bluuebunny/crossref_metadata_2025 huggingface dataset:
The association between functional impairment pre- and post-cystectomy with neoadjuvant chemotherapy use in patients with muscle-invasive bladder cancer.
Authors: Osterman Chelsea K. , Deal Allison Mary , Nyrop Kirsten A. , Milowsky Matthew I. , Muss Hyman B. , Smith Angela
Published: May 2020

e17008

Background: Standard of care treatment for muscle-invasive bladder cancer (MIBC) includes neoadjuvant chemotherapy (NAC) followed by radical cystectomy (RC), which can be associated with major toxicity. It is unknown whether patients who receive NAC have differences in functional impairment prior to RC, degree of functional decline post-RC, or time to return to baseline functional status post-RC compared to patients who do not receive NAC. Methods: A total of 80 patients were included in this study. Patients completed an initial geriatric assessment (GA) post-NAC but prior to RC, which was repeated at 30, 90 days, and 1 year post-cystectomy. Patients were classified as impaired or not impaired on each GA domain based on previously established cut points. Percentage impairment was calculated as the number of domains impaired out of the total number of domain assessments completed for each patient at each time point. Results: Median age was 68 for patients who received NAC (66% received gemcitabine/cisplatin) and 72 for patients who did not (p = 0.06), with elevated creatinine as the most common reason for not receiving NAC (57%). Overall, 74% of patients were impaired on at least 1 GA domain pre-surgery (NAC 75%; no NAC 71%) and 86% at 30 days post-RC (NAC 86%; no NAC 87%). Groups did not differ significantly in percentage of patients impaired on each GA domain or median percentage impairment at any time point. For both groups, median percentage impairment increased significantly at 30 days post-RC compared to pre-RC (NAC: 36% vs. 15%, p < 0.001; No NAC: 32% vs. 15%, p = 0.002), followed by a decrease in percentage impairment at 90 days post-RC compared to 30 days post-RC (NAC: 14% vs. 36%, p < 0.001; No NAC: 16% vs. 32%, p = 0.15). There was no difference in impairment at 90 days post-RC compared to pre-RC (NAC: 14% vs. 15%, p = 0.41; No NAC: 16% vs. 15%, p = 0.31). Conclusions: Patients with MIBC frequently have functional impairments at baseline, and their degree of impairment worsens in the short term post-RC. However, patients return to their baseline function by 3 months post-RC. Receipt of NAC was not associated with increased levels of functional impairment at any time point or a delayed return to baseline.
Evaluation of mood disorders in bladder cancer patients and their primary caregivers.
Authors: Au Daniel , Chestnut Connor , Brevik Andrew , Kirwan Mateo , Taylor John A , Harry Kadie , Dwyer Meagan L , Thompson Jeffrey , Wulff-Burchfield Elizabeth Marie
Published: May 2020

e17013

Background: Mood disorders are prevalent in cancer patients in general and in bladder cancer specifically. New psychiatric diagnoses post-bladder cancer treatment are associated with decreased survival. Bladder cancer management is cost- and labor-intensive from a healthcare and social standpoint. Tools such as Enhanced Recovery After Surgery (ERAS) pathways have been developed to lower this burden of care, but focus entirely on physiologic parameters without addressing the psycho-social burden of bladder cancer or its treatment. Data is lacking regarding prevalence of mood disorders in bladder cancer patients, especially those with non-muscle-invasive disease, their caregivers, and regarding the relationship between patient and caregiver mood disorders. Methods: A cross-sectional dyadic study of 96 bladder cancer patients and their self-designated primary caregivers. Study utilized retrospective chart review and separate telephone interviews of patient and caregiver. Patients must have received initial diagnosis or proven recurrence within the past 24 and 12 months, respectively, and have no metastatic disease. Surveys included Patient Health Questionnaire 9 (PHQ-9) for depression, General Anxiety Disorder-7 (GAD-7) for anxiety, Short Form Health Survey (SF-12) for health-related quality of life, and a financial toxicity measure. Pearson correlation and regression models were used for analysis. Results: 49% (9.3% moderate to severe, 40.2% mild) of bladder cancer patients and 33% of caregivers (7.2% moderate to severe, 24.8% mild) had symptoms of depression. Patients’ PHQ-9 scores were moderately correlated with their caregiver, r = 0.49 (95% CI 0.32,0.63 p < 0.001). GAD-7 scores were not correlated between patient and caregiver r = 0.08 (95% CI 0.12,0.28 p = 0.45). Both patient (r = -0.31, 95%CI -0.48,-0.10 p < 0.004) and caregiver (r = -0.41, 95%CI -0.58,-0.22 p < 0.001) incomes were inversely associated with depression symptoms. Results were similar when stratified by non-muscle-invasive and muscle-invasive status. Conclusions: Depression is common among bladder cancer patients and their caregivers and these symptoms are correlated between patient and their caregiver. This correlation did not appear to hold true with respect to anxiety. Financial situation may play a role as increasing income was negatively correlated with depression symptoms. Patient and caregiver may both experience adverse psycho-social consequences from bladder cancer and treatments and pose a joint opportunity for intervention to lower burden of care.
Small cell bladder cancer: Treatment patterns and clinical outcomes.
Authors: Sekar Rishi Robert , Diamantopoulos Leonidas Nikolaos , Vakar-Lopez, MD Funda , Grivas Petros , Psutka Sarah P. , Schade George R. , Lin Daniel W. , Gore John L. , Montgomery Robert B. , Wright Jonathan L.
Published: May 2020

