnoses were cervical cancer (20%, 4/20), endometrial cancer (65%, 13/20), and other pelvic malignancies (15%, 3/20). Radiotherapy treatments included brachytherapy (55%, 11/20), external beam (15%, 3/20), and combination radiotherapy (30%, 6/20). Prior pelvic surgical treatments included 14 (70%) women treated with radical hysterectomy (with bilateral salpingo-oophorectomy and pelvic lymph node dissection). There were 2 women (10%) who were pre-menopausal, and the remaining 18 women were post-menopausal at time of radiotherapy.
Table 1
Patient characteristics grouped by longest follow-up after radiotherapy
| | | Radiation group by follow-up | |
| | Overall (n = 20) | Short term (n = 12) | Long term (n = 8) | p-value |
Demographics | | | | |
| Age (years, mean ± SD) | 59.1 ± 14.8 | 61.8 ± 14.1 | 55.0 ± 15.9 | 0.30* |
| BMI (kg/m^2, mean ± SD) | 30.1 ± 8.5 | 31.1 ± 10.2 | 28.6 ± 5.3 | 0.73* |
History of pregnancy | | | | |
| Gravity (#, median, IQR) | 2 (0–3) | 1 (1–2) | 2 (0–4) | 0.63* |
| Parity (#, median, IQR) | 2 (0–2) | 2 (0–2) | 2 (0–3) | 0.61* |
Menopause status | | | | |
| Premenopause (n, %) | 2 (10%) | 1 (8.3%) | 1 (12.5%) | 0.54⁺ |
| Postmenopause (n, %) | 18 (90%) | 11 (91.7%) | 7 (87.5%) | |
Primary malignancy | | | | |
| Cervical (n, %) | 4 (20%) | 2 (16.7%) | 2 (25%) | 0.051ᶺ |
| Endometrial (n, %) | 13 (65%) | 10 (83.3%) | 3 (37.5%) | |
| Other (n, %) | 3 (15%) | - | 3 (37.5%) | |
Pelvic surgery | | | | |
| Hysterectomy (n, %) | 14 (70%) | 10 (83.3%) | 4 (50%) | 0.014ᶺ |
| Other (n, %) | 4 (20%) | - | 4 (50%) | |
| None (n, %) | 2 (10%) | 2 (16.7%) | - | |
Radiotherapy | | | | |
| Brachytherapy (n, %) | 11 (55%) | 9 (75%) | 2 (25%) | 0.041ᶺ |
| External beam (n, %) | 3 (15%) | - | 3 (37.5%) | |
| Combination (n, %) | 6 (30%) | 3 (25%) | 3 (37.5%) | |
Follow-up | | | | |
| Time since last XRT (days, median, IQR) | 72 (7 − 4,513) | 9 (7–50) | 6,170 (2,194-8,755) | 0.0001* |
(*) Mann-Whitney-Wilcoxon U test, (⁺) Fischer’s exact, (ᶺ) Kruskal Wallis |
BMI body mass index, IQR interquartile range, SD standard deviation, XRT radiotherapy |
Median follow-up time since last radiotherapy treatment was 77 days (IQR 7 − 4,513) days for the whole group (Table 1). Subjects in the ST group recruited before commencing radiotherapy had a median follow-up of 9 (IQR: 7–50) days since radiotherapy, while patients recruited from urology clinic in the LT follow-up group had a median interval of 6,170 (IQR 2,194-8,755) days since radiotherapy. The ST and LT groups differed in the types of cancer, pelvic surgeries performed and radiotherapy. There were no differences in mean age, gravity, parity, BMI, or menopause status.
For the LUTS storage domains (daytime frequency, urinary urgency, nocturia), there were differences in the magnitude of change over time when correlating the AUASS against the ICIQ-FLUTS (Table 2). Daytime frequency (AUASS #2 vs. FLUTS #5) was decreased by 1 to 2 AUASS points in approximately 50% of the women during brachytherapy, meanwhile FLUTS score increased in most patients over time (Spearman r = 0.443, p = 0.005, Fig. 1). Similarly for the urgency domain (AUASS #4 vs. FLUTS #3) AUA scores had dramatic 2 to 4 point changes in all directions, while FLUTS scores were more consistently changed across patient groups, and were worse after combination radiotherapy (Spearman r = 0.700, p < 0.001, Fig. 1). For the nocturia domain (AUASS #7 vs. FLUTS #2) there were high baseline AUA scores in the brachytherapy group, where some women reported paradoxical improvement in AUASS LUTS, and some worsened following radiotherapy. Meanwhile for the assessment of nocturia, the FLUTS scores appeared more consistent over time (Spearman r = 0.832, p < 0.001, Fig. 1). Generally, women undergoing combination radiotherapy had worse or unchanged nocturia during treatment, and following radiotherapy there was consistently greater nocturia reflected in both the AUASS and FLUTS.
