Association between Patient-Reported Outcomes and Survival in Patients with Advanced Urothelial Carcinoma Treated with Atezolizumab

BACKGROUND: Atezolizumab is an immune checkpoint inhibitor (ICI) and a frontline treatment of patients with cisplatin-ineligible advanced urothelial carcinoma (UC). There is limited evidence on the prognostic value of patient reported outcomes (PROs) in advanced UC treatment, particularly in the context of ICI therapy. OBJECTIVE: To investigate the prognostic association of PROs with survival in patients with advanced UC treated with atezolizumab. METHODS: This study used data from 467 patients with advanced UC initiating atezolizumab in the IMvigor211 trial. Pre-treatment PROs association with overall survival (OS) and progression free survival (PFS) was assessed using Cox proportional hazard analysis. PROs were recorded via the European Organisation for Research and Treatment of Cancer QLQ-C30. Discrimination performance was assessed via the C-statistic (c). RESULTS: Patient reported physical function, pain, appetite loss, global health, fatigue, role function, constipation, nausea and vomiting, dyspnoea, and insomnia were significantly associated with OS and PFS on univariable and adjusted analysis (P < 0.05). Physical function (c = 0.63), pain (c = 0.63), appetite loss (c = 0.62), global health status (c = 0.62), and fatigue (c = 0.62), were the most prognostic factors of OS. The OS discrimination performance of physical function (c = 0.61) was superior to ECOG PS (c = 0.58). Of patients assessed by investigators as having no performance restrictions (ECOG PS of 0), 38 (18%) and 91 (42%) self-reported low and intermediate physical function scores, respectively. CONCLUSION: Pre-treatment PROs were identified as independent prognostic factors of OS and PFS. Patient-reported physical function was more prognostic of OS than ECOG PS. This highlights a potential for PROs to enable improved patient stratification in ICI trials.

Implications for Efficacy and Safety of Total Dose and Dose-Intensity of Neoadjuvant Gemcitabine-Cisplatin in Muscle-Invasive Bladder Cancer: Three-Week Versus Four-Week Regimen

BACKGROUND: Neoadjuvant cisplatin-based chemotherapy is standard care prior to radical cystectomy in patients with muscle-invasive bladder cancer (MIBC). OBJECTIVE: To assess efficacy and safety of two commonly used neoadjuvant schedules with different total doses and dose-intensities of gemcitabine and cisplatin (GC). METHODS: Data were collected retrospectively from all patients treated between 2010 and 2018 with neoadjuvant chemotherapy according to clinical routine at seven centres in Sweden and Denmark. Patients in Sweden received three cycles of a 4-week schedule (GC-4w: cisplatin 70 mg/m2 day 1, gemcitabine 1000 mg/m2 days 1, 8, 15, q 28 days) and in Denmark four cycles of a 3-week schedule (GC-3w: cisplatin 70 mg/m2 day 1, gemcitabine 1000 mg/m2 days 1, 8, q 21 days). Primary endpoint was pathological response at cystectomy (pT0N0 and < pT2N0). RESULTS: A total of 251 patients were treated with GC-4w and 455 with GC-3w. pT0N0 was significantly higher for patients treated with GC-3w compared to GC-4w, 46% versus 32% (adjusted odds ratio [aOR] 1.80; 95% confidence interval [CI] 1.16–2.80; P = 0.009); and for < pT2N0 60% versus 47% (aOR 1.08; 95% CI 0.70–1.66; P = 0.743). There were no significant differences between GC-4w and GC-3w regarding survival parameters. GC-3w patients discontinued treatment more frequently and showed a higher degree of neutropenia. CONCLUSIONS: A significantly higher complete response-rate was observed in the patient group treated with the more cisplatin-dose-intense 3-week schedule. The side-effect profile was in favor of the 4-week approach while relapse-free and overall survival were similar.

Quality of Life and Health State Utilities in Bladder Cancer

BACKGROUND: Bladder cancer treatments may variably impact health-related quality of life (QOL). OBJECTIVE: To characterize the quality of life of patients with bladder cancer at various time points across the continuum of bladder cancer care from non-muscle-invasive disease to metastatic bladder cancer and develop utility scores to inform cost-effective analyses. METHODS: We performed a cross-sectional survey of bladder cancer patients in the Bladder Cancer Advocacy Network Patient Survey Network. Participants were classified into mutually exclusive health states based upon non-muscle invasive (NMIBC), muscle-invasive (MIBC), or metastatic bladder cancer and completed surveys of generic cancer and bladder cancer-specific quality of life, financial toxicity, and work impairment. We constructed generalized linear mixed models to identify patient, clinical, and treatment factors associated with quality of life over time and derived health state utilities. RESULTS: Among 911 self-identified patients with bladder cancer, overall QOL scores and function domains were worse among those with advanced cancer. Financial toxicity was similar among non-metastatic disease states. Work and activity impairment increased with advancing disease (13%and 12%among non-recurrent NMIBC to 63%and 31%for metastatic disease respectively; p < 0.01). On multivariable analysis, bowel-related QOL was diminished among patients with MIBC, with urinary symptoms and physical function most diminished among patients with metastatic disease. Patients with metastatic and MIBC experienced worse emotional functioning (p = 0.04; p = 0.048). Health state utilities were calculated, highest among those with non-recurrent NMIBC and lowest among those with metastatic disease. CONCLUSION: Generic and bladder cancer-specific QOL diminishes with advancing disease. Health state utility estimates derived from this study can inform shared decision making with patients and may be used to inform future cost-effective analyses.

