Protocol of a randomised, controlled trial comparing immediate curative therapy with conservative treatment in men aged ≥75 years with non-metastatic high-risk prostate cancer (SPCG 19/GRand-P).

BACKGROUND: Older men (aged ≥75 years) with high risk, non-metastatic prostate cancer (PCa) are increasingly treated with curative therapy (surgery or radiotherapy). However, it is unclear if curative therapy prolongs life and improves health-related quality of life (HRQoL) in this age group compared to conservative therapy, which has evolved considerably during the last decade. STUDY DESIGN: The Scandinavian Prostate Cancer Group (SPCG) 19/Norwegian Get-Randomized Research Group-Prostate (GRand-P) is a randomised, two-armed, controlled, multicentre, phase III trial carried out at study centres in Norway, Denmark, Finland, and Sweden. ENDPOINTS: The primary endpoints are overall survival and HRQoL (burden of disease scale, European Organisation for the Research and Treatment of Cancer [EORTC] Elderly Cancer patients). Secondary endpoints are PCa-specific survival, metastasis-free survival, role-functioning scale (EORTC quality of life questionnaire 30-item core), urinary irritative/obstructive scale (26-item Expanded Prostate Cancer Index Composite [EPIC-26]), bowel scale (EPIC-26), intervention-free survival, PCa morbidity, use of secondary and tertiary systemic therapies, mean quality-adjusted life-years (QALYs), and mean total healthcare costs. PATIENTS AND METHODS: A total of 980 men (aged ≥75 years) with non-metastatic, high-risk PCa will initially be screened with Geriatric 8 (G8) health status screening tool and Mini-COG© brief cognitive test. Participants identified by G8 as 'fit' or 'frail' will be randomised (ratio 1:1) to either immediate curative therapy (radiotherapy or prostatectomy) or conservative therapy (endocrine therapy or observation). Participants who are unable or unwilling to participate in randomisation will be enrolled in a separate observation group. Randomised patients will be followed for 10 years. TRIAL REGISTRATION: Ethics approval has been granted in Norway (457593), Denmark (H-22051998), Finland (R23043) and Sweden (Dnr 2023-05296-01). The trial is registered on Clinicaltrials.org (NCT05448547).

Treatment Patterns and Efficacy of Chemotherapy After Pembrolizumab in Advanced Urothelial Cancer-a Real-World Study in the pre-Antibody-Drug Conjugate Era.

BACKGROUND: Immune checkpoint inhibitors (ICIs) have been established as a routine treatment in patients with metastatic urothelial cancer (mUC). However, there has been no standard of care after progression on ICIs. We investigated real-world treatment patterns and efficacy of chemotherapy (CHT) after pembrolizumab, in the era before introduction of maintenance avelumab and antibody-drug conjugates (ADC). PATIENTS AND METHODS: An observational, retrospective study was conducted at twelve Nordic centers. Patients with mUC were treated according to investigator´s choice of CHT after pembrolizumab. Primary endpoint was overall response (ORR) and disease control rate (DCR); secondary endpoints were progression-free (PFS) and overall survival (OS). RESULTS: In total, 102 patients were included whereof 23 patients received CHT after pembrolizumab as second line treatment (subcohort A) and 79 patients in third line (subcohort B). Platinum-gemcitabine combinations were the most common regimens in subcohort A, and vinflunine in subcohort B. The ORR and DCR were 36% and 47%, respectively. Presence of liver metastases was independently associated with lower ORR and DCR. The PFS and OS were 3.3 months and 7.7 months, respectively. Eastern Cooperative Oncology Group Performance Status (ECOG PS) and number of previous cycles of pembrolizumab were found to be independent prognostic factors associated with OS. CONCLUSION: In a real-world setting, CHT showed clinically meaningful response rates and survival in mUC patients after progression with pembrolizumab. Clinical benefit may primarily be achieved in patients with favorable ECOG PS, in patients treated with > 6 cycles pembrolizumab as well as in patients without presence of liver metastases.

Profiling of extracellular vesicles of metastatic urothelial cancer patients to discover protein signatures related to treatment outcome.

