Bladder Cancer

Bladder cancer is a condition characterized by the uncontrolled growth of abnormal cancer cells in the bladder lining, which can disrupt normal bladder functioning and extend their reach to nearby organs. Recent projections indicate that 82,290 US adults will receive a bladder cancer diagnosis in 2023, with 62,420 cases among men and 19,870 cases among women. This gender disparity in disease diagnosis raises concerns and calls for further investigation into the underlying factors contributing to this difference.

Executive Summary

  • Bladder cancer is a serious condition characterized by abnormal cell growth in the bladder lining. In 2023, it's projected that 82,290 US adults will be diagnosed with bladder cancer, with a significant gender disparity - 62,420 cases in men and 19,870 in women. This difference raises concerns and calls for further investigation into the underlying factors contributing to this disparity.

  • The main risk factors for bladder cancer include cigarette smoking, chemical exposures (like aromatic amines and aniline dyes), genetic mutations, chronic urinary tract infections, and certain inherited conditions. Smokers are three times more likely to develop bladder cancer compared to non-smokers. Recent research has shown a link between cigarette smoke extract and increased platelet-activating factor accumulation in bladder cancer cells.

  • Bladder cancer is classified and staged based on the extent of tumor invasion. Low-grade tumors are typically non-invasive with a high risk of recurrence but low likelihood of progression. High-grade tumors are more aggressive, often invading deeper layers of the bladder wall and having a poorer prognosis. The TNM classification system is used for staging, which considers tumor depth, lymph node involvement, and presence of metastases.

  • Common symptoms of bladder cancer include blood in urine, changes in bladder habits, and irritation symptoms. However, these symptoms can also be caused by other conditions like UTIs or bladder stones, so it's important to get them checked by a doctor. Early detection and proper diagnosis are crucial for effective treatment and management of the disease.

  • Diagnosis of bladder cancer involves various tests including urine cytology, cystoscopy, biopsy, and imaging studies like CT scans or MRIs. Cystoscopy is considered the most sensitive technique for detecting bladder tumors, while transurethral resection of the bladder (TURBT) is used for determining tumor stage and grade. Genetic counseling and tumor biomarker testing may also be recommended in some cases.

  • Treatment options for bladder cancer include surgery, radiation therapy, chemotherapy, immunotherapy, and targeted therapy. The choice of treatment depends on the cancer stage, grade, and individual patient factors. Surgery options range from transurethral resection to partial or radical cystectomy. Intravesical therapies, where drugs are directly administered into the bladder, are often used for non-muscle invasive bladder cancer.

  • Immunotherapy, particularly the use of Bacillus Calmette-Guérin (BCG), has shown effectiveness in treating bladder cancer and reducing recurrence risk. Newer immunotherapy drugs called checkpoint inhibitors (like atezolizumab and nivolumab) are being used for advanced cases. Targeted therapies, which block specific molecules involved in cancer growth, are also emerging as treatment options.

  • Complementary approaches, including Traditional Chinese Medicine and acupuncture, are being explored as adjuncts to standard treatments. While some studies show potential benefits, more research is needed to establish their efficacy. It's important for patients to discuss any complementary treatments with their healthcare team to ensure safety and avoid potential interactions with standard treatments.

  • Follow-up care and recurrence monitoring are crucial aspects of bladder cancer management. Regular surveillance through cystoscopy, imaging studies, and urine tests is recommended, with the frequency depending on the patient's risk level. The American Urological Association provides guidelines for follow-up schedules based on the risk stratification of the cancer.

  • Future directions in bladder cancer management include the use of artificial intelligence for diagnostics and prognostics, development of better biomarkers for recurrence monitoring, and exploration of new treatment combinations. There's also a focus on improving patient quality of life and reducing the financial burden of treatment through more targeted and effective therapies.

Symptoms

Signs and symptoms of bladder cancer include blood in urine, changes in bladder habits, and symptoms of irritation. These symptoms can be caused by UTI, bladder stones, overactive bladder, or enlarged prostate, and should be checked by a doctor.

Causes

Cigarette smoking is the main risk factor for bladder cancer, with smokers being three times more likely to be at risk compared to non-smokers. New research shows a link between cigarette smoke extract (CSE) and bladder cancer cells, with CSE exposure increasing platelet-activating factor (PAF) accumulation and upregulating PAF-R expression in these cells. Pretreatment with ginkgolide B shows promise in counteracting this effect.

