Adverse Events in Placebo Arms of Cancer Trials.

BACKGROUND/AIM: Adverse events (AEs) in cancer trials may be caused by the investigational agents or the underlying disease. Determining the causality is challenging, especially in early cancer drug development when a control arm is lacking. MATERIALS AND METHODS: We carried out a systematic literature review of AE frequencies in placebo arms of randomized trials for malignant solid tumors and hematologic malignancies reported in PubMed from 2016 to January 2022. RESULTS: Among 148 placebo arms, the AEs with the highest reported mean frequencies among all publications were: Fatigue (20.1%), nausea (16.3%), diarrhea (14.3%), abdominal pain (12.4%), and anemia (10.9%); AEs resulting in drug discontinuation were reported in 5.6% of placebo-treated patients and serious AEs in 18.7% of placebo patients. CONCLUSION: The data presented here may be used as a benchmark to help assess drug causality in early development cancer studies without a control arm.

Fatigue in Cancer Treatment Studies: Analysis of Placebo Arms.

BACKGROUND/AIM: Fatigue and asthenia are common in patients with cancer; and identifying the cause as drug toxicity versus cancer progression is difficult, particularly in clinical trials without control arms. MATERIALS AND METHODS: We carried out a systematic literature review of fatigue in placebo arms of randomized cancer trials reported in PubMed from 2000 to 2021. RESULTS: Fatigue/asthenia were reported in 100 out of 134 placebo cohorts, and the average of reported frequencies was 22.8%, with a range of 0-83%. Grade 3 or higher fatigue/asthenia was reported in 2.3% (0-17%). Fatigue/asthenia was positively correlated with nausea (R=0.683) Conclusion: For detection of drug toxicity, observations should be flagged when they are higher than the maximum reported in the placebo arm, and the assessment should be supplemented by comparing observations in early oncology trials to literature placebo arms, including both sample sizes and event numbers.

Headache Reporting in Oncology Trials Depends on the Demographics of the Study Population.

BACKGROUND/AIM: The frequency of adverse events (AEs) in clinical trials without control arms is difficult to interpret. MATERIALS AND METHODS: This is a systematic literature review of AEs reported from the placebo arms of randomized cancer trials in PubMed between 2008 and 2020. RESULTS: We found 80 placebo patient cohorts in 73 publications, describing 17,968 subjects who received placebo. Headaches were reported in 35 patient cohorts with an average frequency of 12.3% (+/- SD=8.0, range=0.4-34.1), and were more common in cohorts with a median age between 45 and 50 years, with higher performance status, and breast cancer (average 29.8% +/- SD=6.1). AEs leading to discontinuation were reported in 5% of cohorts (+/- SD=5.1, range=0-22.7). CONCLUSION: Considering covariates allows more accurate interpretation of the observed AE frequencies in cancer trials.

Urinary retention is rare after colpocleisis and concomitant midurethral sling: a 10-year experience.

OBJECTIVES: The optimal method of managing stress urinary incontinence (SUI) in women undergoing colpocleisis remains unclear, especially in a setting of urinary retention. We aim to compare postoperative retention after colpocleisis with or without concomitant midurethral sling (MUS). METHODS: A retrospective chart review of all women who underwent colpocleisis with or without MUS from October 2007 to October 2017 was performed. Women with preoperative and 2-week postoperative post-void residual volume (PVR) measurements were included. Urinary retention was defined as PVR of ≥100 ml. Analysis included t tests/Wilcoxon rank, Chi-squared/Fisher's exact, and multivariate linear regression models. RESULTS: A total of 231 women with a mean age of 77.7 years (± 6.0 years SD) met the inclusion criteria. One hundred and thirty-eight women underwent colpocleisis alone, whereas 93 women had colpocleisis with MUS. Preoperative retention rates were high (44.9% vs 34.4%, for colpocleisis alone versus with MUS, p = 0.114). Postoperative retention rates were lower and similar between the groups (10.1% vs 11.8%, for colpocleisis alone vs with MUS, p = 0.69). Linear regression models showed the adjusted odds ratio for postoperative urinary retention in patients with concomitant MUS was 1.68 (95% confidence interval: 0.64-4.41) compared with patients with colpocleisis alone and this did not reach statistical significance (p = 0.292). Fortunately, after colpocleisis, women had high rates of resolution of retention, regardless of MUS (80.3% vs 90.6% for colpocleisis alone vs with MUS; p = 0.20). Few women required reoperation for retention (3.1%). CONCLUSIONS: Placement of an MUS at the time of colpocleisis is a safe and effective therapy. This appears to be unaffected by preoperative urinary retention status.

Diarrhea in Placebo Arms of Cancer Studies.

Background/Aim: Diarrhea is among the most common adverse events in early oncology clinical trials, and drug causality may be difficult to determine. Materials and Methods: This is a systematic literature review of placebo arms of randomized cancer trials. Results: Anemia was reported in 95 of 127 placebo monotherapy cohorts. Publications involving healthy volunteers and cancer prevention studies reported lower frequencies than those with cancer patients. The average reported frequency of diarrhea grade 1 or higher among studies in cancer patients was 15%. The maximal reported frequencies for grades 1, 2, 3, 4, 5 were 56, 24, 6, 2, and 0%, respectively. Conclusion: When higher diarrhea frequencies than those are observed in treatment arms of clinical trials, then drug causality is likely.

Consideration of pelvic floor myofascial release for overactive bladder.