e17014

Background: Small cell bladder cancer (SCBC) is a rare histologic variant associated with poor oncologic outcomes and propensity for metastasis, however, there remains a paucity of data regarding the role of chemoradiation. We review our institutional experience of patients with small cell bladder cancer (SCBC) treated with radical cystectomy (RC) versus concurrent chemoradiotherapy (CCRT). Methods: We retrospectively reviewed our institutional database for pts with SCBC treated with RC or CCRT and compared them to pts with conventional urothelial carcinoma (CUC) treated with RC. Clinicopathologic data and outcomes were captured and compared between treatment groups. Overall (OS) and recurrence-free survival (RFS) were estimated utilizing the Kaplan Meier method. T test, χ2 test and log-rank test were used for group comparisons. Factors significant in the univariate analysis for OS were included in multivariable Cox models. Results: We identified 38 consecutive pts with SCBC, of whom 24 (63%) had SC predominant ( > 50%) histology. At presentation, 31 (82%) had muscle invasion, 8 (22%) had nodal involvement, and 7 (18%) had distant metastasis. Twenty-eight (73%) pts proceeded to definitive therapy, with RC in 20 (53%) and CCRT in 8 (21%). Among pts treated with CCRT, 4 (50%) had complete response on cystoscopy, 2 (25%) had residual disease with 1 (12.5%) proceeding to salvage cystectomy, and 2 (25%) progressed with metastasis. Among pts treated with RC, 15 (75%) received neoadjuvant chemotherapy (NAC) with platinum/etoposide, of whom 3 (20%) experienced a pathologic complete response (pCR, ypT0N0), 3 (20%) had residual UC but no SCBC, and 9 (60%) had residual SCBC. Median OS was comparable between RC and CCRT groups (30.4 vs. 26.2 months, p = 0.633). Compared to pts with CUC treated with RC (n = 457), those with SCBC treated with RC had similar clinical stage, rates of carcinoma in situ, lymphovascular invasion, and positive surgical margins (all p > 0.05). Median OS and RFS were inferior for SCBC treated with RC (30.4 vs 109.7 months, p = .001; 13.1 vs 86.1 months, p = .002). On multivariable analysis among pts treated with RC, SCBC was significantly associated with shorter OS adjusting for pT and pN stage, performance status, and age. Conclusions: Pts with SCBC undergoing RC had significantly worse oncologic outcomes compared to pts with CUC, however RC and CCRT had comparable outcomes in pts with SCBC. The pCR rate to NAC was unexpectedly low. Larger sample size, assessment of other confounders and longer follow-up are needed for validation.
Associations between baseline body composition and cancer-specific mortality following neoadjuvant chemotherapy and radical cystectomy for bladder cancer.
Authors: Diamantopoulos Leonidas Nikolaos , Ngo Steven , Maldonado Reno , O'Malley Ryan Blair , Laidlaw Grace , Fintelmann Florian J. , Holt Sarah K , Gore John L. , Schade George R. , Lin Daniel W. , Grivas Petros , Montgomery Robert B. , Hsieh Andrew Caleb , Cheng Heather H. , Yezefski Todd , Schweizer Michael Thomas , Yu Evan Y. , Wright Jonathan L. , Psutka Sarah P.
Published: May 2020

e17015

Background: Sarcopenia is a modifiable risk factor independently associated with cancer-specific mortality (CSM) in bladder cancer (BC). Sarcopenic obesity, where obesity is measured by fat mass index [FMI, total body fat (kg)/height(m)2], has been proposed as an additive insult. To date, studies have overwhelmingly been performed in patients treated without neoadjuvant chemotherapy (NAC). Herein, we evaluate associations between baseline skeletal muscle index (SMI), FMI, and CSM in patients treated with NAC and radical cystectomy (RC). Methods: Lumbar SMI (cross sectional area of skeletal muscle/height2, cm2/m2) was measured on a computed tomography (CT) image at the level of the third lumbar vertebral body, within 60 days prior to NAC. Total body FMI was calculated from visceral and subcutaneous fat cross-sectional areas. Patients were classified as being sarcopenic, according to sex-specific consensus definitions: Male: SMI < 55, Female: SMI < 39, and as obese if Male: FMI > 9, Female: > 13. Cancer-specific survival (CSS) was estimated using the Kaplan Meier method. Associations with CSM were summarized with multivariable Cox proportional hazards models. Results: 143 patients had CT scans of sufficient quality (2005-18). There were no significant differences in clinicopathologic characteristics between the study cohort and patients without available imaging (N = 261). Cisplatin-based NAC was given to 125 patients (87%), and 18 (13%) received other regimens. In total, 86 (60%) patients were sarcopenic, 52 (36%) obese, and 25 (17%) both sarcopenic and obese, while 48 (34%) were sarcopenic with normal FMI. Median follow-up was 2.7 years (IQR 1.2-6.2), and 43 patients died from BC. Three-year CSS was 61% (sarcopenic) vs. 77% (p < 0.05). Sarcopenic patients with normal FMI had the worst 3-year CSS (55%) compared to those with sarcopenia and FMI-obesity (79%), normal SMI with FMI-obesity (69%), and normal body composition (88%, p = 0.03). On multivariable analysis, neither FMI (HR: 0.77, 95% CI: 0.47-1.3, p = 0.3) nor SMI was independently associated with CSM (HR: 0.98, 95% CI: 0.96-1, p = 0.07) after adjustment for ASA score, pathologic tumor, and nodal stage. Conclusions: In patients treated with NAC+RC, pretreatment SMI trended towards independently predicting risk of CSM. Patients with sarcopenia and normal fat demonstrated the worst CSS. Further study is warranted on the impact of NAC on body composition and the role of the latter in risk stratification of this high-risk patient population.
Immune-related adverse events (irAEs) among urothelial carcinoma (UC) patients treated with PD-1 VS PD-L1 inhibitors: A real-world observational study.
Authors: George Saby , Bell Elizabeth , Engel-Nitz Nicole , White John C , Lal Lincy S. , Liu Frank Xiaoqing , Kim Ruth , Krulewicz Stan , Kasturi Vijay , Zheng Ying
Published: May 2020