The prognosis of metastatic urothelial carcinoma (mUC) patients is poor, and early prediction of systemic therapy response would be valuable to improve outcome. In this exploratory study, we investigated protein profiles in sequential plasma-isolated extracellular vesicles (EVs) from a subset of mUC patients treated within a Phase I trial with vinflunine combined with sorafenib. The isolated EVs were of exosome size and expressed exosome markers CD9, TSG101 and SYND-1. We found, no association between EVs/ml plasma at baseline and progression-free survival (PFS). Protein profiling of EVs, using an antibody-based 92-plex Proximity Extension Assay on the Oncology II® platform, revealed a heterogeneous protein expression pattern. Qlucore bioinformatic analyses put forward a protein signature comprising of SYND-1, TNFSF13, FGF-BP1, TFPI-2, GZMH, ABL1 and ERBB3 to be putatively associated with PFS. Similarly, a protein signature from EVs that related to best treatment response was found, which included FR-alpha, TLR 3, TRAIL and FASLG. Several of the markers in the PFS or best treatment response signatures were also identified by a machine learning classification algorithm. In conclusion, protein profiling of EVs isolated from plasma of mUC patients shows a potential to identify protein signatures that may associate with PFS and/or treatment response.

Different Responses to Neoadjuvant Chemotherapy in Urothelial Carcinoma Molecular Subtypes.

BACKGROUND: For muscle-invasive bladder cancer (MIBC), no tissue biomarkers are available for clinical use to predict response to neoadjuvant chemotherapy. OBJECTIVE: To investigate how molecular subtypes impact pathological response and survival in patients receiving preoperative cisplatin-based chemotherapy. DESIGN, SETTING, AND PARTICIPANTS: Classification of a retrospective cohort of 149 patients was performed by tumor transcriptomic profiling and immunostaining. A cohort treated with radical cystectomy alone and public data sets were used for comparison and external validation. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Complete pathological response in the cystectomy specimen (ypT0N0) and survival were compared in predefined molecular subtypes. Differential gene expression and chemotherapy response were explored beyond molecular subtypes. RESULTS AND LIMITATIONS: Patients with genomically unstable (GU) and urothelial-like (Uro) tumors had higher proportions of complete pathological response (16/31 [52%] and 17/54 [31%]), versus five out of 24 (21%) with the basal/squamous (Ba/Sq) subtype following neoadjuvant chemotherapy and radical cystectomy. Molecular subtype was independently associated with improved survival for patients with GU tumors (hazard ratio [HR] 0.29, 95% confidence interval [CI]: 0.11-0.79) and UroC tumors (HR 0.37, 95% CI: 0.14-0.94) compared with Ba/Sq tumors, adjusting for clinical stage. In addition, expression of the gene coding for osteopontin (SPP1) showed a subtype-dependent effect on chemotherapy response. CONCLUSIONS: Urothelial cancer of the luminal-like (GU and Uro) subtypes is more responsive to cisplatin-based neoadjuvant chemotherapy. A second-generation of subtype-specific biomarkers, for example, SPP1, may be a way forward to develop a more precision-based treatment approach for neoadjuvant chemotherapy in MIBC. PATIENT SUMMARY: This study shows that tumor classification by gene expression profiling and molecular subtyping can identify patients who are more likely to benefit from chemotherapy before radical cystectomy for muscle-invasive bladder cancer. Together with other markers for response, molecular subtypes could have a role in selective administration of such chemotherapy.

Vinflunine/gemcitabine versus carboplatin/gemcitabine as first-line treatment in cisplatin-ineligible patients with advanced urothelial carcinoma: A randomised phase II trial (VINGEM).

BACKGROUND: The present study (VINGEM) is the first randomised trial comparing vinflunine/gemcitabine (VG) to standard carboplatin/gemcitabine (CG) in patients with advanced urothelial carcinoma (aUC) ineligible for treatment with cisplatin. PATIENTS AND METHODS: Patients with aUC, creatinine clearance 30-60 ml/min, performance status ≤1 and no prior chemotherapy for metastatic disease were randomised to the experimental arm (vinflunine 280 or 250 mg/m2 day 1, gemcitabine 1000 mg/m2 days 1 and 8, q21 days) or the control arm (carboplatin AUC 4.5 day 1, gemcitabine 1000 mg/m2 days 1 and 8, q21 days). Primary end-point was progression-free survival (PFS). RESULTS: Sixty-two patients were randomised; a total of 59 patients were treated (29 VG, 30 CG). There was no significant difference in PFS between the treatment arms: median 6.2 months for VG versus 6.3 months for CG (hazard ratio [HR]: 0.75, 95% confidence interval [CI]: 0.44-1.28; P = 0.293). Median overall survival was 12.5 months for VG versus 10.6 months for CG. The overall response rate (ORR) was higher in the VG arm than in the CG arm (63% versus 40%) but was not statistically significant in the intention-to-treat analysis. Furthermore, VG showed a high complete response (CR) rate, 22% versus 3% in CG. In the per-protocol group, both ORR and CR were significantly higher for VG than for CG. The most common adverse events (AEs) were fatigue, haematological toxicities, gastrointestinal disorders and nausea/vomiting. Common grade III/IV AEs were neutropenia (VG 62%, CG 43%), thrombocytopenia (VG 7%, CG 37%) and febrile neutropenia (VG 31%, CG 7%). CONCLUSIONS: The combination of VG did not improve PFS compared with standard treatment with CG in patients unfit for cisplatin due to renal impairment. The response rate of VG indicates, however, an active regimen and warrants further studies. CLINICALTRIALS. GOV NUMBER: NCT02665039.