Table 2
Subjective and objective effects on lower urinary tract stratified by time since radiotherapy
| | Short term | | Long term |
| | Before XRT (n = 12) | During XRT (n = 11) | After XRT (n = 4) | | After XRT (n = 8) |
AUASS questionnaire (mean ± SD) | | | | |
| 1. Incomplete emptying | 0.7 ± 1.4 | 0.6 ± 0.9 | 0.5 ± 0.5 | | 2.6 ± 2.2 |
| 2. Frequency | 1.5 ± 1.7 | 1.0 ± 1.2 | 0.7 ± 0.9 | | 4.0 ± 1.4* |
| 3. Intermittency | 1.1 ± 1.6 | 1.0 ± 1.5 | 1.0 ± 2.0 | | 2.7 ± 2.3 |
| 4. Urgency | 1.5 ± 1.8 | 1.8 ± 2.0 | 1.0 ± 1.1 | | 4.3 ± 0.9** |
| 5. Weak stream | 1.1 ± 1.7 | 0.8 ± 1.4 | 1.0 ± 1.1 | | 2.2 ± 2.0 |
| 6. Straining | 0.6 ± 1.4 | 0.3 ± 0.9 | 0.5 ± 1.0 | | 2 ± 2.1.0 |
| 7. Nocturia | 1.8 ± 1.0 | 2.2 ± 1.2 | 2.2 ± 0.9 | | 3.1 ± 1.7 |
| Total AUA symptom score | 8.5 ± 9.4 | 8.0 ± 6.0 | 7.0 ± 4.2 | | 21.2 ± 10.9* |
| Quality of life | 1.1 ± 1.1 | 2.0 ± 1.5* | 1.5 ± 1.2 | | 4.0 ± 1.1* |
FLUTS questionnaire (mean ± SD) | | | | |
| 2. Nocturia | 1.7 ± 1.0 | 1.7 ± 0.7 | 2.0 ± 0.8 | | 2.8 ± 1.3 |
| 3. Urgency | 1.0 ± 1.0 | 1.4 ± 1.1 | 1.0 ± 1.1 | | 2.5 ± 1.0* |
| 4. Pain | 0.0 ± 0.0 | 0.2 ± 0.6 | 0.2 ± 0.5 | | 1.9 ± 1.8 |
| 5. Micturition frequency | 0.1 ± 0.3 | 0.2 ± 0.4 | 0.0 ± 0.0 | | 2.6 ± 1.7* |
| 6. Hesitancy | 0.2 ± 0.4 | 0.2 ± 0.4 | 0.5 ± 0.5 | | 1.0 ± 1.2 |
| 7. Straining | 0.1 ± 0.3 | 0.3 ± 0.9 | 0.0 ± 0.0 | | 1.6 ± 1.6 |
| 8. Intermittency | 0.7 ± 0.9 | 0.7 ± 0.9 | 0.5 ± 0.5 | | 1.9 ± 1.6 |
| 9. Urge Incontinence | 1.0 ± 1.2 | 1.0 ± 1.3 | 1.0 ± 1.1 | | 2.2 ± 1.3 |
| 10. Incontinence frequency | 1.2 ± 1.6 | 1.1 ± 1.3 | 1.0 ± 1.4 | | 3.1 ± 1.1* |
| 11. Stress Incontinence | 0.9 ± 1.1 | 1.0 ± 1.0 | 0.2 ± 0.5 | | 1.4 ± 1.6 |
| 12. Unawareness incontinence | 0.2 ± 0.4 | 0.1 ± 0.4 | 0.2 ± 0.5 | | 1.2 ± 1.5 |
| 13. Nocturnal enuresis | 0.1 ± 0.5 | 0.3 ± 0.6 | 0.5 ± 1.0 | | 1.6 ± 1.6 |
SF12 questionnaire (mean ± SD) | | | | |
| Overall health (1–5, poor - excellent) | 2.5 ± 1.0 | 2.6 ± 0.9 | 2.0 ± 0.8 | | 3.5 ± 1.1* |
Urinalysis (mean ± SD) | | | | | |
| Leukocyte esterase (0–4, none − 3+) | 0.2 ± 0.6 | 0.2 ± 0.6 | 0.5 ± 1.0 | | 1.3 ± 1.4 |
| Nitrite (0–1, none - positive) | 0.0 ± 0.0 | 0.0 ± 0.0 | 0.0 ± 0.0 | | 0.3 ± 1.5 |
| Blood (0–3, none − 3+) | 0.3 ± 0.9 | 0.0 ± 0.0 | 0.0 ± 0.0 | | 1.3 ± 1.2* |
RTOG GU toxicity (acute, < 90 days) | | | | |
| RTOG grade (mean ± SD) | 0.6 ± 0.7 | 1.1 ± 0.7 | 1.3 ± 0.5 | | n/a |
| RTOG grade 1–2 (n, %) | 6/12 (50%) | 9/11 (82%) | 4/4 (100%) | | n/a |
| RTOG grade 3–4 (n, %) | - | - | - | | n/a |
RTOG GU toxicity (late/chronic) | | | | |
| RTOG grade (mean ± SD) | n/a | n/a | n/a | | 2.5 ± 0.7*ᵝ |
| RTOG grade 1–2 (n, %) | n/a | n/a | n/a | | 3/8 (37%) |
| RTOG grade 3–4 (n, %) | n/a | n/a | n/a | | 5/8 (63%) |
(*) p < 0.05, (**) p < 0.005, (β) acute versus late/chronic |
AUASS American Urological Association Symptom Score, FLUTS Female Lower Urinary Tract Symptoms, GU genitourinary, RTOG Radiation Therapy Oncology Group, SD standard deviation, SF12 Short form 12 item health survey, XRT radiotherapy |