Chemical exposures to bladder cancer include aromatic amines, o-toluidine, and aniline dyes. Genetic mutations in certain chromosomal genes, such as FGFR3, RB1, HRAS, TP53, TSC1, and others, can cause bladder tumors. Genetic variations are crucial for the development and progression of bladder cancer, with about 70% of cases linked to a specific mutation in the TERT gene.

Risk Factors

Gender, age, and ethnicity also play a role in the incidence and mortality rate of bladder cancer. Studies show that individuals aged ≥65 have a higher incidence and mortality rate of cancer compared to those aged <65. The incidence of urothelial carcinoma of the urinary bladder (UCB) increases with age, from approximately 142 per 100,000 men and 33 per 100,000 women aged 65-69 to 296 per 100,000 men and 74 per 100,000 women aged 85 and older.

Several theories have attempted to explain the link between carcinogenesis and aging, such as reduced bladder emptying, reduced water consumption, age-related organ system deterioration, and variations in UCB behavior among genders. Postmenopausal women have a higher risk of developing UCB than premenopausal women, and experiments with androgen receptor (AR) antagonists, RNA interference against AR, and androgen deprivation have shown the significance of the AR signaling pathway in UCB development and progression.

Chronic urinary tract infections (UTIs) are linked to an increased risk of developing bladder cancer due to inflammation damaging the protective layer of cells lining the bladder. Genetics, including Rb1, a gene associated with eye cancer in infants, and colon disease, a syndrome caused by an abnormal PTEN gene, can also increase bladder cancer risks. Lynch syndrome, also known as hereditary non-polyposis colorectal cancer, is linked to colon and endometrial cancer.

Staging and Grading

Pathology and grading are crucial in planning the best treatment for bladder cancer. Staging determines whether cancer has invaded the bladder wall and spread to other parts of the body, and grading refers to cancer cell appearance and multiplication rate. Low-grade (LG) bladder cancers are non-invasive, superficial papillary protrusions, with a high risk of recurrence but a low likelihood of progressing to high-grade (HG), invading, or metastasizing. High-grade (HG) tumors are flat and develop from severe dysplasia or carcinoma in situ, with poor prognosis.

Diagnosis

Cystoscopy is the most sensitive technique for detecting bladder tumors, while transurethral resection of the bladder (TURB) is reliable for determining tumor stage and grade. CT, MRI, and conventional ultrasound are used for staging bladder tumors but not classification. The TNM classification, based on clinicopathological findings, is the standard staging method for bladder cancer, divided into three risk groups: low, intermediate, and high.

Treatment

Treatment for bladder cancer involves surgery, including transurethral resection (TUR) with fulguration, partial cystectomy, and radical cystectomy. Surgery can be performed to remove a part of the bladder, or to reduce urinary symptoms caused by cancer that has spread outside the bladder. 

Radiation therapy, chemotherapy, and intravesical chemotherapy are used to kill or stop cancer cell growth. Systemic chemotherapy involves injecting drugs into a vein, while intravesical chemotherapy is administered through a tube inserted into the bladder via the urethra. Immunotherapy, targeting specific changes or substances in cancer cells, is also used. Intravesical immunotherapy, such as Bacillus Calmette-Guérin (BCG), is used to flush the bladder with cancer-killing drugs post-surgery and reduce cancer recurrence risk. Targeted therapy blocks specific enzymes, proteins, or molecules involved in cancer cell growth and spread.

Alternative treatments include Valrubicin, Gemcitabine, IFN-2α, Taxanes, Keyhole limpet hyocyanin (KLH), Mycobacterium phlei cell wall-nucleic acid complex (MCNA), Mistletoe lectin (ML), and Apaziquone. These treatments aim to prevent disease progression to MIBC and improve survival and quality of life. 

Electromotive drug administration (EMDA) uses electrical current to enhance drug penetrance through the bladder wall. Nanoparticle albumin-bound paclitaxel (nab-paclitaxel) is commonly used for metastatic breast and pancreas cancers due to its effective drug delivery mechanism.