e17017

Background: Anti-PD-1/PD-L1 agents are US FDA-approved for patients with advanced or metastatic UC, but limited information exists on real world irAEs among this patient population. We examined the rates and time to onset of select irAEs in UC patients receiving PD-L1s vs PD-1s in the real world. Methods: This observational study included US commercial and Medicare Advantage health plan members from Optum Research Database with UC and treated with a PD-1 or PD-L1 agent between 01-Sep-14 and 30-Apr-19. Baseline characteristics were assessed ≤ 6-months prior to the first claim for anti-PD-1/PD-L1. 21 irAEs were chosen a priori based on the ASCO clinical guideline on irAE management, clinical input, frequency, and cost of treatment. Patients were followed for newly occurring irAEs, based on claims ICD codes, during the PD-1/PD-L1 therapy and up to 180 days after if no new treatment, study period end, death, or disenrollment. Kaplan-Meier method was utilized to calculate time to onset of irAEs. Results: The study included 240 patients receiving PD-L1s and 317 receiving PD-1s. Baseline demographics were similar (Table). The most common irAEs were 1) thyroid disorders, 2) impaired ventricular function with heart failure and vasculitis, 3) rash, and 4) nephritis. UC patients receiving PD-L1s had a lower rate of irAEs vs PD-1s, mainly driven by lower rates of hematologic and endocrine toxicities (Table). UC patients receiving a PD-L1 also had longer time to irAE onset (p-value = 0.05). Conclusions: UC patients receiving PD-L1s had a lower incidence rate of irAEs and longer time to irAE onset than patients on PD-1s. Findings suggest patients receiving PD-1s may require more intense monitoring for irAEs than patients taking PD-L1s. [Table: see text]
Marker of lipid peroxidation TBARS predicts survival in patients with metastaticurothelial carcinoma (MUC).
Authors: Slopovsky Jan , Kucharska Jarmila , Obertova Jana , Mego Michal , Kalavska Katarina , Gvozdjakova Anna , Palacka Patrik
Published: May 2020

e17023

Background: Oxidative stress plays a significant role in cancer development and progression. A marker of lipid peroxidation TBARS is upregulated in various diseases. The objective of this prospective study was to explore predictive and prognostic values of TBARS in MUC patients (pts.) before the first-line platinum-based chemotherapy. Methods: Seventy-two consecutive pts. (57 men) with MUC (58 bladder, 14 upper GU tract) were enrolled into this study. Performance status ECOG ≥ 2 had 11 pts., visceral metastases were present in 34 pts. Most common type of treatment regimen was gemcitabine and cisplatin (65 pts.), gemcitabine and carboplatin received 7 pts. Based upon TBARS mean of 6,06 μmol/L, pts. were dichotomized into low and high groups. Progression-free survival (PFS), overall survival (OS) and their 95% CI were estimated by Kaplan-Meier method and compared with log-rank test. Results: At median follow-up of 9.6 months, 65 pts. experienced progression and 64 pts. died. Pts. with low TBARS had significantly better survival opposed to pts. with high TBARS (HR 0.44, 95% CI 0.27-0.74; P = 0,0009 for OS and HR 0.51; 95% CI 0.31-0.84; P = 0,006 for PFS, respectively). Pts. with ECOG ≤ 1 had significantly better both, OS and PFS in comparison to pts. with ECOG > 2. Conclusions: In this study, high plasma TBARS levels in patients with MUC before chemotherapy initiation were associated with poor survival. Therefore, this biomarker could be used for identification of patients with worse prognosis and could lead to better patient stratification and treatment decision making. The study was supported by VEGA 1/0614/12. Key Words: Metastatic Urothelial Carcinoma. Platinum-Based Chemotherapy. Lipid Peroxidation. TBARS. Survival.
Effect of epigenetic imprinting biomarkers in urine exfoliated cells (UEC) on the diagnostic accuracy of low-grade bladder cancer.
Authors: Zhou Ning , Cheng Tong , Li Xing , Pineda John P. , Shen Rulong , Wang Xiaonan , Si Han , Shi Panying , Zeng Shuxiong , Xu Chuanliang
Published: May 2020

e17027

Background: Urine Exfoliated Cells (UEC) is the most widely used sample for noninvasive bladder cancer detection. However, current UEC-based methods including urinary cytology and other molecular detections showed low sensitivities especially for low-grade cancer (< 50% sensitivity). Epigenetic alterations such as elevated allelic expression of imprinted genes usually occur at early stages of malignancy, and can be considered as potential bladder cancer biomarkers. In this study, Quantitative Chromogenic Imprinting Gene In-Situ Hybridization (QCIGISH) was conducted to analyze the biallelic expression (BAE) and multiallelic expression (MAE) in UEC, and develop a more accurate method for early stage bladder cancer. Methods: 53 patients with urinary system diseases including 13 low-grade bladder cancer, 24 high-grade bladder cancer and 16 benign lesions, as well as 28 healthy volunteers were recruited in clinical trial NCT03563443 for validation. The total expression (TE), BAE and MAE of imprinted genes GNAS, PEG10, GRB10, SNRPN and HM13 were blindly detected by QCIGISH. The severity of malignancy was predicted by a grading model previously established on 229 tissue FFPE and cystoscopic biopsy samples, and subsequently validated with the pathology and clinical diagnosis results. Results: The QCIGISH method achieved 84.6% and 95.8% sensitivities for low- and high-grade bladder cancers, respectively, with an equally high specificity of 97.7%. The sensitivity of QCIGISH for low-grade bladder cancer is much higher than standard urinary cytology (16%), and FDA-approved molecular tests such as Hemoglobin Dipstick (38%), BTA Stat (36%), NMP22 BladderChek (25%), and ImmunoCyt (47%). Conclusions: The high accuracy of QCIGISH especially for low-grade bladder cancer demonstrated its great potential in becoming an important and powerful clinical tool for noninvasive diagnosis and large-scale screening for early bladder cancer.
Establishment of a primary cell culture of bone metastasis from urothelial carcinoma.
Authors: Spadazzi Chiara , Cocchi Claudia , Casadei Roberto , Brandolini Francesca , Pieri Federica , Bongiovanni Alberto , Recine Federica , Liverani Chiara , De Vita Alessandro , Miserocchi Giacomo , Calpona Sebastiano , Debonis Silvia Angela , Ibrahim Toni , Mercatali Laura
Published: May 2020

