Clinical evidence for the first-line treatment of advanced urothelial carcinoma: Current paradigms and emerging treatment options

Abstract

Background: Patients with advanced urothelial carcinoma (UC) have poor outcomes, with 5-year survival rates of < 5% for those with metastatic, stage IV disease. We have reviewed current treatment paradigms and emerging treatment options for these patients. Methods: The websites of seven national or international organizations were searched for metastatic UC treatment guidelines. Systematic literature reviews were conducted to identify evidence from randomized controlled trials (RCTs) of chemotherapy for patients with previously untreated, unresectable, stage IV UC. Searches included congress databases and articles published between 1990 and 2018. In order to align with the latest treatment paradigms in first-line advanced UC, a focused literature search was conducted to identify evidence supporting immuno-oncology (IO) agents. Results: For advanced UC, guidelines universally recommend cisplatin-based chemotherapy as first-line treatment for eligible patients and carboplatin-based regimens for those unfit to receive cisplatin. Despite the evaluation of a number of different cytotoxic regimens over the years, including triplet combinations, survival outcomes have not improved markedly with chemotherapy. Median overall survival with standard of care chemotherapy is ~13 months. Based on the results of single-arm, phase II studies, recent treatment guidelines have included atezolizumab (anti-PD-L1) and pembrolizumab (anti-PD-1) as first-line options for cisplatin-ineligible patients whose tumors express high levels of PD-L1. However, emerging evidence from RCTs of IO agents, including both cisplatin-eligible and cisplatin-ineligible patients, suggest that survival times exceeding 20 months are possible. Conclusions: After having reached a plateau with chemotherapy, the treatment landscape for advanced UC is evolving. Survival outcomes for patients with advanced UC are improving with treatment modalities involving IO agents.

New Insights into the Diagnosis, Molecular Taxonomy, and Treatment of Bladder Cancer

“…The expected response rate with first-line cisplatin combinations is in the range of 40-60%, with a median survival of 13-16 months (60). Available chemotherapy regimens in metastatic settings include standard MVAC, gemcitabine-cisplatin, and ddMVAC, which are considered standard first-line treatment options for metastatic bladder cancer (61). It was mentioned above how in NMIBC, the use of intravesical BCG activates the immune response.…”

Use of Gemcitabine plus Carboplatin is Associated with Poor Outcomes in Urothelial Carcinoma Patients with Chronic Kidney Disease Stage 4-5

“…Urothelial cancer (UC) is a set of tumors originating from the urothelial cells lining the urethra, bladder, ureters and renal pelvis [1]. For patients with locally advanced and unresectable or metastatic UC, cisplatin-based doublet chemotherapy has been the mainstay treatment, leading to a median overall survival (OS) of 14 to 15 months [2][3][4].…”

“…For patients with locally advanced and unresectable or metastatic UC, cisplatin-based doublet chemotherapy has been the mainstay treatment, leading to a median overall survival (OS) of 14 to 15 months [2][3][4]. However, a substantial proportion of advanced UC patients are ineligible for cisplatin-based treatment because of obstructive uropathy or other chronic kidney disease (CKD) associated with older age and comorbidities, as well as a poor performance status (PS) [1,5,6]. To overcome this problem, the EORTC 39086 study was conducted for cisplatin-unfit patients and showed that the use of second-generation platinum carboplatin in combination with gemcitabine (GCb) yielded an objective response rate (ORR) of 41.2% and a median OS of 9.3 months with acceptable toxicity profiles [7].…”

Temozolomide abrogates the aggressiveness of urothelial carcinoma cells by enhancing senescence and depleting the side population

“…Although non-muscle-invasive UCs are generally not life-threatening, advanced UCs with metastasis are associated with a high risk of mortality ( 3 , 4 ). The 5-year survival rate of patients with stage IV distant metastasis is <5% ( 5 ). The standard first-line chemotherapy for advanced UC is platinum-based combination chemotherapy ( 5 ).…”

“…The 5-year survival rate of patients with stage IV distant metastasis is <5% ( 5 ). The standard first-line chemotherapy for advanced UC is platinum-based combination chemotherapy ( 5 ).…”