INTRODUCTION: Physical therapy has been shown to be effective for women with overactive bladder (OAB). We report on our experience with pelvic floor physical therapy (PFPT) with or without myofascial release as treatment for women with symptoms of urinary urgency or urge incontinence. METHODS: We performed a retrospective chart review, of patients who presented to our tertiary care Urogynecology practice. These women were evaluated and treated between August 2016 and December 2016. We abstracted for symptoms as per history of present illness and the pelvic floor muscle examination. PFPT progress notes were reviewed to determine whether patients received myofascial release techniques, or if therapy was limited to behavioral interventions and urge suppression techniques. We recorded the number of PFPT sessions attended, and whether the patient reported improvement. RESULTS: 77 patients with symptoms of OAB met inclusion criteria and initiated PFPT. Myofascial tenderness of the pelvic floor muscles was found in 56.5% of patients. PFPT was limited to behavioral and urge suppression in 18 patients, while 59 patients received myofascial release techniques. Improvement was reported by 71.4% (n = 55/77) of patients. Improvement increased with number of sessions attended: 1-2: 6% (1/17), 3-5: 94% (16/17), 6-8: 91% (29/32), and >8: 80% (9/11) improved, respectively (p < 0.001). Among patients who had myofascial release, 84.7% reported improvement when compared to only 27.8% of patients without myofascial release. CONCLUSIONS: The data support the inclusion of myofascial release during pelvic floor physical therapy for overactive bladder. At least three sessions of PFPT are necessary for patient reported improvement.

Oral probiotics and the female urinary microbiome: a double-blinded randomized placebo-controlled trial.

PURPOSE: Probiotics may reduce risk of urinary tract infection by preventing colonization of uropathogens. We aimed to determine the change in the ratio between uropathogens:Lactobacillus (U/L) within the lower urinary tract in response to oral probiotic. METHODS: This was a double-blinded randomized controlled trial of healthy pre-menopausal female volunteers. Participants provided daily voided urine for 3 months including three phases of the trial: 1-baseline, 2-intervention, 3-wash-out. Participants were randomized to an oral probiotic (Lactobacillus rhamnosus GR-1 and Lactobacillus reuteri RC-14) versus placebo. The primary outcome was the U/L ratio of daily voided urine, as determined by an enhanced urine culture method. Analysis included t test of the ratios and separate generalized linear mixed effects models (GLMM) for microbiota diversity. RESULTS: 481 samples of seven female participants with mean age 29.1 years (± 5.3 years) were included in the analysis (probiotic n = 4; placebo n = 3). No adverse events were reported. The placebo and probiotic groups had similar mean U/L ratios with no difference between placebo and probiotic groups in Phases 1-3 (p = 0.90, p = 0.58 and p = 0.72, respectively). The probiotic species were never identified in the voided urine. There were no changes between groups in terms of microbiota diversity. CONCLUSION: For young healthy women, the use of oral probiotic did not affect the U/L ratio.

Approach to Ureterovaginal Fistula: Examining 13 Years of Experience.

OBJECTIVE: We describe the management and outcomes of ureterovaginal fistulas over a 13-year period and present a treatment algorithm. METHODS: We performed a review of ureterovaginal fistula cases between January 2005 and December 2017 at our tertiary academic center. Demographics, diagnostic approaches, and treatment outcomes were assessed. RESULTS: Nineteen cases of ureterovaginal fistula were identified. Fistulas developed after hysterectomy in 18 cases and cesarean delivery in 1 case. Our primary treatment was conservative management with ureteral stenting in 12 and reimplantation in 6 cases. There was 1 case of spontaneous resolution. Ureteral stenting was successful in 11 (92%) of 12 patients. Stents were left in place for an average of 66 days (27-92 days). Complications of stents included pyelonephritis in 2 cases (18%) and stricture in 1 case (9%). Ultimately, conservative management was successful in treating ureterovaginal fistulas in 10 (83%) of 12 cases. The indications for primary ureteral reimplantation were concurrent vesicovaginal fistula in 3 cases, history of ureteral injury with surgical repair during the index surgery in 2 cases, and a 1-year delay in diagnosis in 1 case. A variety of follow-up surveillance methods were used, including tampon tests, computed tomographic urograms, retrograde pyelograms, and MAG-3 Lasix renal scans. CONCLUSIONS: In carefully selected patients, ureteral stenting results in high cure rates for posthysterectomy ureterovaginal fistulas and should be considered first-line therapy. Complicated ureterovaginal fistulas may be best managed by primary ureteral reimplantation.

Pelvic floor myofascial pain in patients with symptoms of urinary tract infection.

OBJECTIVE: To correlate lower urinary tract symptoms typically associated with a urinary tract infection (UTI) with physical examination findings of pelvic floor myofascial pain (PFMP). METHODS: This retrospective review included all new patients presenting to a urogynecology clinic between August 2 and December 19, 2016. Patients completed validated questionnaires, had a catheterized urine specimen, and underwent pelvic examination. Associations between demographics, symptoms, urine culture, and PFMP were analyzed. RESULTS: We included 250 patients with urinary frequency (n=160, 64.0%), urgency (n=155, 62.0%), urgency incontinence (n=140, 56.0%), pelvic pain (n=43, 17.2%), and dysuria (n=25, 10.0%). PFMP was detected in 125 (50.0%) patients and culture-proven UTI in 15 (6.0%) patients. Demographics associated with PFMP were lower prolapse stage (P<0.001), age younger than 50 years (P<0.001), lower parity (P=0.028), and non-white ethnicity (P=0.003). Symptoms associated with PFMP were dysuria (adjusted odds ratio 4.13, 95% confidence interval 1.08-15.78), urgency/frequency (2.72, 1.47-5.04), and patient-reported pelvic pain (2.57, 1.08-6.12). These symptoms were independent predictors in multivariable logistic regression analysis. CONCLUSIONS: Most patients had symptoms associated with UTI; however, culture-confirmed diagnosis was infrequent and PFMT was diagnosed in half of participants. Clinicians treating women with these symptoms are advised to examine the pelvic floor muscles.