Bladder Cancer Medication

Updated: Jan 09, 2020
  • Author: Gary David Steinberg, MD, FACS; Chief Editor: Bradley Fields Schwartz, DO, FACS  more...
  • Print
Medication

Medication Summary

The combination of methotrexate, vinblastine, doxorubicin (Adriamycin), and cisplatin (MVAC) is the standard treatment for metastatic bladder cancer. No proven role exists for adjuvant chemotherapy. MVAC has substantial toxicity, which must be weighed against the expected benefit. The major dose-limiting toxicity is myelosuppression.

The new combination regimens show response rates and median survival comparable to those for MVAC but with less toxicity. Gemcitabine plus cisplatin is now considered a first-line treatment for bladder cancer. Therapy with PDL1 inhibitors (eg, atezolizumab, nivolumab, durvalumab, avelumab, pembrolizumab) is now approved by the FDA for advanced urothelial carcinoma. Erdafitinib is the first fibroblast growth factor receptor (FGFR) inhibitor approved by the FDA for urothelial carcinoma in April 2019. The first anti-nectin-4 monoclonal antibody, enfortumab vedotin, was approved for urothelial carcinoma in December 2019.

Next:

Antineoplastics, Antimetabolite

Class Summary

These agents inhibit cell growth and proliferation. They interfere with DNA synthesis by blocking the methylation of deoxyuridylic acid.

Fluorouracil (Adrucil)

Fluorouracil is a pyrimidine antimetabolite. Several mechanisms of action have been proposed, including inhibition of thymidylate synthase and inhibition of RNA synthesis. This agent is also a potent radiosensitizer. Although not approved by the FDA for this indication, it is often used as a treatment for bladder cancer.

Methotrexate (Trexall, Rasuvo, Otrexup, Xatmep)

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 often used as a treatment for bladder cancer, although that is not an FDA-approved indication.

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. Although it does not have FDA approval for this indication, it is often used as a treatment for bladder cancer. Gemcitabine is used in combination with cisplatin for the treatment of advanced or metastatic bladder cancer.

Pemetrexed (Alimta)

Pemetrexed disrupts the folate-dependant metabolic processes important for cell replication, inhibits the enzymes involved in folate metabolism and DNA synthesis, and inhibits protein synthesis. Although it does not have FDA approval for this indication, it is often used for the treatment of metastatic bladder cancer. Folic acid and vitamin B12 are typically given prior to initiation of treatment. Dexamethasone is also given with pemetrexed, to minimize cutaneous reactions.

Previous
Next:

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. Although not FDA approved for this indication, vinblastine is often used as a treatment for bladder cancer in combination with a chemotherapy regimen.

Vinblastine is approved for intravenous use only; the FDA has issued a black box warning regarding possible death with intrathecal administration. Vinblastine is a moderate vesicant and extravasation should be avoided.

Previous
Next:

Antineoplastics, Anthracycline

Class Summary

Anthracycline antineoplastics inhibit DNA and RNA synthesis by steric obstruction. They intercalate between DNA base pairs and trigger DNA cleavage by topoisomerase II.

Doxorubicin (Adriamycin)

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 has a labeled indication for the treatment of bladder cancer. This drug has several black box warnings, including bone marrow suppression, myocardial toxicity, and secondary malignancy.

Valrubicin (Valstar)

Valrubicin is a semisynthetic analog of doxorubicin that inhibits incorporation of nucleosides into nucleic acids. It is indicated for intravesicular treatment of bladder carcinoma in situ (CIS) that is refractory to treatment with bacillus Calmette-Guérin (BCG).

Previous
Next:

Antineoplastics, Alkylating

Class Summary

These agents inhibit cell growth and proliferation. They inhibit DNA synthesis by the formation of DNA cross-links. Alkylating agents can have serious adverse effects, including bone marrow suppression, anaphylactic-like reactions, ototoxicity, renal toxicity, and vomiting.

Cisplatin

Cisplatin is a platinum-containing compound that exerts an antineoplastic effect by covalently binding to DNA, with preferential binding to the N-7 position of guanine and adenosine. It can react with 2 different sites on DNA to produce cross-links. The platinum complex also can bind to nuclear and cytoplasmic protein. Cisplatin has black box warnings, including anaphylactic-like reactions, ototoxicity, and renal toxicity.

Carboplatin

Carboplatin is a platinum alkylating agent that interferes with the function of DNA by producing interstrand DNA cross-links. It can be used in combination with paclitaxel for the treatment of bladder cancer, which is an off-label indication. Carboplatin has black box warnings, including bone marrow suppression, anaphylactic reactions, and vomiting.

Ifosfamide (Ifex)

Ifosfamide is a nitrogen mustard alkylating agent that inhibits DNA and protein synthesis. Although not FDA approved for this indication, ifosfamide is often used as a treatment for metastatic bladder cancer.

Thiotepa (Tepadina)

Thiotepa is an alkylating agent that inhibits DNA, RNA, and protein synthesis by producing cross-links between DNA strands. It is available as a powder for reconstitution and administration by injection. Thiotepa is indicated for the treatment of superficial papillary bladder cancer.

Previous
Next:

Antineoplastics, Antimicrotubular

Class Summary

These agents prevent cell growth and proliferation. They work by enhancing tubulin dimers, as well as by stabilizing existing microtubules and inhibiting their disassembly.

Docetaxel (Taxotere, Docefrez)

Docetaxel inhibits the depolymerization of tubulin, which inhibits DNA, RNA, and protein synthesis. It can be used for the treatment of bladder cancer, which is an off-label indication. It has several black box warnings, including bone marrow suppression, fluid retention, and hypersensitivity reactions. Its use is not recommended in certain patients with hepatic impairment. Patients receiving docetaxel treatment should be premedicated with corticosteroids the day before administration to help reduce fluid retention and hypersensitivity reactions.

Previous
Next:

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.

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.

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.

Durvalumab (Imfinzi)

Human IgG1 kappa monoclonal antibody that blocks PD-L1 binding to PD-1 and CD80, and therefore overcoming/preventing PD-L1-mediated inhibition/suppression of T-cell activation. 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.

Avelumab (Bavencio)

Avelumab is an anti-PD-L1 IgG1 monoclonal antibody.  It is indicated for locally advanced or metastatic urothelial carcinoma (UC) 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.

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.

Previous
Next:

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.

Previous
Next:

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-ejfv)

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.

Previous