Checkpoint inhibitors like atezolizumab and nivolumab are now commonly used to treat advanced and metastatic BCLa that has not responded to platinum-based therapy. Efforts to identify patients who will benefit from BCG, combination therapies, or radical cystectomy are needed.

Complementary approaches, such as Traditional Chinese Medicine (TCM), may also be used to treat bladder cancer. Acupuncture, a medical intervention using fine metallic needles to stimulate the peripheral and central nervous system, can be helpful and safe when used with standard medical treatment. It has been shown to reduce pain and improve urinary function scores in patients undergoing in-clinic pre-BCG instillation acupuncture. 

Other complementary methods include acupuncture, acupressure, aromatherapy, art therapy, biofeedback, labyrinth walking, massage therapy, meditation, music therapy, spirituality and prayer, Tai chi, yoga, and yoga.

Follow-Up Care

Recurrence monitoring is essential for noninvasive bladder cancer cases, as cases progress and patients often experience recurrence. The American Urological Association/Society of Urologic Oncology guidelines recommend surveillance cystoscopy, in-office fulguration, and individualized follow-up plans based on risk levels. Patients with radical cystectomy need regular surveillance to monitor for local recurrence or metastatic disease, with annual abdominal and pelvic CT scans and chest radiographs recommended.

Follow-up care for bladder cancer patients involves monitoring their health, checking for recurrence, and managing side effects. This may include physical exams, medical tests, and routine blood and urine tests. Cancer rehabilitation and survivorship care may include physical therapy, occupational therapy, career counseling, pain management, nutritional planning, financial counseling, and emotional counseling. Rehabilitation aims to restore control and independence in various aspects of life. Survivors may continue seeing their oncologist or urologist or transition to their primary care doctor or another healthcare professional.

Future Directions

AI technology in BCa diagnostics and prognostics can improve patients’ quality of life by preventing unnecessary radical cystectomies and reducing the financial burden of BCa. Artificial neural networks using tumor markers may be more cost-effective for detecting recurrence and progression than cystoscopy and conventional cytology. Nonlinear surveillance strategies can decrease tumor recurrence detection time and optimize resource utilization.

Future treatment directions include AI technology in BCa diagnostics and prognostics, recurrence monitoring using artificial neural networks, and combo-chemotherapy.

With a basic understanding of bladder cancer at our hands, let us take a more detailed look at the various aspects of this disease.

According to recent projections, it is anticipated that 82,290 US adults will receive a bladder cancer diagnosis in 2023, including almost 62,420 cases among men and approximately 19,870 cases among women. This gender disparity in disease diagnosis has raised concerns, prompting further investigation into the underlying factors contributing to this difference. This further emphasizes the need for increased awareness, prevention, and effective treatment strategies to combat this disease. 

Causes and Risk Factors

Smoking

Cigarette smoking is the main risk factor for bladder cancer. New research shows a strong link between smoking and bladder cancer. Smokers are three times more likely to be at risk compared to non-smokers. A study found weak links between cigarette characteristics (tar, nicotine content, and use of filter tips) and bladder cancer risk. 

New research shows a link between cigarette smoke extract (CSE) and bladder cancer cells. CSE exposure increased platelet-activating factor (PAF) accumulation and upregulated PAF-R expression in these cells. A study also found higher levels of PAF and its receptor (PAF-R) in tumor regions compared to surrounding normal tissue. These findings reveal the potential impact of cigarette smoke on bladder cancer development and progression. Another study noted that CSE exposure increases bladder cancer cell adherence to bladder endothelial cells. Pretreatment with ginkgolide B shows promise in counteracting this effect. 

CSE, a key factor, impacts a significant pathway in bladder cancer, contributing to tumor growth and increasing the chance of metastasis. PAF and PAFR interaction is a promising target for managing tumor growth. Targeting this interaction may control tumor progression.

Chemical Exposures

Chemicals known to increase the risk of bladder cancer include:

  • Aromatic Amines: Exposure to aromatic amines in textile dye and rubber tire industries is a significant risk factor for urinary bladder cancer. Recent studies have found that these substances can trigger abnormal cell growth in laboratory animals. 

