Urothelial cancer

The sixth most common form of malignancy.

The 2 most common forms are bladder cancer and upper tract urothelial carcinoma.

Urothelial bladder cancer represents 90-95% of urothelial cancers.

Upper tract urothelial carcinoma affects only 5-10% of patients with urothelial cancer.

Primary uteral or urethral malignancies are rare.

Second most common malignancy of the GU system.

Urothelial, or transitional cell, carcinomas of the bladder are the most common histologic subtype in the US and are categorized as flat or papillary lesions.

Urothelial carcinoma frequently have divergent differentiation and are commonly mixed with squamous cell or glandular features.

Urothelial tumors can be divided into basal and luminal subtypes which are characterized by different patterns of gene expression.

Urothelial carcinomas characterized by genomics instability, programmed cell death ligand 1 protein expression, DNA damage response mutations, and a high tumor mutational burden, which are features associated with increased response to immune checkpoint inhibitors.

Basal tumors are associated with squamous or sarcomatoid differentiation, advanced stage or metastatic disease at presentation and a more aggressive clinical course.

Luminal tumors commonly contain papillary features and harbor variations in sequence similar to those observed in non-muscle invasive bladder cancer suggesting that these malignancies develop from nonmuscle invasive bladder cancer.

Basal tumors arise from urothelial basal cells, and luminal tumors originate from luminal or intermediate cells from the urothelium.

Affects men approximately 4 times more often than women.

Affects primarily Caucasians.

In approximately 10 to 20% of patients, non-muscle invasive bladder cancer progress to muscle invasive bladder cancer and the disease occurs in 10 to 30% of cases.

Stage is the most important independent prognostic variable for assessing the probability of progression in survival.

Five-year survival rate is approximately 77% for all stages of bladder cancer compared with less than 15% for metastatic bladder cancer.

ATM alterations are a biomarker of poor prognosis in advanced and/or relapsed urothelial cancer.

Cisplatinum based chemotherapy has been the standard of care for advanced disease, but results in a median survival of 15 months.

The combiation of methotrexate, vinblastine, doxorubicin, and cisplatin (MVAC) improved overall survival in advanced urolthelial cancer compared with cisplatin monotherapy 12.5 vs 8.2 months, but with significant toxicity.

Gemcitabine and cisplatin are better tolerated than MVAC with similar efficacy.

High-dose MVAC given on a dose dense dose every 2 weeks instead of every 4 weeks for MVAC, results in less toxicity and higher survival, complete response rates and progression free survival.

Only a fraction of patients who receive neoadjuvant cis-platinum based therapy gain a benefit: to save one life 15-20 individuals are treated.

Immune checkpoint inhibitors are active in neoplasms with high PD-L1 when expressions and in those with a high burden of somatic mutations.

Atezolizumab approved for cisplatinum ineligible patients with locally advanced or metastatic urothelial cancer.

Patients treated with Atezolizumab add an overall response rate of 13.4% with five % complete responders.

Five checkpoint inhibitors approved for advanced urothelial carcinomas: atezolizumab, pembrolizumab, avelumab, durvalumab and nivolumab.

Pembrolizumab approved for treatment of patients with locally advanced or metastatic disease who have had progression during or following platinum containing chemotherapy or within 12 months of neoadjuvant or adjuvant treatment with platinum containing drugs.

The use of concurrent chemo immunotherapy is still experimental, but induction platinum-based chemotherapy followed by maintenance with Avelumab remains standard front line therapy in advanced urothelial cancer.
Nivolumab plus Gentimicin-cisplatinum combination resulted in significant better outcomes in patients with previously untreated advanced urothelial carcinoma than gemcitibine-platinum alone.
Enfortumab plus pembrolizumab doubled the overall survival of patients versus chemotherapy in metastatic urothelial  cancer: in untreated patients with locally advanced with metastatic urothelial carcinoma survival was longer in the untreated locally advanced, or metastatic urothelial tumor enfortumumab/pembrolizumab group than  in the chemotherapy group with the median 12.5 months versus 6.1 months.

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