e17030

Background: Urothelial carcinoma (UC) accounts for 90% of cases of bladder cancer. In advanced UC diagnosis, skeletal involvement is frequent. Here we report the establishment of a primary culture of bone metastasis (BM) from High Grade UC derived from 81 years-old patient with a previous diagnosis of papillary urothelial cancer in 2016. After 2 years, patient relapsed to bone and visceral sites and because of poor clinical condition, patient underwent palliative best supportive care. Methods: Patient-derived bone metastatic cell culture was obtained from a surgical specimen. Tumor cells were isolated by collagenase digestion. Cells were seeded on in vitro 2D plates or into 3D collagen scaffolds composed of bovine collagen type I. The establishment of tumor cell isolation was confirmed through the evaluation of cytomorphologic features and positive pan-citokeratin staining. Then, drug treatments was performed and cell survival was evaluated. The study was approved by Ethical Committee and patient signed an informed consent. Results: After a long-term culture, we were able to isolate from a 3D scaffold a tumor clone that successfully growth until passage 20. Stabilized cells generate spheroid-like aggregates, recreating acinar-structures typical of the primary papillary urothelial tumor. Next, we treated cells with: Gemcitabine (Gem), Carboplatin (Carbo), Docetaxel, Carbo+Gem and Bone targeted drugs (Zoledronic Acid and Denosumab). The most effective treatment was Gem+Carbo, in particular 24% of survival in 2D platform and 87% on 3D collagen scaffold. For all treatments, cells cultured on 3D scaffold were more resistant to drugs, mimicking more closely the in-vivo condition. Conclusions: We were able to isolate and establish a BM primary culture from UC using a 3D in-vitro collagen scaffold. This system can recreate microenvironmental conditions more similar to in-vivo ones and it promoted the isolation of tumor cell clones from stromal components of the heterogeneous primary culture. This cell line could be useful to investigate the molecular and genetic profile in order to identify promising molecular targets and to better understard the natural history of BM from UC.
Long-term outcomes among BCG-treated high-risk non-muscle invasive bladder cancer patients in an equal access setting.
Authors: Williams Stephen B. , Howard Lauren , Foster Meagan , Klaassen Zachary William Abraham , Sieluk Jan , Li Haojie , Imai Kentaro , Sbar Eric , De Hoedt Amanda M. , Freedland Stephen J.
Published: May 2020

e17031

Background: Management of high-risk non-muscle invasive bladder cancer (HR NMIBC) represents a clinical challenge due to high failure rates despite prior bacillus Calmette-Guérin (BCG) therapy. We describe real-world patient characteristics, long-term outcomes, as well as the economic burden in the HR NMIBC population. Methods: We identified a random sample of 412 HR NMIBC patients who received ≥ 1 dose of BCG within Veterans Affairs (VA) centers across the United States from January 1, 2000, to December 31, 2016. HR NMIBC was defined as high-grade Ta (TaHG), T1, and/or carcinoma-in-situ (CIS). We analyzed the number of BCG instillations received, as well as used the Kaplan-Meier method to estimate event-free survival for cystectomy and bladder cancer-specific death. All-cause expenditures were summarized as medians with corresponding interquartile ranges (IQR) and adjusted to 2019 USD. Results: The median (IQR) age at diagnosis was 67 years (61-74), with most patients being white (84%) and male (81%). At HR NMIBC diagnosis, 69 (17%) patients had CIS +/- T1 or TaHG, and 341 (83%) had TaHG or T1, no CIS. The vast majority of patients [n = 363, (90%)] received six BCG instillations (range: 1-7) within 365 days of the first dose. The total follow-up was 2,694 person-years. From BCG initiation to end of follow-up, the median all-cause expenditures per patient were $358,593 (257,699 – 652,853). Conclusions: In this equal access setting, the vast majority of HR NMIBC patients received 6 instillations of BCG within 1 year, although the interval over which the instillations were given varied among patients. Patients with CIS appeared to have a worse prognosis, as 24% underwent cystectomy, and 13% died of bladder cancer at 10 years of follow-up. These findings also highlight the considerable economic burden of HR NMIBC. [Table: see text]
Clinical outcome in terms of survival and treatment response of patients with metastatic urothelial carcinoma harboring FGFR alterations compared to wild-type tumors.
Authors: Sevillano Elena , Rodriguez-Moreno Juan Francisco , Barquin Arantzazu , Yagüe Monica , Ruiz Sergio , Navarro Paloma , Amarilla Sandra , Polo Ojea Patricia , García-Donas Jesús
Published: May 2020

e17042

Background: FGFR gene alterations are a new target in metastatic urothelial carcinoma (mUC). However, controversial data have been published regarding the outcome of these tumors.In order to assess the prognostic value of this gene, we aimed to compare survival and response to treatment of patients harboring FGFR alterations vs wild type (WT) tumors. Methods: Medical records of patients with advanced urothelial cancer screened for FGFR mutations or fusions at our center were reviewed. Results: Between May 2011 and December 2019 up to 149 patients completed any screening test for FGFR alterations. 30 cases (20,1%) were deemed as positive (mutations: 12, amplifications: 9, rearragements /fusions: 4 and not specified in 5). 30% of the cases were Upper Tract Urothelial carcinoma (UTUC) versus 70% bladder UC. 8% patients had liver metastases and 100% PS ≤ 1 at first line.. 73% (22/30) received chemotherapy (1st line:15, 2nd line; 4, 3rd line: 4) with 1CR, 9 PR, 2SD in first line. 50% (15/30) received a checkpoint inhibitor (1st line:5, 2nd line:5, 3rd line:5). Of these, 2 cases responded, 2 remained stable and 8 progressed. Overall, 40% (12/30) received an FGFR inhibitor (1st line: 7, 2nd line: 4, 3rd line: 1). 54% (6/11) experimented tumor response (complete:1, partial:5). Median overall survival for the whole FGFR population was 24,6 month. Median progresion free survival was:1st line: 4,1 mo, 2nd line: 4,1, 3rd line: 7,1 respectively. Among the 119 cases deemed as FGFR WT. 95% of primary tumors were located at the bladder. 64% had liver metastases and PS ≥2: 34% at first line treatment. 43%(52/119) received chemotherapy: 1st line:33, 2nd line:13, 3rd line: with 4CR, 11PR, 4SD, 9PD. And 40% (48/119 ) CPI: 1st line: 30, 2nd line: 15, 3rd line:3 with 1CR, 3 PR, 4SD, 19PD. The median OS was 9,9 months for patients with wild-type patients. Median progresion free survival was: 1st line: 4,5 mo, 2nd line: 2,3, 3rd line: 0.8 month. Conclusions: FGFR is a relatively common molecular alteration in UC. Patients harboring a FGFR alteration present a better prognosis than wild type tumors. Clinical benefit with chemotherapy and CPIs was similar in both populations.
Oncotherad immunotherapy elicits promising responses in Bacillus Calmette-Guérin-unresponsive non–muscle invasive bladder cancer: Results from phase I/ II study.
Authors: Alonso João Carlos Cardoso , Reis Ianny Brum , Gonçalves Juliana Mattoso , Sasaki Bianca Ribeiro de Souza , Cintra Adriano Angelo , Duran Nelson , Billis Athanase , Fávaro Wagner José
Published: May 2020

