by Dr. C.H. Weaver M.D. updated 11/2021
Patients with stage IV bladder cancer have cancer that has extended through the bladder wall and invaded the pelvic and/or abdominal wall and/or has lymph node involvement and/or spread to distant sites. Stage IV bladder cancer is also referred to as “metastatic” bladder cancer.
Currently, only a minority of patients with stage IV bladder cancer can be cured following treatment with standard therapies. This is because most patients have cancer that has already spread outside the area of the pelvis. Because the majority of patients with stage IV bladder cancer have disease that has already spread and cannot be removed with surgery, systemic treatment that can kill cancer cells throughout the body is necessary. Standard systemic treatment consists of chemotherapy, immunotherapy and precision cancer medicines, and occasionally surgery and radiation. Participation in a clinical trial should be considered and may offer access to better treatments and advance the existing knowledge about treatment of bladder cancer.
Some patients with bladder cancer have stage IV disease based only on the presence of local lymph node involvement and they have no evidence of distant spread of cancer. These patients with involvement of pelvic organs by direct extension and small volume metastasis to regional lymph nodes can be managed the same as stage III patients if all the cancer can be surgically removed by radical cystectomy and bilateral lymph node dissection.More information at Treatment of Stage III Bladder Cancer.
Systemic Treatment of Stage IV Bladder Cancer
Before the development of effective chemotherapy, the average survival of patients with stage IV bladder cancer was only 3-6 months from diagnosis. Bladder cancer, however, is sensitive to chemotherapy and may respond to treatment frequently and rapidly. Although long-term survival has been reported in some patients, chemotherapy is administered primarily to improve the symptoms of bladder cancer. Patients in good clinical condition should enter treatment with curative intent because some patients have prolonged remissions without cancer recurrences.
Combinations of chemotherapy agents are usually used for treatment of bladder cancer, as no single chemotherapy agent will produce a complete response in more than an occasional patient. Two commonly used chemotherapy regimens are GC and MVAC. GC is the combination of Gemzar® (gemcitabine) and cisplatin. MVAC is the combination of methotrexate, vinblastine, doxorubicin, and cisplatin. A phase III trial that compared these two regimens suggested that they were similarly effective, but that GC produced fewer side effects.1,2
Precision Cancer Immunotherapy
Precision cancer immunotherapy that helps to restore the body’s immune system improves outcomes when administered alone or in combination with chemotherapy in all settings.
There are several PD-1 and PD-L1 inhibitors that work in bladder cancer and they are collectively referred to as “checkpoint inhibitors”. Checkpoint inhibitors create their anti-cancer effect by blocking a specific proteins used by cancer cells called PD-1 and PD-L1, to escape an attack by the immune system. Once PD-L1 is blocked, cells of the immune system are able to identify cancer cells as a threat, and initiate an attack to destroy the cancer.3-6
Checkpoint inhibitors improve survival duration when combined with chemotherapy or administered alone and can be also be used as "maintenance" therapy.
- Keytruda (pembrolizumab)12
- Imfinzi (durvalumab)14
- Tecentriq (atezolizumab)13
- Bavencio (avelumab)8
- Opdivo (nivolumab)10
Maintenance Bavencio Prolongs Survival: The FDA approved the checkpoint inhibitor Bavencio for the treatment of patients with locally advanced or metastatic bladder cancer based on the results of the JAVELIN Bladder 100 clinical trial. Bavencio treatment improved overall survival from 14.3 months to 21.4 months on average when compared to treatment with best supportive care.8,11
Precision Cancer Medicines
Precision cancer medicine utilizes molecular diagnostic testing, including DNA sequencing, to identify cancer-driving abnormalities in a cancer’s genome. Once a genetic abnormality is identified, a specific targeted therapy can be designed to attack a specific mutation or other cancer-related change in the DNA programming of the cancer cells.
Trodelvy (sacituzumab govitecan (IMMU-132) is a precision cancer medicine that is designed to deliver a toxic payload directly to the cancer cells. The drug is a fusion of an antibody that recognizes a protein expressed by cancer cells known as trop2 and the metabolite of an established chemotherapy drug (irinotecan), SN-38. Trop-2, a calcium signal transducer that drives cancer cell growth in a majority of TNBC patients.9
Surgery for Stage IV Bladder Cancer
Radical cystectomy (removal of the bladder, tissue around the bladder, the prostate and seminal vesicles in men and the uterus, fallopian tubes, ovaries, anterior vaginal wall and urethra in women, with or without pelvic lymph node dissection) is sometimes recommended for treatment of patients with stage IV bladder cancer to control local spread and the complications this creates. Surgery is also utilized after an incomplete response of the primary cancer to radiation therapy and/or chemotherapy.
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Strategies to Improve Treatment
Most new treatments are developed in clinical trials. Clinical trials are studies that evaluate the effectiveness of new treatment strategies. The development of more effective cancer treatment for bladder cancer requires that new and innovative therapies be evaluated in patients. Participation in a clinical trial may offer access to better treatments and advance the existing knowledge about treatment of bladder cancer. Patients who are interested in participating in a clinical trial should discuss the risks and benefits with their physician.
Precision Cancer Medicines:
Precision cancer medicine uses targeted drugs and immunotherapies engineered to directly attack the cancer cells with specific abnormalities, leaving normal cells largely unharmed. Precision medicines are being developed for the treatment of bladder cancer and patients should ask their doctor about undergoing genomic testing to determine whether treatment with a precision cancer medicine is an option. Individuals should consider participating in clinical trials evaluating precision medicines alone or in combination with other systemic cancer treatments such as chemotherapy.