    In bladder carcinogenesis, reactive intermediates of carcinogens in tobacco smoke, aromatic amines (AAs), and polycyclic aromatic hydrocarbons (PAHs) can lead to the formation of DNA adducts and, finally, mutations. PAHs and AA can't cause mutations on their own. Instead, they must be triggered (or detoxified) through different metabolic pathways, like oxidation. Also, new studies also reveal the health risks of genotoxic aromatic amines. These compounds can cause tumors in different parts of the body, depending on their substrate specificity and bio-activation pathways.

    Recent research suggests that 4-aminobiphenyl may cause cancer in humans. Carcinogenicity is believed to occur through a genotoxic mechanism involving metabolic activation, DNA adduct formation, and mutagenic and clastogenic effects. 

  • O-toluidine: A recent study found that lower doses of o-toluidine HCI had a significant impact on their health. Female mice had more liver tumors (hepatocellular carcinomas and adenomas) while male mice had more blood vessel tumors (hemangiosarcomas).  

  • Aniline dyes: Aniline HCI has been linked to a higher risk of fibromas and sarcomas in both genders, according to a recent study.

Genetic Factors

New studies have shown that genetic mutations in certain chromosomal genes, such as FGFR3, RB1, HRAS, TP53, TSC1, and others, can cause bladder tumors. Mutations play a significant role in the formation of harmful growths. Genes play a crucial role in regulating cell division and preventing uncontrolled proliferation. 

Bladder cancer is caused by gene alterations on human chromosome 9. However, bladder cancer can be caused by genetic mutations on chromosome 22. Genetic variations are important for this cancer's development and progression. Recent research on bladder cancer found that about 70% of cases are linked to a specific mutation in the TERT gene. The TERT gene is important for DNA protection, cellular aging, and its potential role in cancer.

Gender, Age, and Ethnicity

Studies show that individuals aged ≥65 have a higher incidence and mortality rate of cancer compared to those aged <65. The incidence of urothelial carcinoma of the urinary bladder (UCB) increases with age, from approximately 142 per 100,000 men and 33 per 100,000 women aged 65-69 to 296 per 100,000 men and 74 per 100,000 women aged 85 and older.

Several theories have attempted to explain the link between carcinogenesis and aging. As people age, they are exposed to carcinogens from smoking, workplace, and polluted living conditions. Aging allows cellular events that can lead to neoplastic transformation. The lag time between exposures, cellular events, and clinical expression of malignancy may explain why UCB appears in older people. Aging may lead to reduced bladder emptying, which can increase the time of exposure to carcinogens excreted in urine. 

Also, as people age, they may drink less water due to bothersome voiding symptoms. Over time, this would increase elderly exposure to carcinogens in urine. Furthermore, age-related organ system deterioration may reduce the ability to detoxify potential carcinogens, leading to an increase in the urinary concentration of carcinogens.

A theory also suggests that variations in the behavior of UCB among genders may be due to sex steroids and their receptors. Postmenopausal women have a higher risk of developing UCB than premenopausal women, according to an epidemiological study. Furthermore, experiments with androgen receptor (AR) antagonists, RNA interference against AR, and androgen deprivation showed the significance of the AR signaling pathway in UCB development and progression. However, mechanisms underlying the regulation of AR activity in UCB cells are unknown.

Chronic Bladder Issues

Patients with chronic UTIs have an increased risk of developing bladder cancer. The two illnesses are most likely related because inflammation damages the protective layer of cells lining the bladder. The body responds by attempting to mend itself by replacing those cells. And each new generation of cells represents another possibility for mutations to occur, possibly leading to bladder cancer.

Family History

Studies noted twice the risk of bladder cancer in close relatives of bladder cancer patients. A twin study also found that 31% of bladder cancer risk is due to genetics. Here are some factors that can contribute to bladder cancer:

  • Rb1, a gene associated with eye cancer in infants, may increase bladder cancer risks.

  • Cowden disease is a syndrome caused by an abnormal form of the PTEN gene. It can lead to breast cancer, thyroid cancer, and an increased risk of bladder cancer.

  • Lynch syndrome, also called hereditary non-polyposis colorectal cancer, is linked to colon and endometrial cancer. This syndrome may increase the risk of bladder and ureter cancer.