e17048

Background: Standard treatment for high-grade non-muscle-invasive bladder cancer (HGNMIBC) is transurethral resection of the bladder tumor followed by intravesical Bacillus Calmette-Guérin (BCG) immunotherapy. Up to 40% of patients with HGNMIBC will fail intravesical BCG therapy. A promising therapeutic perspective is represented by OncoTherad immunotherapy. OncoTherad is a nanostructured inorganic phosphate complex associated to glycosidic protein developed by University of Campinas/Brazil that exhibits antitumor properties. The aims of this study were to evaluate the efficacy and safety of OncoTherad immunotherapy for BCG-refractory or relapsed HGNMIBC. Methods: We conducted a prospective, single-center (Municipal Hospital of Paulinia, São Paulo, Brazil), single-arm phase I/ II study of OncoTherad immunotherapy in 29 (18 male, 11 female) patients with BCG-unresponsive HGNMIBC (≥ 1 previous course of BCG intravesical therapy). The schedule was initiated with weekly intravesical (120 mg/mL) and intramuscular (25 mg/mL) OncoTherad treatment for 6 weeks, followed by one every other week application for 3 months and, one monthly application until the end of the treatment (24 months). Follow-up was performed with systematic mapping biopsies of the bladder, cystoscopy and ultrasound. The primary endpoint was pathological complete response (pCR) and recurrence-free survival (RFS). The recurrence was defined as histology proven tumor recurrence (any grade) and monitored at 3-month intervals. Secondary endpoints were time to disease recurrence and safety response. Results: The median age of the 29 patients was 64 years (range 34-94). At baseline pTis, pTaG2-3, pT1G2-3 occurred in 10%, 59% and 31% of patients respectively. OncoTherad treatment showed pCR rates (95% CI) of 100% at 3, 6 and 9 months, 89,6% (26/29) at 12 months and, 89,6% (26/29) at 24 months. A 24-months RFS rate in all patients was 79,3%. Also, the median time to disease recurrence for patients was 459 days (15,3 months; 95% CI) at 24-months follow-up. 95% of adverse events were Grade 1 or 2. The most commonly reported treatment-related adverse events were dysuria (51,7%), cystitis (34,5%), pruritus (44,8%), rash (27,6%), arthralgia (27,6%) and fatigue (27,6%). Conclusions: In conclusion, OncoTherad seems a safe and effective treatment option for BCG-unresponsive HGNMIBC patients and may provide benefit for preventing tumor recurrence. Clinical trial information: RBR-6swqd2.
Chemotherapy-induced peripheral neuropathy (CIPN) as a predictor of decreased quality of life and cognitive impairment in testicular germ cell tumor survivors.
Authors: Chovanec Michal , Galikova Dominika , Vasilkova Lucia , De Angelis Valentina , Rejlekova Katarina , Obertova Jana , Sycova-Mila Zuzana , Palacka Patrik , Kalavska Katarina , Svetlovska Daniela , Mladosievicova Beata , Mardiak Jozef , Mego Michal
Published: May 2020

e17063

Background: Chemotherapy-induced peripheral neuropathy (CIPN20) after curative treatment for testicular germ cell tumors (GCTs) has been previously reported. The impact of CIPN on long-term quality of life (QOL) in GCT survivors remains unclear. Herein, we aimed to evaluate chemotherapy-induced peripheral neuropathy (CIPN20) in association with QOL in GCT survivors. Methods: European Organisation for Research and Treatment of Cancer (EORTC) CIPN20, QLQ-C30 and Functional Assessment of Cancer Therapy-Cognitive Function (FACT-Cog) questionnaires were prospectively completed by GCT survivors (N = 153) at National Cancer Institute in Slovakia during their annual follow-up. The median follow-up was 10 years (range 4-25). Upon obtaining the scores from each questionnaire per recommended guidelines, each score from QLQ-C30 and FACT-Cog was correlated with CIPN defined as high or low (above and below median) as obtained from CIPN20. Results: GCT survivors with CIPN high reported impairment in quality of life in QLQ-C30. The global health status was lower in survivors with high vs low CIPN (mean score ± SEM: 66.5 ± 1.9 vs. 86.2 ± 1.8, P < 0.00001). Survivors with CIPN high reported substantially worse physical, role, emotional, cognitive and social functioning compared to CIPN low (all P < 0.00001). CIPN high survivors perceived more fatigue, nausea, pain, dyspnoea, appetite loss and more sleeping disorders compared to CIPN low (all P < 0.0001). Higher burden of CIPN was associated with more financial problems vs CIPN low (mean score ± SEM: 19.6 ± 2.6 vs. 6.67 ± 2.3, P = 0.0002). Cognitive impairment was higher in all FACT-Cog domains including the overall cognitive function score (all P < 0.001) for CIPN high. Spearman analysis has confirmed negative correlations of CIPN20 overall score with QLQ-C30 global health status (R = -0.54, P < 0.0001) and with FACT-Cog overall cognitive function score (R = -0.52, P < 0.0001). Conclusions: CIPN is a powerful predictor of disturbances in QOL and cognitive functioning among GCT survivors. Physicians should never over-treat patients unnecessarily and novel therapies with lower burden of late toxicity should be researched
Risk of hypocalcemia in cancer patients treated with cabozantinib: A meta-analysis.
Authors: Khorasanchi Adam , Wu Shenhong
Published: May 2020

