Stage 4 Bladder Cancer

What is stage 4 Bladder Cancer?

Bladder cancer is divided into 4 stages, depending on how far they have spread. Stage 4 bladder cancer is the last stage in which cancer has spread into the abdominal or pelvic wall. In some cases, cancer has spread to the lymph nodes outside the pelvis or other body parts, such as the lungs, bones, or liver.[1],[2]

What are the subtypes of stage 4 Bladder Cancer?

There are three main subtypes of bladder cancer which are diagnosed depending on how the tumor cells look under a microscope. These are,

Adenocarcinoma - this cancer subtype is very rare and accounts for only 2% of all bladder cancers. It develops from granular cells.[1]

Urothelial carcinoma - this type of cancer begins in the urothelial cells that line the urinary tract and is responsible for 90% of all bladder cancers. It grows in finger-like projection from the inner surface of the bladder towards the hollow center. It is treatable and has positive outcomes.[1],[3]

Squamous cell carcinoma - it accounts for only 4% of all bladder cancers. It occurs due to the development of squamous cells in response to irritation and inflammation in the bladder lining.[1]

Bladder cancers are also differentiated based on how invasive they are and how deeply they have spread into the bladder wall. For instance, noninvasive bladder cancer is only found in the innermost layer, whereas invasive bladder cancers have progressed past the first cell layer and are more challenging to treat.[3]

Stage 4 bladder cancer staging and diagnosis

Bladder cancer staging

In general, the TNM system is used to describe and classify cancers, including bladder cancer, where:

• T (tumor) describes the size and location of the tumor
• N (nodes) indicates whether or not it has spread to nearby lymph nodes
• M (metastasis) describes if and how far the cancer has spread from its origin

How common is stage 4 bladder cancer?

About 4.2% of all new cases are bladder cancer cases.[⁵] In 2023, around 82,290 adults were diagnosed with bladder cancer in the United States. It is a global health problem that is more prevalent among men and is the fourth most common cancer in men. It is 4 times more likely to be diagnosed in men, especially white men.

It is also common in elders aged 50 or above. It has a poor mortality rate, and around 212,536 people died worldwide in 2020 due to bladder cancer. Overall, it is the eighth most common cause of death in men in the United States.[¹]

How is stage 4 bladder cancer diagnosed?

Multiple diagnostic modalities are used in diagnosing stage 4 bladder cancer, such as

History and physical - people are only diagnosed with bladder cancer once they show symptoms. Your doctors will conduct a physical examination, including looking for abnormal lumps and growth around the pelvis, or a pelvic exam for women.

Imaging

• Cystoscopy - it is the gold standard for the initial management of bladder cancer. In this procedure, a thin, lighted, flexible tube called a cystoscope enables doctors to see inside the body. It is used to observe abnormal growth and evaluate the need for surgery or biopsy. It doesn’t require anesthesia.[1]
• Biopsy - it involves the removal of a small amount of tissue to study under a microscope. It is a surgical procedure commonly known as transurethral bladder tumor resection or TURBT. This procedure is done after abnormal growth is detected with cystoscopy.
• Computed tomography (CT) scan - uses x-rays to take 3D pictures of the body’s inside. It helps determine the tumor’s size or enlarged lymph nodes, indicating cancer has spread.
• Magnetic resonance imaging (MRI) - uses magnetic fields to create images of the body’s inside and has the same purpose as a CT scan. Similar to a CT scan, a contrast dye is used, but it is slightly different as it can be injected into a patient’s vein.
• Bone scan - a radioactive tracer is used to look at the inside of bones. The tracer is injected into the patient’s vein and collected at specific bone areas detected by a special camera.
• PET scan - uses a radioactive substance that is injected into the body and taken up by cells that use the most energy. The principle behind this is that cancer cells use energy actively, and a scanner produces images of the inside of the body.
• Ultrasound - uses sound waves and doesn’t require a contrast medium. It helps detect kidney or ureter blockage.

Urine test - these tests are conducted when blood is found in the urine. It helps in detecting tumor cells. If a patient undergoes a cystoscopy, an additional urine test is recommended. The bladder is rinsed, and liquid is collected through a cystoscope or a small tube inserted into the urethra. The samples are analyzed under a microscope or through molecular analysis.[¹]

Stage 4 bladder cancer symptoms

In the early stages of bladder cancer, no signs and symptoms are apparent. However, as the disease progresses, multiple symptoms are developed. It is important to note that these symptoms can either be due to bladder cancer or other diseases, such as an enlarged prostate, urinary tract infection, bladder stones, etc.[⁶]

Following are the signs and symptoms associated with stage 4 bladder cancer:

• Lower back pain
• Blood or blood clots in the urine
• Frequent urination
• Burning sensation during urination
• Feeling the need to urinate but unable to pass urine or feeling the need to urinate multiple times throughout the night.

