by Dr. C.H. Weaver M.D. updated 1/2020
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 treatment consists of chemotherapy, immunotherapy with 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. For more information about treatment of this type of stage IV bladder cancer click on 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 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 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. Precision cancer medicine uses targeted drugs and immunotherapies engineered to directly attack the cancer cells with specific abnormalities, leaving normal cells largely unharmed. Researchers are currently evaluating whether precision cancer immunotherapy that helps to restore the body’s immune system can improve outcomes for bladder cancer 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)
- Keytruda (pembrolizumab)
- Imfinzi (durvalumab)
- Tecentriq (atezolizumab)
- Bavencio (avelumab)
- Opdivo (nivolumab)
Maintenance Bavencio Prolongs Survival: In 2017, the FDA approved the checkpoint inhibitor Bavencio for the treatment of patients with locally advanced or metastatic bladder cancer. The JAVELIN Bladder 100 clinical trial compared maintenance Bavencio plus best supportive care (BSC) to BSC alone in patients with locally advanced or metastatic bladder cancer whose disease did not progress after completion of first-line platinum-containing chemotherapy. A total of 700 patients whose disease had not progressed after induction chemotherapy were treated with either Bavencio plus BSC or BSC alone.
Preliminary trial results suggest that first-line maintenance therapy with Bavencio prolonged survival duration compared to BSC alone. Full trail results will be released at an upcoming medical meeting and patients should discuss the potential role of Bavencio with their doctor.
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. To learn more about radical cystectomy, go to Surgery for Bladder Cancer.
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.
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.
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.
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.
For example, a phase II clinical trial suggested that the targeted therapy 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.
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.