For the LUTS voiding domains (weak stream, urinary hesitancy, straining, intermittency), there were differences in the magnitude of change over time when contrasting the AUASS against the FLUTS (Table 2). Urinary hesitancy (FLUTS #6) was not a common problem during brachytherapy in the ST group, however was common in the LT group after external beam and combination radiotherapy, although this may reflect a referral pattern for the LT group. Similarly, straining was not a common problem during brachytherapy, as reflected by FLUTS scores, but was more pronounced during and after external beam and combination radiotherapy. Straining to void scores (AUASS #6 vs. FLUTS #7) were closely correlated (Spearman r = 0.753, p < 0.001, Fig. 1). Intermittent urinary stream scores (AUASS #3 vs. FLTUS #8) were closely correlated (Spearman r = 0.827, p < 0.001, Fig. 1). Intermittency fluctuated over the acute time course, with the brachytherapy group having fairly high baseline AUA scores which seemed to improve during/after radiotherapy, meanwhile FLUTS scores did not show this trend through the course of radiotherapy. Women undergoing combination radiotherapy had higher AUA scores, but only a mild increase in FLUTS scores during radiotherapy. Meanwhile in the LT group after external beam radiotherapy, there were consistently higher scores in both the AUASS and FLUTS.
For the LUTS incontinence domains (Table 2), women had relatively high incontinence scores at baseline (FLUTS #9–12). There were paradoxical changes in incontinence score during/after brachytherapy, discordant with expected pathophysiology of radiation, which has been classically associated with exacerbation of storage symptoms. Combination treatment was associated with increased or no change in incontinence during radiotherapy, meanwhile in the LT group after external beam and combination radiotherapy, women usually had high incontinence scores, although this may reflect a referral pattern to a moderate volume urology practice specialized in the management of radiation induced bladder dysfunction. Bladder pain (FLUTS #4) was temporarily increased during brachytherapy and combination radiotherapy, whereas on long-term follow-up bladder pain was much greater in each of these groups. For the overall and quality of life domains, perception of overall health (SF12) was reported as “good” or “very good” by most brachytherapy patients, with no clear trend during treatment, and improvement after radiotherapy ended. On correlation analysis, external beam and combination radiotherapy women had generally worse perception of overall health (SF12) and AUASS quality of life, and overall for all groups scores between these domains were moderately correlated (AUASS quality of life vs. SF12 overall health, Spearman r = 0.450, p = 0.005, Fig. 1). For the rest of the questions on the SF12 questionnaire, there were no significant differences in SF12 questions among subjects before, during and after radiotherapy in the ST group, or in the LT follow up group. Patients in the LT follow-up group had worse scores for questions asking about pain interfering with normal work (#8), feeling clam and peaceful (#9) and having energy (#10), but these differences did not reach statistical significance.
Urinalysis results were mostly normal before, during and after radiotherapy in the ST group (Table 2), with different and abnormal/elevated results mostly in the LT group after radiotherapy, reaching statistical significance only for blood on urinalysis (p = 0.037). RTOG scores were minimally and insignificantly elevated during and after radiotherapy, with no patient experiencing any grade 3 or 4 toxicity in the ST group (Table 2). In the LT group, RTOG scores were significantly worse, when compared to the ST post-radiotherapy acute RTOG scores, with 5 of 8 (63%) women found to have grade 3 toxicity on 1 or more follow-up visits, although this may reflect a referral pattern for the LT group.