Stage 4 bladder cancer treatment

Treatment for stage four bladder cancer varies depending on the extent of localization and how far the cancer has spread. It is also based on the patient’s health, history, age, and preference.[7] Generally, the first line of treatment is surgery, but it is not an optimal option for everyone. For instance, surgery should only be considered if the tumor is removable or the patient is healthy enough. Surgery physically removes the entire tumor and the immediately surrounding healthy tissue to prevent a recurrence. Second-line treatments are available for patients who are not ideal candidates for surgery, such as chemotherapy, radiation therapy, immunotherapy, etc.

Stage 4 bladder cancer primary/first-line treatment

Different surgeries are available for bladder cancer, and the choice between these depends on the cancer’s stage and grade. For instance, for stage 4 bladder cancer, the following surgeries are recommended:

• Radical cystectomy - to control the local spread and prevent the complications of stage four bladder cancer, a radical cystectomy is recommended. The procedure removes the whole bladder, along with nearby organs and tissues. In men, prostate and seminal vesicles, and in women uterus, ovaries, fallopian tubes, and urethra are removed.

During this procedure, the surgeon makes multiple cuts rather than one large incision and uses telescoping machinery to remove the bladder. In some cases, a partial cystectomy, removing only the affected part of the bladder, is also considered.[¹],[⁷],[⁸]

Urinary diversion - when the entire bladder is removed, doctors have to develop a new way to pass urine. Generally, a urinary bag is attached to a stoma outside of the body, which uses a section of the small intestine or colon to divert the urine into the bag.

If patients don’t prefer a urinary bag, surgeons can also use part of the small or large intestine to create a urinary reservoir. The reservoir sits inside the body and can also be connected to the urethra to create an orthotopic neobladder and allow the patient to pass the urine outside the body. However, patients don’t feel the urge to urinate and, thus, need to learn to urinate on a schedule to avoid complications. Another option includes creating an internal pouch from the small or large intestine and connecting it to the belly or abdomen. Using a catheter, the user must drain the pouch several times throughout the day.[¹],[⁸]

There are multiple risks associated with stage 4 bladder cancer surgery, such as infection, blood clots, urine leaks, damage to pelvic nerves, and a prolonged healing time.[¹]

It is important to remember that in most stage 4 bladder cancer cases, cancer has spread dramatically and cannot be removed via surgery. Thus, systemic treatment is necessary to kill all cancer cells. Moreover, surgery is only considered when systemic or second-line treatment proves ineffective or incomplete.[⁷]

Other types of treatment for stage 4 bladder cancer

Medications are also used to treat stage 4 bladder cancer and are found to be more effective in the metastatic stage. Medications are given via oral pills or an intravenous tube. These medications can be given in combination or one at a time, and each person responds differently.[¹]

Chemotherapy - before chemotherapy, the survival of stage 4 bladder cancer patients was only 3 to 6 months after diagnosis. It uses drugs to destroy cancer cells to stop their growth. It consists of several cycles given over a set period. There are typically two types of cancer treatments based on the stage of cancer: [¹],[⁸]

• Intravesical chemotherapy - a tube, called a catheter, is inserted into the urethra to deliver medicine directly into the bladder. Common drugs include Mitomycin-C, gemcitabine, docetaxel, and valrubicin. It is useful for the local treatment of low-grade bladder cancer.
• Systemic chemotherapy - the medicine is injected into the patient’s vein through an IV or pill. Usually, a combination of drugs works better than a single drug. It is useful for stage 4 bladder cancer and helps shrink cancer and prevent a recurrence. Common treatment regimens include Cisplatin and gemcitabine, MVAC, which includes 4 drugs: methotrexate, doxorubicin, vinblastine, and cisplatin, and Dose-dense (DD)-MVAC with growth factor support.[¹]

Radiation therapy - it is used along with chemotherapy or immunotherapy. The therapy includes high-energy X-rays to treat cancer cells. One common type is external beam radiation therapy, recommended when surgery effectively reduces symptoms and improves the quality of life.[⁸]

Immunotherapy - it uses the body’s natural defense system and improves the immune system’s ability to attack and kill cancer cells. It can be given locally or systemically. Bacillus Calmette-Guerin (BCG) is the standard drug given through a catheter in local immunotherapy. It causes symptoms like fatigue, flu, fever, etc. Sometimes, interferon is given with BCG to treat cancer.

In systemic immunotherapy, immune checkpoint inhibitors like Nivolumab and Pembrolizumab are used. They are PD-1 inhibitors recommended when chemotherapy is found ineffective, and the patient suffers from metastatic urothelial carcinoma. Pembrolizumab can also be used for non-invasive bladder cancer. Common side effects of immunotherapy include weight changes, diarrhea, skin reactions, fatigue, flu-like symptoms, and gut inflammation.[¹],[⁸]

Can stage 4 bladder cancer be cured?