e17067

Background: Cabozantinib as a multiple tyrosine kinase inhibitor has been used extensively in cancer treatment and clinical trials, and is associated with the development of hypocalcemia. Its impact on calcium metabolism is not clear. We have performed a meta-analysis to determine the overall risk of hypocalcemia with cabozantinib in cancer patients. Methods: Databases including PubMed and Google Scholar until January 2020 were used to identify relevant studies. Studies of patients assigned to cabozantinib with available data on hypocalcemia were included. Incidence and relative risk (RR) of hypocalcemia were calculated using a random-effects or fixed effects model, depending on the heterogeneity of the included studies. Results: 88 articles were screened with a total of eight studies including 1,460 cancer patients were selected for analysis. For patients receiving cabozantinib, the overall incidences of all-grade and high-grade (grade 3 or 4) hypocalcemia were 15.5% (95% CI: 12.1-42.5%) and 3.5% (95% CI: 1.1-6.8%), respectively. The incidences of all-grade and high-grade hypocalcemia varied significantly with tumor types and cabozantinib dose. Cabozantinib was associated with a significantly increased risk of all-grade and high-grade hypocalcemia with RR of 6.2 (95% CI: 2.6-14.5, p < 0.001) and 10.7 (95% CI: 2.0-56.2, p = 0.005) in comparison with controls including placebo or sunitinib. Conclusions: Cabozantinib was associated with a significantly increased risk of developing all-grade and high-grade hypocalcemia in cancer patients. Further studies are needed to understand the effect of cabozantinib on calcium metabolism and patient outcome.
The serum level of the components of the renin-angiotensin system correlates with its tumor tissue expression in kidney cancer patients.
Authors: Osokin Roman , Komarova Ekaterina , Aboyan Igor , Maksimov Aleksey Yu. , Ushakova Natalya D. , Ischenko Roman , Shatova Olga , Komarova Elizaveta
Published: May 2020

e17068

Background: To date, it has not been decided whether the locally-generated components of the renin-angiotensin system (RAS) involved in the pathogenesis of kidney cancer and arterial hypertension, and are local and systemic RAS related? The aim was to assess the relationship of the level of RAS in the tumor tissue and peripheral blood in patients with localized kidney cancer with arterial hypertension. Methods: In patients with localized kidney cancer T1N0M0 (KС) and arterial hypertension of the I-II stage (AH), tissue and serum levels of angiotensin I, angiotensin II, angiotensin (1-7), as well as angiotensin converting enzymes (ACE and ACE2) were determined in the following groups: patients with KC without AH (n = 35, KC) and with concomitant AH (n = 30; KC+ AH). The normative values of peripheral blood indices were revealed in healthy donors (n = 30). Results: The level of all studied RAS peptides in the serum of patients with KC was increased in comparison with healthy donors regardless of concomitant hypertension, and the activity of both circulating angiotensin-converting enzymes, on the contrary, was increased only in patients with hypertension. The level of AT1 exceeds the control indicators by 1.7 times (KC) and 2.8 times (KC + AH). The formation of AT2 is higher in the KC + AH compared to KC (2.2 times versus 1.7 times, at p < 0.05). The content of AT (1-7) significantly exceeds the control (1.3 times on average, p < 0.05) and higher in the KC + AH. Increased enzyme activity was detected in KC + AG: increased by 1.5 times (p < 0.05) and 1.7 (p < 0.05) compared with the control for ACE and ACE2, respectively. The pair correlation coefficients between the serum RAS and the studied tissues in the KC were: for AT1 -0.78/0.65; АТ2-0.64/0.59 and АТ (1-7) - 0.56/0.51; ACE2 0.55/0.65 (for tumor/peritumoral tissue: in all cases at p < 0.05). In the KC+AH, these ratios were: for AT1 -0.85/0.81; АТ2-0.72/0.74 and АТ (1-7) - 0.65/0.59; ACE2 0.61/0.52 (for tumor / peritumoral tissue: in all cases at p < 0.05). Conclusions: The serum content of RAS peptides had positive statistical relationships with the corresponding parameters in tumor and peritumoral tissues of kidney cancer pts. However, in hypertensive patients with kidney cancer the correlations found had a tightness of higher strength. Positive correlations of the level of locally generated tumor parameters of RAS with their circulating analogues indicate the possibility of their use as diagnostic markers of the development of kidney cancer.
Sequential treatment with pazopanib followed by nivolumab in patients with renal cell carcinoma: Updated interim results of the non-interventional study PAZOREAL.
Authors: Bedke Jens , Boegemann Martin , Schostak Martin , Hering-Schubert Christiane , Welslau Manfred , Schleicher Jan , Petzoldt Alexander , Doehn Christian , Gruellich Carsten , Goebell Peter-Juergen , Steiner Thomas , Degenkolbe Elisa , Hanson Sven , Grünwald Viktor
Published: May 2020