Pathology and Grading

To plan the best treatment for bladder cancer, the doctor needs to know the stage of the disease. Staging determines whether cancer has invaded the bladder wall and spread to other parts of the body and helps predict cancer growth and spread. Grading refers to cancer cell appearance and multiplication rate. Higher grades result in more uneven and multiplying cells. The stages are listed below:

  • Ta: Tumor is located on the bladder lining and does not extend into any deeper layers of the bladder.

  • Tis (Carcinoma in situ): This high-grade cancer appears to be a reddish, velvety patch located on the bladder lining.

  • T1: Tumor extends through the bladder lining but does not reach the muscle layer.

  • T2: Tumor extends into the muscle layer of the bladder

  • T3: Tumor extends past the muscle layer into tissues surrounding the bladder

  • T4: Tumor extends outside of the bladder to nearby structures (lymph nodes and prostate in men or lymph nodes and vagina in females)

Staging Based on the Depth of Invasion

Jewett and Strong studied the relationship between penetration depth (stage) and local extension and metastases. In 1948, McDonald and Thompson found that vascular and lymphatic invasion is related to prognosis. These early findings laid the foundation for the TNM classification which describes tumor (T), node (N), and metastasis (M) categories. TNM classification is now the standard staging method for bladder cancer based on clinicopathological findings. It is divided into three risk groups low, intermediate, and high, based on grade, depth, and number of tumors.

Specifically, transitional cell carcinoma (TCC), also called urothelial cell carcinoma (UCC) of the bladder, is divided into two subgroups: non-muscle-invasive (superficial) and muscle-invasive (deep) disease. 

Low-Grade vs High-Grade Tumors:

Approximately 70% of diagnosed BCs are low-grade (LG) BCs (Ta/pT1/CIS). These tumors are typically non-invasive, superficial papillary protrusions. They are genetically linked to FGFR3 mutations and have a high risk of recurrence but a low likelihood of progressing to high grade (HG), invading, or metastasizing. A small percentage (10-15%) of LG tumors can progress to HG and become invasive, possibly due to acquired TP53 mutations.

30% of BCs are high grade (HG) and associated with TP53 mutations, progressing quickly to become invasive tumors (pT2-4). They are flat BCs that develop from severe dysplasia or carcinoma in situ (CIS) and are associated with therapy resistance and poor prognosis.

Cystoscopy is the most sensitive technique for detecting bladder tumors, while transurethral resection of the bladder (TURB) is reliable for determining tumor stage and grade. However, TURB is invasive and necessitates sedation or anesthesia. On the other hand, CT, MRI, and conventional ultrasound (US) are used for staging bladder tumors but not classification. CT and MRI can accurately detect bladder tumor neovascularization, indicating progression, using contrast agents.

Signs and Symptoms

Blood in the Urine

Blood in urine is often the first sign of bladder cancer. Blood in urine can cause it to turn orange, pink, or dark red. Occasionally, urine may appear normal in color but contain small amounts of blood when tested for other symptoms or during a general medical check-up. You might notice blood in your urine one day and not the other, with clear urine for weeks or months. However, if someone has bladder cancer, blood will eventually reappear in the urine.

Symptoms of advanced bladder cancer

Bladder tumors that grow in size or spread to other areas of the body may occasionally manifest additional symptoms, including:

  • Inability to urinate

  • lower back discomfort on one side

  • appetite loss and weight reduction

  • feeling weary or feeble

  • Feet swelling 

  • Bone ache

Changes in bladder habits or symptoms of irritation

Bladder cancer can cause changes in urination like:

  • Frequent urination

  • Pain or burning while urinating.

  • Feeling a strong urge to urinate, even with an empty bladder.

  • Difficulty urinating or weak urine stream.

  • Frequent nighttime urination

Possible causes of these symptoms include UTI, bladder stones, overactive bladder, or enlarged prostate (in men). It's important to have them checked by a doctor for diagnosis and treatment, if necessary.

Diagnosis

Tests for bladder cancer include:

Urine tests

A urine cytology test can be performed if blood is found in the urine. Urine cytology uses a random urine sample to detect tumor cells. During a cystoscopy, the bladder may be rinsed and the liquid collected through the cystoscope or another small tube inserted into the urethra. The sample is then examined under a microscope. Other urine tests using molecular analysis can be done alongside urinary cytology to help detect cancer.