About Padcev (Enfortumab Vedotin)
Padcev is a novel precision cancer medicine known as an antibody drug conjugate, a type of therapy that combines an antibody that targets a specific protein on the surface of tumor cells with a payload of powerful chemotherapy. It is composed of an anti-Nectin-4 monoclonal antibody attached to a microtubule-disrupting agent, MMAE. Padcev targets Nectin-4, a cell adhesion molecule identified as an ADC target which is expressed on many solid tumors. This antibody is chemically linked with an agent that penetrates the tumor cell and destroys its structure.11
In the original multi-institutional clinical trial reported at ASCO 2019 Padcev produced responses in 44% of patients with locally advanced or metastatic urothelial cancer who had been previously treated with chemotherapy and checkpoint inhibitors. Among 125 patients who had received both standard chemotherapy plus a checkpoint inhibitor and Padcev, 12% had a complete response with no detectable sign of cancer and the median overall survival was 11.7 months. Notably, 38% of people whose cancer had spread to the liver responded to the treatment.
Herceptin® (trastuzumab); a drug used to treat breast cancers that over express a protein known as HER2) may be effective in combination with chemotherapy for patients with HER2-positive advanced bladder cancer.7
Immunotherapy: The goal of immunotherapy is to help the immune system recognize and eliminate cancer cells by either activating the immune system directly, or by inhibiting mechanisms of suppression of the cancer.
The immune system is an elaborate network of cells and organs that protect the body from infection. The immune system is also part of the body’s innate disease-fighting capability to treat cancer. With cancer, part of the problem is an ineffective immune system. The immune system recognizes cancer cells as foreign and up to a point can get rid of them or keep them in check. Cancer cells are very good at finding ways to hide from, suppress, or wear out the immune system and avoid immune destruction. The immune system may not attack cancer cells because it fails to recognize them as foreign and harmful.
General types of immunotherapy include interferon, interleukin, and colony stimulating factors (cytokines), which generally activate the immune system to attack the cancer. These general immunotherapies however are not specific and their activation of the immune system can cause severe side effects by attacking normal cells along with cancer cells. Immunotherapy treatment of cancer has progressed considerably over the past 30 years and has evolved from a general to more precisely targeted immunotherapy treatment. Examples of precision immunotherapy include checkpoint inhibitors, CAR T cells, and vaccines.
In an attempt to improve the chance of cure, immunotherapies are being tested alone or in combination with chemotherapy in clinical trials.
Sotigalimab The monoclonal antibody drug sotigalimab, combined with Opdivo immunotherapy results in tumor shrinkage in patients with advanced melanoma whose tumors have progressed on prior immunotherapy. Opdivo blocks PD-1, a protein that helps keep immune cells from attacking non-harmful cells in the body. Sotigalimab was designed to further stimulate antitumor immune response and to target CD40, which is a key co-stimulatory receptor.
New Chemotherapy Regimens: Development of new multi-drug chemotherapy treatment regimens that incorporate new or additional anti-cancer therapies for use as treatment is an active area of clinical research carried out in phase II clinical trials.
Phase I Clinical Trials: New chemotherapy or immunotherapy drugs continue to be developed and evaluated in patients with recurrent cancers in phase I clinical trials. The purpose of phase I trials is to evaluate new anti-cancer medications in order to determine the safety and tolerability of a drug and the best way of administering the drug to patients.
- von der Maase H, Hansen SW, Robers JY et al. Gemcitabine and cisplatin versus methotrexate, vinblastine, doxorubicin, and cisplatin in advanced or metastatic bladder cancer: results of a large, randomized, multinational, multicenter, phase III study. Journal of Clinical Oncology. 2000;18:3068-77.
- von der Maase H, Sengelov L, Roberts JT et al. Long-term survival results of a randomized trial comparing gemcitabine plus cisplatin, with methotrexate, vinblastine, doxorubicin, plus cisplatin in patients with bladder cancer. Journal of Clinical Oncology. 2005;20:4602-8.
- Merck’s KEYNOTE-045 Studying KEYTRUDA® (pembrolizumab) in Advanced Bladder Cancer (Urothelial Cancer) Meets Primary Endpoint and Stops Early
- United States Food and Drug Administration. (2016.) News Release. FDA approves new, targeted treatment for bladder cancer.
- Durvalumab (Imfinzi)
- FDA approves new, targeted treatment for bladder cancer. Accessed May 31, 2016.
- Hussain MHA, MacVicar GR, Petrylak DP et al. Trastuzumab, paclitaxel, carboplatin, and gemcitabine in advanced human epidermal growth factor receptor-2/neu-positive urothelial carcinoma: results of a multicenter phase II National Cancer Institute Trial. Journal of Clinical Oncology. 2007;25:2218-2224.
- Maintenance avelumab + best supportive care (BSC) versus BSC alone after platinum-based first-line (1L) chemotherapy in advanced urothelial carcinoma (UC): JAVELIN Bladder 100 phase III interim analysis.
- US Food and Drug Administration. FDA grants accelerated approval to sacituzumab govitecan for advanced urothelial cancer. Accessed April 13, 2021.
- First results from the phase 3 CheckMate 274 trial of adjuvant nivolumab vs placebo in patients who underwent radical surgery for high-risk muscle-invasive urothelial carcinoma (MIUC).
- FDA approves new type of therapy to treat advanced urothelial cancer
- Merck’s KEYNOTE-045 studying keytruda in advanced bladder cancer (urothelial cancer) meets Primary Endpoint and stops early. [Press release.] Can be retrieved here
- FDA Approves Atezolizumab in Bladder Cancer