Many long noncoding RNAs (lncRNAs) are deregulated in cancer and contribute to oncogenesis. In urothelial carcinoma (UC), several lncRNAs have been reported to be overexpressed and proposed as ...biomarkers. As most reports have not been confirmed independently in large tissue sets, we aimed to validate the diagnostic and prognostic value of lncRNA upregulation in independent cohorts of UC patients. Thus, expression of seven lncRNA candidates (GAS5, H19, linc-UBC1, MALAT1, ncRAN, TUG1, UCA1) was measured by RT-qPCR in cell lines and tissues and correlated to clinicopathological parameters including follow-up data (set 1: N n = 10; T n = 106). Additionally, publicly available TCGA data was investigated for differential expression in UC tissues (set 2: N n = 19; T n = 252,) and correlation to overall survival (OS). All proposed candidates tended to be upregulated in tumour tissues, with the exception of MALAT1, which was rather diminished in cancer tissues of both data sets. However, strong overexpression was generally limited to individual tumour tissues and statistically significant overexpression was only observed for UCA1, TUG1, ncRAN and linc-UBC1 in tissue set 2, but for no candidate in set 1. Altered expression of individual lncRNAs was associated with overall survival, but not consistently between both patient cohorts. Interestingly, lower expression of TUG1 in a subset of UC patients with muscle-invasive tumours was significantly correlated with worse OS in both cohorts. Further analysis revealed that tumours with low TUG1 expression are characterized by a basal-squamous-like subtype signature accounting for the association with poor outcome. In conclusion, our study demonstrates that overexpression of the candidate lncRNAs is found in many UC cases, but does not occur consistently and strongly enough to provide reliable diagnostic or prognostic value as an individual biomarker. Subtype-dependent expression patterns of lncRNAs like TUG1 could become useful to stratify patients by molecular subtype, thus aiding personalized treatments.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
For several decades, platinum-based chemotherapy has been the standard first-line option for patients with advanced inoperable or metastatic (or both) urothelial carcinoma. This paradigm, in which ...platinum-based chemotherapy was considered to be the only effective first-line chemotherapy, was implemented in the 1980s
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and remained unchanged even after immune checkpoint inhibitors were introduced in recent years as part of the treatment regimen for metastatic urothelial carcinoma. Treatment advances were made by replacing older treatments with less toxic combinations (e.g., gemcitabine and cisplatin
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) or by replacing cisplatin with carboplatin in patients who were ineligible to receive cisplatin
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rather than by improving treatment . . .
Abstract Background Single-agent taxanes are commonly used as salvage systemic therapy for patients with advanced urothelial carcinoma (UC). Objective To study the impact of combination chemotherapy ...delivering a taxane plus other chemotherapeutic agents compared with single-agent taxane as salvage therapy. Design, setting, and participants Individual patient-level data from phase 2 trials of salvage systemic therapy were used. Interventions Trials evaluating either single agents (paclitaxel or docetaxel) or combination chemotherapy (taxane plus one other chemotherapeutic agent or more) following prior platinum-based therapy were used. Outcome measurements and statistical analysis Information regarding the known major baseline prognostic factors was required: time from prior chemotherapy, hemoglobin, performance status, albumin, and liver metastasis status. Cox proportional hazards regression was used to evaluate the association of prognostic factors and combination versus single-agent chemotherapy with overall survival (OS). Results and limitations Data were available from eight trials including 370 patients; two trials ( n = 109) evaluated single-agent chemotherapy with docetaxel ( n = 72) and cremophor-free paclitaxel ( n = 37), and six trials ( n = 261) evaluated combination chemotherapy with gemcitabine–paclitaxel (two trials, with n = 99 and n = 24), paclitaxel–cyclophosphamide ( n = 32), paclitaxel–ifosfamide–nedaplatin ( n = 45), docetaxel–ifosfamide–cisplatin ( n = 26), and paclitaxel–epirubicin ( n = 35). On multivariable analysis after adjustment for baseline prognostic factors, combination chemotherapy was independently and significantly associated with improved OS (hazard ratio: 0.60; 95% confidence interval, 0.45–0.82; p = 0.001). The retrospective design of this analysis and the trial-eligible population were inherent limitations. Conclusions Patients enrolled in trials of combination chemotherapy exhibited improved OS compared with patients enrolled in trials of single-agent chemotherapy as salvage therapy for advanced UC. Prospective randomized trials are required to validate a potential role for rational and tolerable combination chemotherapeutic regimens for the salvage therapy of advanced UC. Patient summary This retrospective study suggests that a combination of chemotherapy agents may extend survival compared with single-agent chemotherapy in selected patients with metastatic urothelial cancer progressing after prior chemotherapy.
We evaluated the impact of the number of cycles of platinum based, first line chemotherapy (fewer than 6 cycles vs the conventional 6 cycles or more) on the survival of patients with metastatic ...urothelial carcinoma.
We used the RISC (Retrospective International Study of Invasive/Advanced Cancer of the Urothelium) database. The association of the number of cycles of chemotherapy with overall survival was investigated by Cox multiple regression analysis after controlling for recognized prognostic factors. We excluded patients who received fewer than 3 or more than 9 platinum chemotherapy cycles to reduce confounding factors. The primary analysis was a comparison of overall survival for 3 to 5 vs 6 to 9 cycles using 6-month landmark analysis when 281 death events were observed.