Qualitative Analysis of Pain in Patients With Locally Advanced or Metastatic Urothelial Carcinoma

Background: Pain is not well described in patients with locally advanced or metastatic urothelial cancer (la/mUC). Objective: To characterize pain and assess the content validity of the Brief Pain Inventory Short Form (BPI-SF) worst pain item in patients with la/mUC receiving first-line treatment in the US. Methods: Qualitative interviews were conducted in patients aged≥45 years with confirmed la/mUC, self-reported la/mUC-attributed pain before enrollment, and no major surgery≤3 months prior to being interviewed. Interview participants were asked open-ended questions about their la/mUC symptoms and pain. “Think aloud” cognitive debriefing was conducted for the BPI-SF worst pain item. Results: Ten participants with laUC and six (38%) with mUC were interviewed. First-line treatments included cisplatin (n = 14; 88%) or carboplatin (n = 2; 13%). The average past-week worst pain score (0–10 scale) was 6.2 (range, 3–10); seven (44%) participants reported severe pain (score≥7). Pain was most frequently reported in the back (n = 14; 88%) and/or pelvic/lower abdominal area (n = 10; 63%). Pain impacted all participants’ physical and daily activities; 81%reported it impacted their overall quality of life. All participants interpreted and completed the BPI-SF worst pain item without difficulty; 15 (94%) reported it was relevant to their la/mUC experience. Participants understood the 24-hour recall period; most supported daily (n = 13; 81%) or weekly (n = 14; 88%) assessment, preferring electronic administration using their phone (n = 14; 88%). Conclusions: Pain attributed to la/mUC impacted physical and daily activities in all participants undergoing first-line treatment for la/mUC. Content validity was demonstrated for the BPI-SF worst pain item in this population.

Sensitivity and Specificity in Urine Bladder Cancer Markers – Is it that Simple?

Marker research and, in particular urine bladder cancer marker research throughout the past three decades, devours enormous scientific resources in terms of manpower (not to mention time spent on reviewing and editorial efforts) and financial resources finally generating large numbers of manuscripts without affecting clinical decision making. This is mirrored by the fact that current guidelines do not recommend marker use due to missing level 1 evidence. Although we recognize the problems and obstacles, the authors of this commentary feel that the time has come to abandon the current procedures and move on to prospective trial designs implementing marker results into clinical decision making. Our thoughts and concerns are summarized in this comment.

Safety and Pharmacokinetics of Intravesical Chitosan/Interleukin-12 Immunotherapy in Murine Bladders

BACKGROUND: Intravesical administration of interleukin 12 (IL-12) co-formulated with the biopolymer, chitosan (CS/IL-12), has demonstrated remarkable antitumor activity against preclinical models of bladder cancer. However, given historical concerns regarding severe toxicities associated with systemic IL-12 administration in clinical trials, it is important to evaluate the safety of intravesical CS/IL-12 prior to clinical translation. OBJECTIVE: To evaluate the pharmacokinetics as well as the local and systemic toxicities of intravesical CS/IL-12 immunotherapy in laboratory mice. METHODS: Local inflammatory responses in mouse bladders treated with intravesical IL-12 or CS/IL-12 were assessed via histopathology. Serum cytokine levels following intravesical and subcutaneous (s.c.) administrations of IL-12 or CS/IL-12 in laboratory mice were compared. Systemic toxicities were evaluated via body weight and liver enzyme levels. RESULTS: Intravesical IL-12 and CS/IL-12 treatments did not induce significant local or systemic toxicity. IL-12 dissemination and exposure from intravesical administration was significantly lower compared to s.c. injections. Weekly intravesical CS/IL-12 treatments were well-tolerated and did not result in blunted immune responses. CONCLUSIONS: Intravesical CS/IL-12 is safe and well-tolerated in mice. In particular, the lack of cystitis and acute inflammation justifies continued investigation of intravesical CS/IL-12 immunotherapy in larger animals and patients with bladder cancer.

Cost of Care in Open Cystectomy Patients Across Time and Space: Does it matter?

BACKGROUND: Many variables may affect the cost of open radical cystectomy (RC) care, including surgical approach, diversion type, patient comorbidities, and postoperative complications. OBJECTIVE: To determine factors associated with changes in cost of care following open radical cystectomy (ORC) for bladder cancer using the National Inpatient Sample (NIS). METHODS: Patients in the NIS with a diagnosis of bladder cancer who underwent ORC with ileal conduit from 2012–2017 using ICD-9-CM and ICD-10-CM codes were identified. Baseline demographics including age, race, region, postoperative complications, and length of stay were obtained. Univariable and multivariable logistic regression were used to identify factors associated with cost variation including demographics, clinical characteristics, surgical factors, and discharge quarter (Q1-Q4). RESULTS: 5,189 patients were included in the analysis, with 4,379 at urban teaching hospitals. On multivariable regression analysis, female sex [$1,734 ($1,024–2,444) p < 0.001)], a greater Elixhauser comorbidity score [$93 ($62–124), p < 0.001], presence of any inpatient complication [$1,531 ($894–2,168), p < 0.001], and greater length of stay [$1,665 ($1,536–1,793), p < 0.001] were associated with a greater cost of hospitalization. Discharge in Q3 (July to September) relative to Q2 (April to June) was associated with a higher cost [$1,113 ($292–1,933), p = 0.008. Trends were similar at urban non-teaching and rural hospitals, except discharge quarter was not associated with a significant change in cost. CONCLUSIONS: Significant differences in cost of ORC with ileal conduit exist with respect to patient sex, medical comorbidities, and discharge timing. These differences may relate to greater disease burden in female patients, patient complexity, and variation in postoperative care in academic programs.