Biopsy/Transurethral resection of bladder tumor (TURBT)

If abnormal tissue is found, a biopsy will be done during a cystoscopy. A biopsy is the removal of tissue for microscope examination via a surgical procedure called TURBT. During TURBT, the doctor removes the tumor and a sample of the bladder muscle. The doctor may perform additional biopsies of other bladder areas based on the cystoscopy results. EUA (exam under anesthesia) is often done before a TURBT. The urologist evaluates the bladder for masses. Tissue samples from TURBT are analyzed by a pathologist.

TURBT helps diagnose bladder cancer, determine the tumor type, depth of growth, and identify any additional cancerous changes or carcinoma in situ (CIS). A TURBT can also be used to treat non-muscle-invasive tumors.

Cystoscopy

Cystoscopy is essential for diagnosing bladder cancer. A cystoscope is a thin, lighted tube that allows doctors to see inside the body. Flexible cystoscopy is done in a doctor's office without anesthesia. This procedure detects bladder growth and determines if a biopsy or surgery is needed.

Genetic counseling

Genetic factors can increase the risk of bladder cancer. Speaking with a genetic counselor and sharing a detailed family medical history can help identify your risk and that of your family members, including extended family.

Tumor biomarker testing

Your doctor may suggest lab tests on a tumor sample to identify unique genes, proteins, and factors. This is also known as tumor molecular testing. Test results can determine treatment options, especially in cases where tumor cells have spread.

Imaging Tests

Imaging tests can determine if bladder cancer has spread and assist with staging. Imaging tests show the body's internal pictures.

CT scan

A CT scan uses X-rays to take pictures of the body from different angles. A computer creates a detailed 3D image from these pictures to detect abnormalities or tumors. A CT scan can measure tumor size and identify enlarged lymph nodes, indicating possible cancer spread. A contrast medium dye is sometimes used before a scan to improve image detail. The dye can be injected into a vein or swallowed as a liquid.

Patients should inform the medical team if they have allergies to iodine or other contrast media before taking the test. Patients with kidney problems should inform the staff before a CT scan due to the potential renal problems caused by the contrast dye.

Ultrasound

Ultrasound uses sound waves to create internal organ images. It helps detect kidney or ureter blockages. No contrast medium is needed for this test.

After the tests are conducted, your doctor will review the diagnostic test results. The results help describe the cancer if it is diagnosed, wherein the doctor stages and grades the cancer.

Magnetic resonance imaging (MRI)

MRI uses magnetic fields to produce detailed body imaging. MRI measures tumor size and identifies enlarged lymph nodes, indicating potential cancer spread. A contrast medium dye is given before the scan for a clearer picture. This dye is different from the one used for a CT scan and can be injected into a patient's vein.

Positron emission tomography (PET) or PET-CT scan

A PET scan is often combined with a CT scan to create a PET-CT scan. Your doctor may refer to this procedure as a PET scan. PET scan creates images of an organ and tissues. A small amount of radioactive substance is injected into the patient. This substance is taken up by high-energy cells. Cancer absorbs more radioactive substances due to its active energy usage. The radiation in the substance is not harmful. A scanner detects the substance to produce body images.

Research suggests that a PET scan may be more effective than a CT scan or MRI in certain cases for detecting the spread of bladder cancer. However, PET scans are not standard imaging for bladder cancer and are not commonly used.

Treatment

Surgery

Surgery is the primary treatment for bladder cancer. Surgery type depends on the cancer location. Additional treatments may be given alongside surgery.

Preoperative therapy or neoadjuvant therapy

Preoperative therapy or neoadjuvant therapy is treatment given before surgery. Chemotherapy can be used before surgery to shrink the tumor and minimize the amount of tissue to be removed.

Before an operation, you undergo a battery of tests to ensure your health is fit enough for an anesthetic, if one is required, and that you will recover normally.

The following examinations may be administered to you:

  • Examination of your kidney function and general health through bloodwork

  • Swab test to rule out any illnesses

  • An electrocardiogram to make sure your heart is healthy

  • Lung function tests

  • A painless examination of the heart or an echocardiography.

