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Bladder Cancer Medication

  • Author: Gary David Steinberg, MD, FACS; Chief Editor: Bradley Fields Schwartz, DO, FACS  more...
 
Updated: Jun 02, 2016
 

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 the PDL1 inhibitor, atezolizumab, is now approved by the FDA for advanced urothelial carcinoma. 

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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, Rheumatrex)

 

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.

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Antineoplastics, Vinca Alkaloid

Class Summary

Vinca alkaloids act on the G and S phases of mitosis, inhibiting microtubule formation and inhibiting DNA/RNA synthesis.

Vinblastine (Velban)

 

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.

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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, Caelyx, Rubex)

 

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).

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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 (Paraplatin)

 

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 (Thioplex, TSPA)

 

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.

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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.

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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 have disease progression during or following platinum-containing chemotherapy, or disease progression within 12 months of neoadjuvant or adjuvant treatment with platinum-containing chemotherapy.

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Contributor Information and Disclosures
Author

Gary David Steinberg, MD, FACS The Bruce and Beth White Family Professor and Vice Chairman of Urology, Director of Urologic Oncology, Section of Urology, Department of Surgery, The University of Chicago Medical Center and Cancer Center

Gary David Steinberg, MD, FACS is a member of the following medical societies: American Association for Cancer Research, Society of Laparoendoscopic Surgeons, American Society of Clinical Oncology, Societe Internationale d'Urologie (International Society of Urology), American College of Surgeons, American Urological Association, Society of Urologic Oncology

Disclosure: Received consulting fee from Abbott Molecular for consulting; Received consulting fee from Endo Pharmaceuticals for consulting; Received consulting fee from Bioniche for consulting; Received consulting fee from Tengion for consulting; Received consulting fee from Archimedes for review panel membership; Received consulting fee from PhotoCure for review panel membership; Received consulting fee from Taris Biomedical for review panel membership; Received none from Cold Genesys for other; Received h for: Photocure; Taris Biomedical; Heat Biologics: Cold Genesys; Merck; Roche/Genentech; Karl Storz; Mdx Health, Telesta.

Coauthor(s)

Kush Sachdeva, MD Southern Oncology and Hematology Associates, South Jersey Healthcare, Fox Chase Cancer Center Partner

Disclosure: Nothing to disclose.

Bagi RP Jana, MD Associate Professor of Medicine (Genitourinary Oncology), Division of Hematology and Oncology, University of Texas Medical Branch

Bagi RP Jana, MD is a member of the following medical societies: American Cancer Society, American Medical Association, SWOG, American Society of Clinical Oncology

Disclosure: Nothing to disclose.

Chief Editor

Bradley Fields Schwartz, DO, FACS Professor of Urology, Director, Center for Laparoscopy and Endourology, Department of Surgery, Southern Illinois University School of Medicine

Bradley Fields Schwartz, DO, FACS is a member of the following medical societies: American College of Surgeons, Society of Laparoendoscopic Surgeons, Society of University Urologists, Association of Military Osteopathic Physicians and Surgeons, American Urological Association, Endourological Society

Disclosure: Nothing to disclose.

Acknowledgements

Sujeet S Acharya, MD Resident Physician, Department of Surgery, Section of Urology, University of Chicago Division of the Biological Sciences, The Pritzker School of Medicine

Disclosure: Nothing to disclose.

Brendan Curti, MD Director, Genitourinary Oncology Research, Robert W Franz Cancer Research Center, Earle A Chiles Research Institute, Providence Cancer Center

Brendan Curti, MD is a member of the following medical societies: American College of Physicians, American Society of Clinical Oncology, Oregon Medical Association, and Society for Biological Therapy

Disclosure: Nothing to disclose.

Edward M Gong, MD Fellow, Department of Surgery, Division of Urology, Children's Hospital Boston

Disclosure: Nothing to disclose.

Mark H Katz, MD Fellow in Urologic Oncology and Minimally Invasive Surgery, University of Chicago Medical Center

Mark H Katz, MD is a member of the following medical societies: Alpha Omega Alpha, American Urological Association, Endourological Society, and Society of Urologic Oncology

Disclosure: Nothing to disclose.

Hyung L Kim, MD Associate Professor, Cedars-Sinai Medical Center

Disclosure: Nothing to disclose.