Safety and Activity of Sorafenib in Addition to Vinflunine in Post-Platinum Metastatic Urothelial Carcinoma (Vinsor): Phase I Trial.

LESSONS LEARNED: First trial to report safety and activity of the microtubule inhibitor vinflunine plus the tyrosine kinase inhibitor sorafenib in post-platinum metastatic urothelial cancer (mUC) patients.A recommended phase II dose was identified for the treatment combination of vinflunine plus sorafenib, with main adverse events including fatigue, febrile neutropenia, neutropenia, hypertension, and hyponatremia.An overall response rate of 41% to second-line vinflunine plus sorafenib treatment in patients with platinum-resistant mUC was confirmed. BACKGROUND: Platinum-progressive metastatic urothelial carcinoma (mUC) is a clinical challenge. The tyrosine kinase inhibitor sorafenib has demonstrated varied activity in mUC. This trial was designed to examine safety and activity of vinflunine plus sorafenib in mUC. METHODS: In addition to standard dose of vinflunine (320 or 280 mg/m2), patients received sorafenib (400, 600, or 800 mg/day), in a 3 + 3 dose-escalation phase I design. RESULTS: Twenty-two patients (median age 62.5 years) were included. Five patients received vinflunine 320 mg/m2 and 17 received 280 mg/m2. The maximum tolerated dose (MTD) of sorafenib with vinflunine 280 mg/m2 was 600 mg, and with vinflunine 320 mg/m2 it was not determined, owing to toxicity. Adverse events (AEs) grades 3 + 4 consisted of neutropenia (6 patients), febrile neutropenia (5), and hyponatremia (5). The overall response rate (ORR) in the efficacy-evaluable patients was 41% (7 of 17), all partial responses evaluated by RECIST version 1.1. Median overall survival (OS) was 7.0 months (1.8-41.7). CONCLUSION: The defined recommended phase II dose (RPTD) was vinflunine 280 mg/m2 plus sorafenib 400 mg. Sorafenib was too toxic in combination with vinflunine 320 mg/m2. The ORR of 41% to this second-line combination treatment of mUC is noteworthy and supports further trials.

Erratum: Vinflunine treatment in patients with metastatic urothelial cancer: A Nordic retrospective multicenter analysis.

[This corrects the article DOI: 10.3892/ol.2016.4775.].

Vinflunine treatment in patients with metastatic urothelial cancer: A Nordic retrospective multicenter analysis.

In 2009, vinflunine was introduced as a second-line treatment to be used after the failure of platinum therapy in patients with metastatic urothelial carcinoma (mUC). The present study investigated the administered vinflunine to patients with mUC in standard clinical practice with the aim of evaluating treatment patterns, response, survival parameters and side-effects. Data were collected retrospectively from the first 100 mUC patients treated with vinflunine at three Nordic cancer centers associated with the Nordic Urothelial Cancer Oncology Group. The overall response rate was 23% and complete response was observed in one patient. The median progression-free survival (mPFS) and median overall survival (mOS) were 2.8 (range, 0.5-34.3) and 6.3 (range, 0.3-39.7) months, respectively. An Eastern Cooperative Oncology Group performance status (ECOG PS) of 2 was present in 20% of the patients, and those patients exhibited significantly shorter mOS (4.1 vs. 7.0 months, P=0.001) and a significantly higher degree of grade 3/4 toxicity (P=0.026) compared with ECOG PS 0-1 patients. Furthermore, patients without visceral metastases had significantly longer mOS than patients with visceral metastases (10.6 vs. 6.0 months, P=0.008). The median number of cycles of vinflunine was 3 (range, 1-28). The current data confirms that vinflunine is an active agent for second-line treatment in an unselected clinical cohort of patients with mUC. ECOG PS and presence of visceral metastases were significant prognostic parameters. In particular, patients with ECOG PS 2 receiving vinflunine had a shorter mOS and a higher frequency of severe toxicity, and, thus, should be treated with caution. Furthermore, the present study observed large inter-individual differences in radiological response and OS, indicating the need for further development of improved patient selection tools to optimize vinflunine treatment in platinum-refractory mUC patients.