e17075

Background: Real-world evidence is urgently needed to monitor the translation of new treatment approaches into routine clinical practice as well as to improve cancer treatment and survivorship care. Methods: PAZOREAL is a prospective, multicenter, non-interventional study to evaluate effectiveness, tolerability, safety, and quality of life (QoL) in patients (pts) with advanced or metastatic renal cell carcinoma (mRCC) treated with 1st-line pazopanib (PAZO) followed by 2nd-line nivolumab (NIVO). The primary variable was time on drug (TD) in the respective treatment (Tx) lines. Other endpoints include overall survival (OS), safety and QoL evaluated by EQ-5D-5L. Results: Between December 2015 and September 2017, 414 pts were enrolled and 388 pts started first-line PAZO Tx, 136 pts subsequently received NIVO as second-line Tx. At time of data-cut (30 Sep 2019) median TD was 6.5 months (95%CI 5.7-7.6) for 1st-line PAZO and 4.6 months (95%CI 3.3-6.0) for 2nd-line NIVO. 9.0% of 1st-line PAZO pts and 5.9% of 2nd-line NIVO pts achieved a complete response and disease control rate was 58.0% (95% CI 53.0-62.8) and 44.9% (95% CI 36.8-53.2) for PAZO or NIVO, respectively. Median OS was 32.6 months (95% CI 28.0-38.9) for all pts, 32.6 months (95%CI 28.2-NA) for pts with 2nd-line NIVO and 32.3 months (95%CI 18.8-NA) for pts with other 2nd-line Tx. The most commonly reported treatment emergent AEs were diarrhea (37.2%), nausea (21.7%) and fatigue (19.1%) for PAZO Tx and diarrhea (8.8%), peripheral edema (5.9%) and dyspnea, fatigue, nausea, rash, vomiting (5.1% each) for NIVO. 66 pts (17.1%) discontinued PAZO and 7 pts (5.1%) discontinued NIVO due to related TEAEs. During 1st-line PAZO Tx, mean EQ-5D-5L utility scores initially decreased slightly by time, returned to baseline level and remained stable afterwards. During 2nd-line NIVO Tx the utility scores initially increased by time and remained stable thereafter. Similar tendencies were reported for mobility, self-care, usual activities, pain/discomfort, and anxiety/depression. Conclusions: The interim results of the PAZOREAL study confirm favorable clinical trial outcomes, the good benefit-risk profile and the sustained QoL in pts with mRCC in a real-world setting. The sequential treatment with PAZO followed by NIVO is effective and well tolerated. Clinical trial information: NIS-Nr.: 6687.
Sorafenib as second-line treatment in metastatic renal cell carcinoma: A prospective cohort.
Authors: Martin Aguilar Ana Elena , Núñez-López Haidé Nayeli , Ramirez-Sandoval Juan C. Carlos
Published: May 2020

e17077

Background: Sequential inhibition of the vascular endothelial growth factor (VEGF) pathway with sorafenib could be useful for patients with advanced or metastatic renal cell carcinoma (RCC). Our aim was to determine the activity and tolerability of sorafenib as a 2nd-line therapy in advanced RCC initially treated with a different VEGF-tyrosine kinase inhibitor (TKI). Methods: Prospective observational cohort in Mexico City (July 2012 to July 2019). We included 148 subjects with metastatic RCC, treated by nephrectomy and who had RCC progression despite treatment with sunitinib (n = 144) or pazopanib (n = 4). All patients received sorafenib 400 mg orally twice a day on a continuous dosing schedule until disease progression or intolerable toxicity. The primary endpoint was time to progression evaluated every 12-16 weeks. Risk factors were classified according to the International Metastatic Renal Cell Carcinoma Database Consortium (IMDC-RF) prognostic model. Results: Mean age of cohort was 58±10 years, 104 (70%) were male, 51 (35%) had none of IMDC-risk factors, and the most common sites of metastasis before sorafenib treatment were lung (n = 79, 53%) and bone (n = 30, 20%). The median progression-free survival and survival after the introduction of sorafenib treatment was 8.5 months (95% IC 6.8-10.2) and 40.1 months (95% IC 35.2-45.0) respectively. Median overall survival from RCC diagnosis to death was 71 months (95% CI 63.9-79.4). Median progression-free survival was longer in advanced RCC with none IMDC-RF compared with subjects with ≥2 IMDC-RF (10.3 [95%CI 6.1-14.6] vs 7.9 [95%CI 5.8-9.9] mo. respectively, p = 0.035). Age > 65 decreased risk of progression after sorafenib therapy (OR 0.33, 95% CI 0.14-0.77, p = 0.010). Median progression-free survival in subjects > 65 yrs old was longer (14 months, 95% CI 9.2-17.9) compared to subjects ≤65 yrs (7.2 months, 95% CI 5.5-8.9, p = 0.018). Adverse events associated to sorafenib occurred in 118 (80%) subjects: hand-foot syndrome (n = 118, 80%), diarrhea (n = 113, 76%), hypothyroidism (41, 28%), and mucositis (84, 57%). Any adverse events corresponding to a grade > 2 occurred in 48 (32%) patients. Conclusions: Sequential inhibition of VEGF with sorafenib as a 2nd-line treatment may benefit patients with metastatic RCC, especially in subjects > 65 yrs old. Further clinical trials are needed.
Predictors of first line systemic therapy for metastatic renal cell carcinoma in IMDC favorable risk patients.
Authors: Mizuno Ryuichi , Takamatsu Kimiharu , Tanaka Nobuyuki , Hayakawa Nozomi , Kosaka Takeo , Kikuchi Eiji , Oya Mototsugu
Published: May 2020