Francisco Talavera, PharmD, PhD Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference

Disclosure: Medscape Salary Employment

Dan Theodorescu, MD, PhD Paul A Bunn Professor of Cancer Research, Professor of Surgery and Pharmacology, Director, University of Colorado Comprehensive Cancer Center

Dan Theodorescu, MD, PhD is a member of the following medical societies: American Cancer Society, American College of Surgeons, American Urological Association, Medical Society of Virginia, Society for Basic Urologic Research, and Society of Urologic Oncology

Disclosure: Key Genomics Ownership interest Co-Founder-50% Stock Ownership; KromaTiD, Inc Stock Options Board membership

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In an ileal conduit, a small segment of ileum is taken out of continuity with the gastrointestinal tract but is maintained on its mesentery. Ureters are anastomosed to one end of this ileal segment, and the other end is brought out as a stoma to the abdominal wall.
In an Indiana pouch, a urinary reservoir is created from detubularized right colon and an efferent limb of terminal ileum. Terminal ileum is plicated and brought to the abdominal wall. The continence mechanism is the ileocecal valve.
In an orthotopic neobladder, a segment of ileum is used to construct a neobladder, which is connected to the urethra. Orthotopic neobladder most closely restores the natural storage and voiding function of the native bladder.
The classic appearance of carcinoma in situ as a flat, velvety patch. However, using special staining techniques such as 5-aminolevulinic acid, it has been shown that significant areas of carcinoma in situ are easily overlooked by conventional cystoscopy. Courtesy of Abbott and Vysis Inc.
Papillary bladder tumors such as this one are typically of low stage and grade (Ta-G1). Courtesy of Abbott and Vysis Inc.
Sessile lesions as shown usually invade muscle, although occasionally a tumor is detected at the T1-G3 stage prior to muscle invasion. Courtesy of Abbott and Vysis Inc.
Photograph in which fluorescence in situ hybridization centromere staining identifies aneuploidy of chromosome 3. Multiple instances of overexpression of the chromosome (note the multiple red dots, which identify centromeres of this chromosome) prove aneuploidy.
Cross-section through the bladder, uterus, and vagina with squamous cell carcinoma of the bladder infiltrating through the bladder wall into the vaginal wall.
High power, Pap stain showing high grade urothelial carcinoma on a bladder wash cytology.
Intermediate power, H and E stain of urothelial carcinoma in situ. The superficial cells shed into the urine and correlate with those seen in cytologic bladder washing or urine cytology.
High power, H and E stain of high grade urothelial carcinoma. This tumor is now invasive into the muscularis propria (smooth muscle seen in center of image).
Histopathology of bladder shows eggs of Schistosoma haematobium surrounded by intense infiltrates of eosinophils and other inflammatory cells.
(A) When infused into the bladder, the optical imaging agent hexaminolevulinate (Cysview) accumulates preferentially in malignant cells. (B) On blue-light cystoscopy, the collection of hexaminolevulinate within tumors is visible as bright red spots. Courtesy of Gary David Steinberg, MD, FACS.
Table 1. Clinical Findings and Recommended Action in Patients with Negative Cystoscopy
Cystoscopy Findings Urine Cytology Findings FISH* Findings Action
Negative Negative Negative† Routine follow-up
Negative Negative Positive‡ Increased frequency of surveillance, whether FISH findings are false positive or anticipatory positive
Negative Positive Negative or positive Cancer until proven otherwise
  • Upper tract imaging with contrast
  • Cystoscopy with retrograde pyelography, washings, and/or ureteroscopy
  • Evaluate urethra
  • Increased frequency of surveillance upon negative findings
*FISH - Fluorescent in situ hybridization.



†Negative predictive value 95%.



‡Positive predictive value 30%.



Table 2. Recurrence and Progression Rates at 5 Years for Ta, T1, and CIS TCC of the Bladder Treated With BCG
Stage Recurrence, % Progression, %
Ta 55 11
T1 61 31
CIS 45 23
G1 61 2-4
G2 56 5-7
G3 50-70 30-40
Table 3. Most Common Complications of Radical Cystectomy
Early Complications Rate, % Late Complications Rate, %
Ileus 10 Small-bowel obstruction 7.4
Wound infection 5.5 Ureteroenteric stricture 7.0
Sepsis 4.9 Renal calculi 3.9
Pelvic abscess 4.7 Acute pyelonephritis 3.1
Hemorrhage 3.4 Parastomal hernia 2.8
Wound dehiscence 3.3 Stomal stenosis 2.8
Bowel obstruction 3.0 Incisional hernia 2.2
Enterocutaneous fistula 2.2 Fistula 1.3
Rectal injury 2.2 Rectal complications < 1
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