Of the 1,020 patients in the RISC 472 received cisplatin or carboplatin, of whom 338 and 134, respectively, were evaluable. A total of 157 patients received 3 to 5 cycles (median 4) and 315 received 6 to 9 cycles (median 6). There was no significant difference in overall survival between 3 to 5 and 6 to 9 cycles (HR 1.02, 95% CI 0.78–1.33, p = 0.91). No significant interactions were observed for the type of platinum (p = 0.09) and completed planned chemotherapy (p = 0.56). The limitations of a hypothesis generating, retrospective analysis applied.
Four cycles of platinum based, first line chemotherapy appeared adequate and did not significantly compromise the survival of patients with advanced urothelial carcinoma. The omission of excessive cycles may avoid unnecessary cumulative toxicity and facilitate a better transition to second line therapy and investigational switch maintenance therapy strategies. These results require prospective validation but they may impact practice in select patients.
Abstract Background Outcomes for patients in the second-line setting of advanced urothelial carcinoma (UC) are dismal. The recognized prognostic factors in this context are Eastern Cooperative ...Oncology Group (ECOG) performance status (PS) >0, hemoglobin level (Hb) <10 g/dl, and liver metastasis (LM). Objectives The purpose of this retrospective study of prospective trials was to investigate the prognostic value of time from prior chemotherapy (TFPC) independent of known prognostic factors. Design, setting, and participants Data from patients from seven prospective trials with available baseline TFPC, Hb, PS, and LM values were used for retrospective analysis ( n = 570). External validation was conducted in a second-line phase 3 trial comparing best supportive care (BSC) versus vinflunine plus BSC ( n = 352). Outcome measurements and statistical analysis Cox proportional hazards regression was used to evaluate the association of factors, with overall survival (OS) and progression-free survival (PFS) being the respective primary and secondary outcome measures. Results and limitations ECOG-PS >0, LM, Hb <10 g/dl, and shorter TFPC were significant prognostic factors for OS and PFS on multivariable analysis. Patients with zero, one, two, and three to four factors demonstrated median OS of 12.2, 6.7, 5.1, and 3.0 mo, respectively (concordance statistic = 0.638). Setting of prior chemotherapy (metastatic disease vs perioperative) and prior platinum agent (cisplatin or carboplatin) were not prognostic factors. External validation demonstrated a significant association of TFPC with PFS on univariable and most multivariable analyses, and with OS on univariable analyses. Limitations of retrospective analyses are applicable. Conclusions Shorter TFPC enhances prognostic classification independent of ECOG-PS >0, Hb <10 g/dl, and LM in the setting of second-line therapy for advanced UC. These data may facilitate drug development and interpretation of trials.
Abstract Introduction Efficacy of palliative second-line treatment in patients suffering from advanced urothelial cancer (aUC) is limited. Accordingly, careful observation of patient-reported and ...treatment-related changes of quality of life (QoL) is mandatory. Therefore, we evaluated “typical” ailments and treatment related QoL changes in these patients. Patients and methods Results of the EORTC QLQ-C30 questionnaire were reviewed in 129 patients included in 2 prospective trials on paclitaxel-based treatment of cisplatin-resistant aUC (gemcitabine/paclitaxel: 102 patients AB 20/99; paclitaxel/everolimus: 27 patients AB 35/09). Eligible patients had completed EORTC QLQ-C30 questionnaire questionnaire before treatment start and available data on response. Global health status (QL), functional scales (FuSc) and symptom scales (SySc) were compared with published normative data for patients suffering from metastatic/recurrent cancers. Treatment related changes of QoL were evaluated. For statistical evaluation 2-way analysis of variance was used. Results A total of 87 patients were eligible (63 men and 24 women, median age = 65 interquartile range: 60-71 y, AB 20/99: 63 patients 72%, AB 35/09: 24 patients 28%). Compared with metastatic/recurrent cancers normative data, impaired emotional FuSc (−11.6 95% CI:−21.0 to−2.1 points, P <0.01) and higher pain SySc (+12.9 CI: 3.7–22.1 points, P <0.001) were the most relevant differences. QL and further FuSc/SySc were comparable. Pain SySc was significantly lower after 3 (−15.8 CI:−31.4 to−0.7 points, P <0.01 and 4 cycles (−13.6 CI:−29.2–2.1 points, P <0.05). Further changes of QL, FuSc or SySc during treatment were not observed. QL, FuSc, and SySc at baseline and during treatment did not differ between responders and nonresponders. Conclusions Patients with aUC who received additional treatment demonstrated QoL changes similar to persons with other recurrent/metastatic cancers. Special emphasis should be attributed to pain and emotional problems. Despite treatment related side effects, patients did not report impairment of QoL.
Prediction of treatment response is a crucial issue in individualised treatment for cancer patients. In this context, Nassar and colleagues in the accompanying study published in the British Journal ...of Cancer analysed retrospectively a cohort of 62 metastatic urothelial cancer patients treated with immune checkpoint inhibitors and of whom not only clinical but also genomic characteristics were available. Combining molecular and clinical factors in a multivariable analysis they identified lack of visceral metastases, neutrophil-to-lymphocyte ratio (NLR) <5, and high single nucleotide variant (SNV) count (≥10) as independent predictors of treatment response.
Micro-Abstract This study examined the association of progression-free survival at 6 months with overall survival in the context of second-line therapy of advanced urothelial carcinoma in pooled ...patient-level data from 10 phase II trials and then externally validated in a large phase III trial. Progression-free survival at 6 months was significantly correlated with overall survival and is an innovative primary endpoint to evaluate new agents in this setting.
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