  • X-ray of the chest to determine the state of one's lungs

  • A cardiopulmonary exercise test to measure your heart and lung capacity at rest and during physical activity.

You also undergo a blood test to ensure that any transfusions you may need after surgery will be a match for your blood type.

On the day of your surgery, your doctor or nurse will give you specific instructions. This includes advice on whether or not to stop taking any medications, as well as when to cease eating and drinking. Unless your doctor tells you to, keep taking your prescribed medications regularly.

You should jot down your concerns or any questions before your appointment. The whole process will appear less terrifying the more you prepare for it.

Mechanism of Action – Cancer Cells:

Pembrolizumab's mechanism centers around the inhibition of the PD-1 pathway:

  • PD-1 Blockade: By binding to PD-1, Pembrolizumab blocks the interaction between PD-1 and its ligands, PD-L1 and PD-L2.

  • Enhancing Immune Response: By inhibiting PD-1, it boosts the T cells' ability to recognize and attack cancer cells, overcoming the "brakes" that cancer cells apply to the immune system.

  • Promoting Tumor Infiltration: It can increase the infiltration of immune cells into the tumor, promoting a more effective immune attack.

Surgery for bladder cancer includes:

  • Transurethral resection (TUR) with fulguration
    During TUR with fulguration, a doctor inserts a cystoscope into the bladder through the urethra. A wire loop tool is used to remove the cancerous tumor via a process called fulguration.

  • Partial cystectomy
    Partial cystectomy involves the removal of a part of the bladder. This is done for patients with a low-grade tumor that has invaded the bladder wall but is confined to one area of the bladder. Patients can urinate normally after recovering from bladder surgery as only a portion of the bladder is removed. It is also known as segmental cystectomy.

  • Cystectomy with urinary diversion
    Radical cystectomy involves bladder removal, including lymph nodes and nearby organs. This surgery is performed when bladder cancer invades the muscle layers or when non-muscle-invasive bladder cancer affects a large portion of the bladder.

    In some cases, surgery to remove only the bladder may be done to reduce urinary symptoms caused by cancer that has spread outside the bladder and cannot be fully removed. When the bladder is removed, a procedure called urinary diversion is performed to create an alternative way for urine storage and passage. Methods for managing urinary issues include redirecting urine to the colon, using catheters to drain the bladder, or creating an opening in the abdomen for collecting urine in a bag outside the body.

Adjuvant therapy

Adjuvant therapy is given after surgery to reduce the risk of cancer recurrence. After surgery, patients may receive chemotherapy, radiation therapy, immunotherapy, and/or targeted therapy to eliminate any remaining cancer cells.

At the hospital:

The average length of stay in the hospital is four to five days.

When you wake up from surgery, you'll probably find yourself surrounded by wires and machines. You might encounter the following:

  • A Jackson Pratt drain (JP drain) is placed in the patient's abdomen to collect and drain blood and other fluids that may collect at the surgical site. Typically, this is taken out just before the discharge.

  • Intravenous drug administration.

  • An electrocardiogram device.

  • There are two stents (little plastic tubes) emerging from your stoma. During your follow-up appointment after surgery, when your urologist deems it appropriate, he or she will remove these.

  • Oxygen delivery through a nasal cannula.

At home:

Unfortunately, complications after bladder removal are possible. Most of these side effects, however, are rather minor.

  • Infection of the urinary tract

  • Ileus (a condition in which the bowels are "asleep" and require time to "wake up")

  • Obstruction of the small intestine

  • Infectious wounds

  • Heart-related issues

  • Pneumonia, shortness of breath, and other respiratory problems

  • Clotted blood

  • Issues with the nervous system that manifest as tingling, paralysis, or weakness

  • Leaking urine

  • Electrolyte or metabolic imbalance

About a quarter of patients who are discharged from the hospital may need to be readmitted for treatment. It is crucial to get in touch with your urological care team as soon as possible if you are suffering any adverse effects after returning home.

Radiation therapy

Radiation therapy kills or stops the growth of cancer cells using high-energy X-rays or radiation. Bladder cancer is treated with external beam radiation therapy. External radiation therapy targets cancerous areas of the body with radiation. Radiation therapy can be given alone or with chemotherapy.