The cure or survival rate of any cancer depends on the patient’s overall health and the tumor’s size, stage, and location. The prognosis for stage 4 bladder cancer is not good, and only a minority of patients are cured at this stage through a combination of systemic therapies. This is because the cancer has spread outside of the pelvis area. Early detection can improve prognosis; however, in bladder cancer, early detection is difficult, and symptoms are not apparent until the cancer has spread. It is important to note the death rate for bladder cancer decreased by over 2% annually from 2016 to 2020.[¹],[⁷]

Prognosis: Stage 4 bladder cancer survival rate

Stage 4 bladder cancer survival rate

According to the national cancer institute, the 5-year survival rate of bladder cancer from 2012 to 2018 is 77-1%.[⁵] According to ethnicity, the relative 5-year survival rate is higher in Non-Hispanic Asian / Pacific Islanders (75.9%) as compared to Non-Hispanic Black (64.9%).[⁹] However, the 5-year survival rate of invasive bladder cancers that have spread from the bladder to the surrounding tissue and lymph nodes is 39%.[¹]

Stage 4 bladder cancer recurrence rate

Stage 4 bladder cancer recurrence rate is higher than other types of cancer. About 50% of patients experience a recurrence of bladder cancer following treatment. Patients with stage 4 bladder cancer or muscle-invasive bladder cancer call for an extensive treatment regime, and the chances of recurrence are high, around 30 to 54%. It is also difficult to predict the time of recurrence; for instance, it can come back anywhere from between 5 to 15 years after treatment.[¹⁰]

Stage 4 bladder cancer growth rate

As stated above, the prognosis for stage 4 bladder cancer is not good, and as the disease progresses and spreads, the survival rate falls to 5%.[¹¹] The disease can progress rapidly, and only early detection can provide prompt treatment options. In patients with non-invasive muscle bladder cancer, around 10 to 30% of the cases progress to life-threatening invasive muscle bladder cancer. This percentage can vary for low-risk grade cancers.[¹⁰]

Lifestyle changes for preventing and managing bladder cancer

After bladder cancer diagnosis, certain lifestyle changes can help prevent the disease or reduce its symptoms.

Diet

Bladder cancer occurrence can be delayed or prevented by maintaining a healthy diet that reduces exposure to carcinogens or blocks the carcinogenic process. By increasing fluid intake, you can decrease urinary mutagenicity. A Health Professionals Follow-up Study tested fluid intake. It concluded that patients with high fluid intake (>2531 ml per day) were associated with a 49% reduction in bladder cancer risk when compared with the lowest intake (<1290 ml per day).

Vegetables and fruits are also recommended as they modulate the phase I/II enzyme system to alter carcinogen metabolism and facilitate detoxification. However, the micronutrients and phytochemicals in vegetables and fruits are heat sensitive; thus, the cooking style also matters.[¹²]

Physical Activity

By maintaining a healthy diet and weight through physical activity, you can indirectly reduce the risk of bladder cancer. A meta-analysis supported the theory by studying nearly 5.5 million subjects and 27,784 bladder cancer cases. Results were measured in high vs. low levels of physical activity and were associated with a 15% reduction in the risk of bladder cancer. There was also a difference in the type of physical activity followed, such as recreational activity resulted in a 19% reduced risk, and occupational activity resulted in a 10% reduced risk.[¹²]

Smoking

Tobacco smoking is the strongest risk factor associated with bladder cancer. It accounts for 50% of bladder cancer cases in the U.S. Multiple studies conclude that smoking increases the risk three-fold in current smokers and two-fold in former smokers. The risk is also dose-dependent, and research shows that around 15 cigarettes a day is the peak risk factor.[¹²]

Conclusion

Takeaway

Stage 4 bladder cancer is highly prevalent, with new cases diagnosed at 18.7 per 100,000 men and women annually.[⁵] It is the terminal stage or metastatic stage of cancer where the cancerous cells have spread beyond the bladder to nearby tissues, lymph nodes, and distant organs like lungs, bones, and liver. In such cases, surgery is not a viable option; thus, systemic or second-line treatments like immunotherapy, radiation therapy, chemotherapy, and targeted therapy are recommended. After treatment, the patient should make specific lifestyle changes and focus on follow-up care. According to the American Urological Association guidelines, a medical check-up within 3 to 4 months following treatment, then again up to 4 times a year for the first 4 or 5 years, and annually, or at the patient’s and physician’s suggestion, is recommended. The prognosis isn’t ideal, but patients can reduce symptoms and prevent a recurrence with the right treatment and follow-up care.[¹⁰]