Melphalan-flufenamide is cytotoxic and potentiates treatment with chemotherapy and the Src inhibitor dasatinib in urothelial carcinoma.

BACKGROUND: Chemotherapy options in advanced urothelial carcinoma (UC) remain limited. Here we evaluated the peptide-based alkylating agent melphalan-flufenamide (mel-flufen) for UC. METHODS: UC cell lines J82, RT4, TCCsup and 5637 were treated with mel-flufen, alone or combined with cisplatin, gemcitabine, dasatinib or bestatin. Cell viability (MTT assay), intracellular drug accumulation (liquid chromatography) apoptosis induction (apoptotic cell nuclei morphology, western blot analysis of PARP-1/caspase-9 cleavage and Bak/Bax activation) were evaluated. Kinome alterations were characterized by PathScan array and phospho-Src validated by western blotting. Aminopeptidase N (ANPEP) expression was evaluated in UC clinical specimens in relation to patient outcome. RESULTS: In J82, RT4, TCCsup and 5637 UC cells, mel-flufen amplified the intracellular loading of melphalan in part via aminopeptidase N (ANPEP), resulting in increased cytotoxicity compared to melphalan alone. Mel-flufen induced apoptosis seen as activation of Bak/Bax, cleavage of caspase-9/PARP-1 and induction of apoptotic cell nuclei morphology. Combining mel-flufen with cisplatin or gemcitabine in J82 cells resulted in additive cytotoxic effects and for gemcitabine also increased apoptosis induction. Profiling of mel-flufen-induced kinome alterations in J82 cells revealed that mel-flufen alone did not inhibit Src phosphorylation. Accordingly, the Src inhibitor dasatinib sensitized for mel-flufen cytotoxicity. Immunohistochemical analysis of the putative mel-flufen biomarker ANPEP demonstrated prominent expression levels in tumours from 82 of 83 cystectomy patients. Significantly longer median overall survival was found in patients with high ANPEP expression (P = 0.02). CONCLUSION: Mel-flufen alone or in combination with cisplatin, gemcitabine or Src inhibition holds promise as a novel treatment for UC.

Predicting Nonhemolytic Neonatal Hyperbilirubinemia.

BACKGROUND: Before hospital discharge, newborn infants should be assessed for the risk of excessive hyperbilirubinemia. We determined maternal and obstetric risk factors for hyperbilirubinemia in infants born at term (gestational age ≥37 weeks) to form an individualized risk assessment tool for clinical use. METHODS: This was a population-based study with data from the Swedish Medical Birth Register from 1999 to 2012, including 1,261,948 singleton infants. Outcome was defined as infants diagnosed with hyperbilirubinemia (N = 23,711), excluding all cases of hemolytic (immune-mediated or other specified hemolytic) diseases of the newborn. RESULTS: Risk factors with an adjusted odds ratio (aOR) for neonatal hyperbilirubinemia of ≥1.5 (medium-sized effect or more) were gestational age 37 to 38 weeks (aOR = 2.83), failed vacuum extraction (aOR = 2.79), vacuum extraction (aOR = 2.22), Asian mother (aOR = 2.09), primipara (aOR = 2.06), large-for-gestational-age infant (aOR = 1.84), obese mother (aOR = 1.83), and small-for-gestational-age infant (aOR = 1.66). Planned cesarean delivery (CD) was associated with a reduced risk (aOR = 0.45). Without any of these risk factors (normal birth weight infant delivered vaginally at 39 to 41 weeks' gestation by a non-Asian, nonobese, multiparous mother) the rate of nonhemolytic neonatal hyperbilirubinemia was 0.7%. In relation to the combined load of different risk factors, rates of neonatal hyperbilirubinemia ranged from 0.2% to 25%. CONCLUSIONS: Collection of a few easily available maternal and obstetric risk factors predicts >100-fold variation in the incidence of neonatal hyperbilirubinemia. The information provided herein enables individualized risk prediction with interactions between different risk factors taken into account.