Medication Summary
Chemotherapy and BCG are often administered intravesically. Intravesical therapy may reduce or delay the progression of cancer to a higher stage. Most commonly used chemotherapy agents are mitomycin and gemcitabine. [24]
Patients may also receive systemic chemotherapy depending on severity and recurrence of the tumors. Neoadjuvant chemotherapy may be considered for select patients with UTUC (eg, higher stage, grade tumor). Immunotherapy is used for second-line treatment.
Antineoplastics, Antibiotic
Mitomycin pyelocalyceal (Jelmyto, Vesigel)
Mitomycin is an alkylating drug isolated from the broth of Streptomyces caespitosus. It inhibits DNA synthesis. At high concentrations of mitomycin, cellular RNA and protein synthesis are also suppressed. This formulation is for pyelocalyceal use only. It is indicated for treatment of adults with low-grade upper tract urothelial cancer (LG-UTUC).
Mitomycin
Mitomycin selectively inhibits DNA synthesis. At high concentrations of the drug, cellular RNA and protein synthesis are also suppressed. Like BCG intravesical, this formulation of mitomycin is for intravesical use.
Biological Response Modifiers
Class Summary
These agents modify immune responses, either by enhancing or suppressing it.
BCG intravesical live (Tice BCG)
BCG intravesical contains live, attenuated mycobacteria. It is indicated for prophylaxis of primary or recurrent stage Ta and/or T1 papillary tumors following transurethral resection (TUR). Not recommended for stage TaG1 papillary tumors, unless diagnosed as high risk of tumor recurrence.
Antineoplastics, Antimetabolite
Class Summary
These agents inhibit cell growth and proliferation. They interfere with DNA synthesis by blocking the methylation of deoxyuridylic acid.
Methotrexate
Methotrexate inhibits dihydrofolate reductase (DHFR), causing a block in the reduction of dihydrofolate to tetrahydrofolate. This inhibits the formation of thymidylate and purines and arrests DNA, RNA, and protein synthesis. It is one of the components in the MVAC regimen and is used for the treatment of urothelial carcinoma.
Gemcitabine (Gemzar)
Gemcitabine is a pyrimidine analog. After intracellular metabolism to its active nucleotide, it inhibits ribonucleotide reductase and competes with deoxycytidine triphosphate for incorporation into DNA. Gemcitabine is used in combination with cisplatin is the preferred perioperative chemotherapy regimen for urothelial cancer.
Antineoplastics, Vinca Alkaloid
Class Summary
Vinca alkaloids act on the M and S phases of mitosis, inhibiting microtubule formation and inhibiting DNA/RNA synthesis.
Vinblastine
A vinca alkaloid with a cytotoxic effect (as a result of causing mitotic arrest), vinblastine binds to a specific site on tubulin, prevents polymerization of tubulin dimers, and inhibits microtubule formation. It used as a treatment for urothelial carcinoma in the MVAC regimen.
Antineoplastics, Anthracycline
Class Summary
Anthracyclines inhibit DNA and RNA synthesis by steric obstruction. They intercalate between DNA base pairs and trigger DNA cleavage by topoisomerase II.
Doxorubicin
Doxorubicin is an anthracycline antineoplastic that causes DNA strand breakage through effects on topoisomerase II and direct intercalation into DNA, which causes DNA polymerase inhibition. It used as a treatment for urothelial carcinoma in the MVAC regimen.
Antineoplastics, Alkylating
Class Summary
Alkylating agents inhibit cell growth and proliferation. They inhibit DNA synthesis by the formation of DNA cross-links.
Cisplatin
Cisplatin is a platinum-containing compound that covalently binds to DNA, binds to the N-7 position of guanine and adenosine. It can react with 2 different sites on DNA to produce cross-links. This may interference with DNA transcription and/or replication, which may trigger cytotoxic effects.
PD-1/PD-L1 Inhibitors
Class Summary
PDL1 is expressed on the surface of activated T cells under normal conditions. PDL1 interaction inhibits immune activation and reduces T-cell cytotoxic activity when bound. This negative feedback loop is essential for maintaining normal immune responses and limits T-cell activity to protect normal cells during chronic inflammation. Tumor cells may circumvent T-cell–mediated cytotoxicity by expressing PDL1 on the tumor itself or on tumor-infiltrating immune cells, resulting in the inhibition of immune-mediated killing of tumor cells.
Pembrolizumab (Keytruda)
Monoclonal antibody to programmed cell death-1 protein (PD-1); blocks the interaction between PD-1 and its ligands, PD-L1 and PD-L2. Pembrolizumab is indicated as first-line treatment for locally advanced or metastatic urothelial carcinoma (UC) in patients who are not eligible for cisplatin-containing chemotherapy. It is also indicated for patients with disease progression during or following platinum-containing chemotherapy or within 12 months of neoadjuvant or adjuvant treatment with platinum-containing chemotherapy. Additionally, pembrolizumab is indicated for treatment of BCG-unresponsive, high-risk, nonmuscle invasive bladder cancer (NMIBC) with carcinoma in situ (CIS) with or without papillary tumors in patients who are ineligible for, or have elected not to undergo cystectomy. It is also indicated in combination with enfortumab vedotin for locally advanced or metastatic urothelial carcinoma in adults who are not eligible for cisplatin-containing chemotherapy.
