Radiation induced bladder dysfunction is a common problem after gynecologic oncology radiation. Genitourinary radiation toxicity in the acute phase includes urinary urgency, frequency, nocturia, dysuria, bladder spasm, urothelial ulceration and hemorrhage with an incidence of 20 to 80% depending on dose of radiation. Following an asymptomatic latent period, epithelial atrophy, reduction in capacity, loss of compliance and bladder necrosis manifests as a result of progressive vascular damage, obliterative arteritis, ischemia and fibrosis. Long term urinary adverse events following radiotherapy represent a significant disease burden. Given the close proximity of the cervix and vaginal cuff to the bladder, RTOG grade 1 and 2 urinary adverse events are present in up to 45% of patients at 5-years and major complications related to grade 3 adverse events noted in 14% of patients at 20-years. Our overarching aims were to prospectively (i) characterize changes in storage and voiding dysfunction during the acute phase of radiotherapy [brachytherapy, combination, external beam (EBRT)] in women treated with radiotherapy for endometrial and cervical cancer; and (ii) systematically quantify the burden of storage and voiding dysfunction in women presenting to a moderate volume practice specializing in chronic radiation induced bladder dysfunction.

Women undergoing (i) pelvic radiotherapy and (ii) presenting with bladder complaints following pelvic radiotherapy were prospectively enrolled in an observational cohort. Women with endometrial and cervical cancer treated with radiotherapy [brachytherapy, combination, EBRT] were enrolled from radiation oncology clinic prior to first radiation exposure, with plan for at least 1-year follow-up to assess changes in lower urinary tract symptoms following exposure to radiation. In order to assess long term changes following radiotherapy, women with chronic radiation induced bladder dysfunction were enrolled from urology clinic. History was recorded and participants answered self-administered questionnaires including the American Urological Association Symptom Score (AUASS), the International Consultation on Incontinence Questionnaire Female Lower Urinary Tract Symptoms (ICIQ FLUTS), and the 12 item short form health survey (SF12). Primary outcome was change in LUTS before, during and after radiotherapy. Data were analyzed using Statistical Analysis System software (SAS, Cary, NC) and presented as mean +/- standard deviation. Spearman’s rho was used to test for non-parametric correlations between corresponding questionnaire items. A p-value <0.05 was considered statistically significant.

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 complete questionnaire sets which were completed (AUASS, ICIQ FLUTS, SF12). Mean age was 59.1 +/- 14.8 years (range 19-77). Cancer diagnoses included: 4 cervical cancer, 13 endometrial cancer, and 3 other pelvic malignancies (ovarian cancer, sarcoma). Radiotherapy treatments included 11 women who underwent brachytherapy, 3 EBRT, and 6 combination radiotherapy (brachytherapy + EBRT). Prior pelvic surgical treatments included 14 women treated with radical hysterectomy (with bilateral salpingo-oophorectomy and pelvic lymph node dissection). There were 2 women who were pre-menopausal, and the remaining 18 women were post-menopausal at time of radiotherapy. Women previously had a median number of 2 (range 0-8) pregnancies and 2 (range 0-5) deliveries. Mean BMI was 30.1 +/- 8.5 kg/m^2.

For the LUTS storage domains (daytime frequency, urinary urgency, nocturia), there were differences in the magnitude of change over time when contrasting the AUASS against the ICIQ-FLUTS (Figure 1). Daytime frequency (AUASS #2, FLUTS #5) was decreased by 1-2 AUASS points in approximately 50% of the women during brachytherapy, meanwhile FLUTS score increased in most patients over time (AUASS #2 vs. FLUTS #5 Spearman r=0.443, p=0.005). Similarly for the urgency domain (AUASS #4, 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 in combined radiotherapy (AUASS #4 vs. FLUTS #3 Spearman r=0.700, p<0.001). For the nocturia domain (AUASS #7, FLUTS #2) there were high baseline AUA scores in the brachytherapy group, where some had paradoxical improvement and some worsened following radiotherapy, meanwhile the FLUTS scores appeared more consistent (AUASS #7 vs. FLUTS #2 Spearman r=0.832, p<0.001). 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.

For the LUTS voiding domains (weak stream, urinary hesitancy, straining, intermittency), there were again differences in the magnitude of change over time when contrasting the AUASS against the ICIQ-FLUTS (Figure 2). Urinary hesitancy (FLUTS #6) was not a common problem during brachytherapy, however manifest more long-term after EBRT and combination radiotherapy, although this may reflect a referral pattern for these groups. Similarly, straining (AUASS #6, FLUTS #7) was not a common problem during brachytherapy, as reflected by FLUTS scores, but was more pronounced during and after EBRT and combination radiotherapy. Straining scores were closely correlated (AUASS #6 vs. FLUTS #7 Spearman r=0.753, p<0.001). Intermittency domain (AUASS #3, FLTUS #8) scores fluctuated over the acute time course, with brachytherapy group having fairly high AUA baseline 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 at long term follow-up after EBRT there were consistently higher scores in both the AUASS and FLUTS. Intermittency scores were closely correlated (AUASS #3 vs. FLTUS #8 Spearman r=0.827, p<0.001).

For the LUTS incontinence domains, 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. Combination treatment was associated with increased or no change in incontinence during radiotherapy, meanwhile on long-term follow-up combination and EBRT women usually had high incontinence scores, although this may reflect a referral pattern. 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 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 treatment has ended (Figure 2). Combination radiotherapy and EBRT patients had generally worse perception of overall health (SF12) and AUASS QOL, and overall for all groups scores between these domains were moderately correlated (AUASS QOL vs. SF12 Spearman r=0.450, p=0.005).

In women who underwent brachytherapy and combination radiotherapy, the ICIQ-FLUTS storage and voiding domains scores were more consistent than the AUA scores with respect to the expected pathophysiology of radiation induced bladder dysfunction. Incontinence was prevalent at baseline, during and after radiotherapy. Pain was mostly a problem for combination radiotherapy and EBRT. Perception of overall health was generally better with brachytherapy than in combination or EBRT groups. Paradoxical changes in LUTS scores observed over the course of radiotherapy warrant further clinical discussion and clarification should be sought in women regarding changes in LUTS before, during and after radiotherapy.

Both FLUTS and AUA scores have utility at characterizing change in storage, voiding and incontinence during the course of radiotherapy. Classically radiotherapy has been associated with urinary urgency, frequency and worsening incontinence, which appear to be better captured by the FLUTS questionnaire. Both the AUASS and FLUTS demonstrate paradoxical changes over time which warrants further research.