e17086

Background: With the induction of molecular targeted agents, which interfere with proteins that play critical roles in tumor growth and progression, and immune checkpoint inhibitors (ICI), the scenario of systemic treatment of metastatic renal cell carcinoma (mRCC) have dramatically been changed with improved survival. Prognostic risk assessment is essential for choosing the most appropriate first line treatment option, with selection based on International Metastatic RCC Database Consortium (IMDC) Risk Category. This study was designed to evaluate the actual efficacy of systemic therapy in the IMDC favorable risk group patients with mRCC. Methods: A total of 218 patients with mRCC who received systemic therapy were retrospectively reviewed (Institutional review board approval No 2013-0425). Among them, 55 (25%) patients were classified as favorable risk group based on the IMDC Risk Category. These mRCC patients in the favorable risk were divided into 2 groups by following factors; gender (male or female), age (≥70, or not), baseline serum CRP levels (≥0.6, and < 0.6 mg/dl), metastatic sites (exclusive lung, or lung and others), BMI (≥22, or < 22), respectively. The overall survival (OS) of patients in the favorable risk group were compared between the two cohorts. Results: The median PFS for first line treatment and OS of patients in favorable risk group were 31.6 (95% CI 19.9–33.7)) and 85.8 (56.8-NE) months, respectively. The median OS in patients with BMI≥22 and < 22 was 65.6 (95% CI 56.8–NE) and 56.8 (95% CI 30.8–NE) months, respectively (p = 0.0497). The median OS in patients with exclusive lung metastasis, and lung and other metastases were 115.1 (95% CI NE) and 65.6 (95% CI 43.9–NE) months, respectively (p = 0.0073). No significant difference was found in OS between male and female, age≥70 and < 70, and baseline serum CRP levels ≥0.6 mg/dl and < 0.6, respectively. Conclusions: The first line systemic treatment for mRCC patients in IMDC favorable risk group was feasible and effective in patients with BMI≥22 or exclusive lung metastasis.
Safety of inactivated vaccines in patients with genitourinary (GU) malignancies receiving immune checkpoint inhibitors (ICI).
Authors: Wulff-Burchfield Elizabeth Marie , Kurkowski Austin , Grauer Dennis , Ralph Shelbie , Mahmoudjafari Zahra , Parikh Rahul Atul , Martin Grace
Published: May 2020

e17108

Background: ICI therapy has become the standard of care for many advanced GU cancers, but immune-related adverse events (IRAE) may result in treatment delays or discontinuation. Concurrent vaccine use has been posited to increase the IRAE risk, but safety data is mixed. There are no published data regarding safety of concurrent inactivated vaccines other than influenza, including and especially in the GU cancer population. Methods: We performed a single-institution, retrospective, matched-cohort (1:2, cohort A:B, vaccinated to control) study of all GU cancer patients treated with an inactivated vaccine 30 days prior to or 60 days following ICI therapy from 2015-2019. Baseline clinical characteristics were abstracted from the electronic health record (EHR). Clinically significant IRAEs were defined as any event developing during or 30 days following ICI therapy requiring therapy with ≥ Prednisone 20 mg daily (or equivalent) or other immunosuppression. Delays were defined as ICI therapy given > 14 days past expected date for cycle 2 or beyond. Bivariate analysis with chi-squared statistics were used to describe incidence. Results: Sixty patients were included: 20 in cohort A (vaccinated) and 40 in cohort B (control). Thirty-seven (61.7%) patients had renal cell carcinoma, 17 (31.7%) had urothelial carcinoma, and 4 (6.7%) had prostate cancer. There was no difference in incidence of clinically significant IRAEs between cohorts A and B (15% vs 32.5%, p = 0.148), nor were differences observed in rates of treatment delays (10% vs 12.5%, p = 0.776) or discontinuation (10% vs 12.5%, p = 0.776) due to IRAEs. Most common vaccines were inactivated influenza (n = 18, 90%) and pneumococcal vaccine (n = 3, 15%). Among the 16 patients experiencing clinically-significant IRAEs, the most common were colitis (n = 3), dermatitis (n = 3), and pneumonitis (n = 3). All patients requiring immunosuppressive therapy received systemic corticosteroids. Conclusions: This retrospective cohort study demonstrates that GU cancer patients receiving inactivated vaccines during ICI therapy does not increase IRAE incidence, treatment delays, or discontinuation, suggesting that inactivated vaccines may be safely administered during ICI therapy in this population. Though influenza vaccines were still the most common, this is the first study to include other inactivated vaccines. Limitations include sample size, EHR accuracy and use of surrogate markers for determination of IRAE incidence. Next steps will include a multi-institutional retrospective study.
First-line PD-1/PD-L1 inhibitor monotherapy for advanced renal cell carcinoma (aRCC): A multi-institutional cohort.
Authors: Hatton Whitley , Basu Arnab , Koshkin Vadim S , Kilari Deepak , Jaeger Ellen , Ledet Elisa Marie , Cotogno Patrick , Manogue Charlotte , Lewis Brian E. , Layton Jodi Lyn , Krane Spencer , Sartor Oliver A. , Bilen Mehmet Asim , Desai Arpita , Barata Pedro C.
Published: May 2020

e17109

Background: Combination regimens containing a programmed cell death protein 1 (PD-1) or a programmed cell death ligand 1 (PD-L1) inhibitor improve the clinical outcomes of previously untreated aRCC. These regimens are clinically active but are associated with adverse events (AEs). One prospective study (KEYNOTE-427) has shown clinical activity of pembrolizumab monotherapy in aRCC. We aimed to describe the utilization and outcomes of single-agent PD-1/PD-L1 in previously untreated aRCC patients (pts). Methods: Consecutive pts treated with front-line PD-1/PD-L1 monotherapy for aRCC were included. Descriptive statistics were used to analyze outcomes including overall response rate (ORR), progression-free survival (PFS) and safety. Results: A total of 28 pts (median age 60; 32% ECOG 2/3; intermediate/poor risk 86%/14%; 35% non-clear cell aRCC) were identified. Common sites of metastases included lung (57%), lymph nodes (39%), bone (21%) and brain (21%). Pts received pembrolizumab (n = 9), avelumab (n = 1) or nivolumab (n = 18) due to pt/physician’s decision (46%), poor performance status (29%) or clinical trial (21%). In evaluable pts (n = 24), the ORR was 33% in ccRCC and 30% in nccRCC. With a median follow up of 13 months (mo), the median PFS was 6.3 mo (CI 95%, 1.5-11.1) and 16 pts progressed on therapy. Frequent AEs (57%) included fatigue (21%), myalgias/arthralgias (11%) and hypothyroidism (7%). No significant grade AEs (G3+) were noted. After progression on PD-1/PD-L1 (n = 16), 39% received a subsequent anti-VEGF (cabozantinib n = 6; sunitinib n = 4; pazopanib n = 1), 42% went to hospice or died and 21% were lost to follow up. Conclusions: First-line single-agent treatment with PD-1/PD-L1 inhibitors showed a favorable safety profile and clinical activity in patients with clear cell and non-clear cell aRCC who were not considered for a combination regimen. [Table: see text]