Nivolumab (Opdivo)
Monoclonal antibody to programmed cell death ligand-1 protein (PDL1). It blocks the interaction between PDL-1 and its ligands. It is indicated for locally advanced or metastatic urothelial carcinoma in patients who have disease progression during or following platinum-containing chemotherapy, or disease progression within 12 months of neoadjuvant or adjuvant treatment with platinum-containing chemotherapy.
Atezolizumab (Tecentriq)
Monoclonal antibody to programmed cell death ligand-1 protein (PDL1). It blocks the interaction between PDL-1 and its ligands. It is indicated for locally advanced or metastatic urothelial carcinoma in patients who are not eligible for cisplatin-containing chemotherapy, or have disease progression during or following platinum-containing chemotherapy, or disease progression within 12 months of neoadjuvant or adjuvant treatment with platinum-containing chemotherapy.
Anti-Nectin-4 Monoclonal Antibodies
Class Summary
Nectin-4 is a cell adhesion molecule that is expressed on many solid tumors.
Enfortumab vedotin (Padcev)
Enfortumab vedotin is an antibody-drug conjugate (ADC) composed of an anti-nectin-4 monoclonal antibody attached to the cell-killing agent, monomethylauristatin E (MMAE). Once the antibody attaches to nectin-4 that is expressed on the tumor, the complex is internalized in the lysosome, which releases MMAE. Enfortumab vedotin is indicated for locally advanced or metastatic urothelial cancer in patients who have received a PD-1/L1 inhibitor and platinum-containing chemotherapy in the neoadjuvant/adjuvant, locally advanced, or metastatic setting. It is also indicated in combination with pembrolizumab for locally advanced or metastatic urothelial carcinoma in adults who are not eligible for cisplatin-containing chemotherapy.
FGFR Inhibitors
Class Summary
Fibroblast growth factor receptor (FGFR) regulate important biological processes including cell proliferation and differentiation, which are part of a complex signaling pathway in tumorigenesis.
Erdafitinib (Balversa)
Erdafitinib inhibits FGFR phosphorylation and signaling, and thereby, decreases cell viability in cell lines expressing FGFR genetic alterations, including point mutations, amplifications, and fusions. It is indicated for locally advanced or metastatic urothelial carcinoma that has FGFR2 or FGFR3 genetic alterations and progressed during or following at least 1 line of prior platinum-containing chemotherapy, including within 12 months of neoadjuvant or adjuvant platinum-containing chemotherapy.
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Intravenous pyelogram (IVP) demonstrating an upper calyx filling defect characteristic of upper tract urothelial carcinoma (UTUC). Blunting of the involved calyx is noted. Courtesy of Andrew J. Taylor, MD, University of Wisconsin Medical School.
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CT scan demonstrating right renal pelvis upper tract urothelial carcinoma (UTUC). Contrast in the renal pelvis is displaced by the tumor. Courtesy of Andrew J. Taylor, MD, University of Wisconsin Medical School.
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CT scan demonstrating left distal ureteral upper tract urothelial carcinoma (UTUC). The left ureter is dilated and a medial filling defect is noted. Courtesy of Andrew J. Taylor, MD, University of Wisconsin Medical School.
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Left retrograde ureterogram demonstrating the classic "goblet" sign of ureteral upper tract urothelial carcinoma (UTUC). Ureteral dilation distally and proximally to the tumor is present. The narrowed wall of the ureter is irregular. Courtesy of Andrew J. Taylor, MD, University of Wisconsin Medical School.
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CT scan demonstrating bulky right renal pelvis upper tract urothelial carcinoma (UTUC) replacing the majority of the renal parenchyma. A pericaval lymph node metastasis is noted. Courtesy of Andrew J. Taylor, MD, University of Wisconsin Medical School.
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CT scan demonstrating metastatic upper tract urothelial carcinoma (UTUC) of the right adrenal gland. A heterogeneous adrenal mass is noted adjacent to the spine. The superior portion of the right kidney is observed. Courtesy of Andrew J. Taylor, MD, University of Wisconsin Medical School.
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Graphic representation of templates for lymph node dissection in patients with upper tract urothelial carcinoma, as proposed by Matin et al. For tumors in the right pelvis and upper ureter, dissection encompassing the right hilar, paracaval, and retrocaval regions (orange) will remove 82.9% of the involved lymph nodes. Adding the inter-aortocaval region (green) will improve coverage to 95.8%. For left-sided pelvic tumors, removal of hilar and para-aortic lymph nodes (violet) will ensure removal of 86.9% of the involved nodes. Adding inter-aortocaval lymph nodes (green) will increase the coverage to 90.2% of involved nodes. The level of dissection along the great vessels varies for pelvic tumors. The lower limit is the inferior mesenteric artery. For upper ureteric tumors, dissection should extend up to the aortic bifurcation. For distal ureteric tumors, pelvic template dissection involving the common iliac, external iliac, obturator, and internal iliac nodes will remove 75% of involved nodes on the right side and 83.3% of involved nodes on the left side (orange and violet circles). However, adding paracaval groups for tumors on the left side (orange rectangle) and para-aortic groups for those on the right side (violet rectangle) will improve coverage to almost 100%.