Bladder Cancer Journal Vol. 8, Issue 1

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

Abstract: 

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 the 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.

CD274 (PD-L1) Copy Number Changes (Gain) & Response to Immune Checkpoint Blockade Therapy in Carcinomas of the Urinary Tract

ABSTRACT:

Systematic Review and Meta-Analysis of Cisplatin Based Neoadjuvant Chemotherapy in Muscle Invasive Bladder Cancer

Abstract: 

BACKGROUND: Cisplatin-based neoadjuvant chemotherapy is the standard of care for muscle invasive bladder cancer (MIBC).

OBJECTIVE: To compare the efficacy and safety of the two most commonly used cisplatin-based regimens; gemcitabine, and cisplatin (GC) vs. accelerated (dose-dense: dd) or conventional methotrexate, vinblastine, adriamycin, and cisplatin (MVAC). METHODS: We searched MEDLINE, Embase, Scopus and other sources. Outcomes of interest included overall survival, downstaging to pT≤1, pathologic complete response (pCR), recurrence, and toxicity. Meta-analysis was conducted using the random-effects model.

RESULTS: We identified 24 studies. Efficacy outcomes were comparable between MVAC and GC for MIBC. dd-MVAC was associated with favorable efficacy compared to GC in terms of downstaging (OR 1.45; 95%CI 1.15–1.82) and all-cause mortality at longest follow-up (OR 0.63; 95%CI 0.44–0.81). However, GC was associated with a better safety profile in terms of febrile neutropenia (OR 0.32; 95%CI 0.13–0.80), anemia (OR 0.32; 95%CI 0.18–0.54), nausea and vomiting (OR 0.27; 95%CI 0.12–0.65) compared to dd-MVAC. Compared to MVAC, patients receiving GC had an increased risk of developing grade 3–4 thrombocytopenia (OR 4.70; 95%CI 1.59–13.89) and a lower risk of nausea and vomiting (OR 0.05; 95%CI 0.01–0.31). Certainty in the estimates was very low for most outcomes.

CONCLUSIONS: Efficacy and safety outcomes were comparable between MVAC and GC for MIBC. Including non-peer-reviewed studies showed higher efficacy with dd-MVAC. A phase III randomized trial comparing the two regimens is needed to guide clinical practice.

Identification of a Novel Ferroptosis-Related Gene Signature for Prediction of Prognosis in Bladder Urothelial Carcinoma

Abstract: 

BACKGROUND: sBladder urothelial carcinoma is the most prevalent type of bladder cancer, characterized by drug resistance, high recurrence rate, and unfavorable prognosis. Ferroptosis is a newly discovered type of non-apoptotic cell death, which has been reported to be strongly correlated with tumor occurrence and development.

OBJECTIVE: In this study, we characterized ferroptosis-specific biomarkers to elucidate the association between ferroptosis-related genes (FRGs) and bladder urothelial carcinoma. METHODS: The TCGA and GEO databases were adopted to obtain data and corresponding clinicopathological information. Univariate and multivariate cox regressions were performed to establish a ferroptosis-related model. Besides, the KM plot visualized prognosis between high-risk and low-risk groups. Moreover, cBioportal platform was used to gather information on genetic alteration and DNA methylation of hub FRGs in BLCA patients. Additionally, the GSEA software was used to detect the difference in gene expression between high-risk and low-risk subgroups.

RESULTS: Six ferroptosis-related genes were identified to be highly correlated with overall survival. Besides, we explored the genetic variations of these FRGs, as well as the correlation between FRG expression and copy number values. Additionally, the DNA methylation status of these FRGs was determined. Moreover, we constructed a ferroptosis risk model with the six FRGs to predict the prognosis of BLCA. The results demonstrated that a higher risk score indicated an unfavorable prognosis. The ferroptosis signature was associated with clinical and molecular characteristics and could be regarded as an independent prognostic factor for BLCA patients.

CONCLUSIONS: In summary, we established and verified a ferroptosis risk model which had the potential to independently predict the prognosis of bladder urothelial carcinoma.

Accuracy of Inchworm Sign on Diffusion-Weighted MRI in Differentiating Muscle-Invasive Bladder Cancer

Abstract: 

BACKGROUND: Inchworm sign is a finding on diffusion-weighted magnetic resonance imaging (DWI-MRI) and is used to better stratify T-staging in muscle-invasive (MIBC) and non-muscle-invasive bladder cancer (NMIBC). An uninterrupted low submucosal signal on DWI, defined as inchworm sign (IS), indicates NMIBC. OBJECTIVE: We aimed to define the diagnostic accuracy of IS in primary bladder cancer, as well as find agreement between the urologists and the radiologist.

METHODS: Between December 2018 and December 2020, we retrospectively analyzed 95 primary bladder cancer patients who had undergone multiparametric-MRI before transurethral resection. Patients with former bladder cancer history, tumors smaller than 10 mm, and MRI without proper protocol, as well as patients who did not attend follow-up, were excluded. In total, 71 patients’ images were evaluated by a genitourinary specialist radiologist and two urologists. Sensitivity, specificity, positive and negative predictive values of IS and VI-RADS in differentiating MIBC and NMIBC, and interreader agreement between the radiologist and urologists were analyzed.

RESULTS: During follow-up, 38 patients (53.5%) were IS-positive, while 33 patients (46.5%) were negative. Among the 33 patients with negative IS, 14 patients (42.4%) had MIBC. Meanwhile, two out of the 38 IS-positive patients (5.3%) had MIBC (p  = 0.00). Sensitivity, specificity, and positive and negative predictive values of IS in predicting MIBC were 87.5%, 63.6%, 41.2%and 94.6%, respectively. The interobserver agreement between the urologists and radiologist was almost perfect (K  = 0.802 and K  = 0.745)

CONCLUSION: The absence of IS on DWI is useful in differentiating MIBC from NMIBC. It is a simple finding that can be interpreted by urologists. 

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

Abstract: 

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

Quality of Life and Health State Utilities in Bladder Cancer

Abstract: 

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.

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

Abstract: 

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.

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

Abstract: 

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

Challenging Cases in Urothelial Cancer: Case 23

Clinical Trials Corner Issue 8(1)

Antibiotics and BCG