Overview:

Your radiation team will measure angles and determine the radiation dose before starting treatments. The planning session, called simulation, typically involves imaging tests like CT or MRI scans. This helps locate the tumor in your body. Empty your bladder before simulation and each treatment.

The treatment is similar to an x-ray, but with stronger radiation. Radiation is not harmful. Treatment lasts a few minutes, but setup time is usually longer.

Long-term side effects

Effects may resolve over time after treatment, but some individuals may experience prolonged issues. For example:

  • Radiation treatments can cause incontinence in some individuals.

  • Radiation can harm the bladder lining. Radiation cystitis can cause issues like blood in urine and painful urination.

  • Nerves and blood vessels nearby may be damaged, causing erection problems in men.

Discuss radiation therapy side effects with your healthcare team. They can suggest ways to ease them.

Side effects of radiation therapy

Radiation side effects vary based on dose and treatment area. Chemo and radiation together worsen the side effects. They can include:

  • Skin changes from radiation can include redness, blistering, and peeling

  • Nausea and vomiting

  • Bladder symptoms include burning or painful urination, frequent urination, and blood in the urine.

  • Diarrhea

  • Blood in stool or urine

  • Fatigue

  • Low blood counts can cause fatigue, bruising, bleeding, or infection risk.

Chemotherapy

Chemotherapy uses drugs to stop cancer cell growth by killing or stopping cell division. Chemotherapy can be given alone or with other treatments. Its administration varies based on the cancer type and stage.

Systemic chemotherapy

Systemic chemotherapy for bladder cancer involves injecting chemotherapy drugs into a vein. When given this way, drugs enter the bloodstream to reach cancer cells in the body. Systemic chemotherapy drugs for bladder cancer treatment include:

  • Carboplatin

  • Cisplatin

  • Doxorubicin

  • 5-fluorouracil

  • Gemcitabine

  • Methotrexate

  • Mitomycin

  • Paclitaxel

  • Vinblastine

Intravesical chemotherapy

Chemotherapy for bladder cancer can be intravesical, administered through a tube inserted into the bladder via the urethra. Intravesical treatments flush the bladder with cancer-killing drugs after surgery. This reduces cancer recurrence.

Mitomycin and gemcitabine are used for intravesical chemotherapy in bladder cancer treatment. These drugs can also be administered systemically.

Possible side effects include:

Bladder irritation. 

  • Frequent and urgent urination

  • You may find blood in your urine. Contact the hospital immediately if the bleeding worsens, blood clots are present in your urine, you experience severe pain while urinating, or you are unable to urinate and have severe pain.

  • You may get a rash on your hands or feet briefly after treatment. Skin rashes can become red, sore, and swollen. Some people experience severe itching. 

  • Certain chemotherapies can raise infection risk. Having a catheter increases your risk of infection.  

Immunotherapy

Immunotherapy fights cancer by boosting the immune system. Your doctor may recommend biomarker tests to predict your response to immunotherapy drugs. 

Systemic immunotherapy

Systemic immunotherapy drugs for urothelial cancer include:

  • Avelumab

  • Nivolumab

  • Pembrolizumab

These drugs have multiple mechanisms to kill cancer cells. They are targeted therapy since they target specific changes or substances in cancer cells.

Side effects may include:

Tiredness 

  • Feeling sick

  • Decreased appetite

  • Fever

  • UTIs

  • Rash

  • Diarrhea

  • Constipation

Use:

Pembrolizumab has a broad spectrum of uses, including:

  • Melanoma: Both unresectable and metastatic.

  • Non-Small Cell Lung Cancer: Especially when tumors express PD-L1.

  • Head and Neck Squamous Cell Cancer: As primary treatment or after failure of other treatments.

  • Hodgkin's Lymphoma: In relapsed or refractory cases.

  • Bladder Cancer: Particularly urothelial carcinoma.

  • Microsatellite Instability-High (MSI-H) or Mismatch Repair Deficient (dMMR) Cancers: Regardless of the tissue of origin.

Intravesical immunotherapy

Bacillus Calmette-Guérin (BCG) is used to treat bladder cancer. BCG is administered via a catheter directly into the bladder. Intravesical treatments flush the bladder with cancer-killing drugs post-surgery and reduce cancer recurrence risk.

Rare, severe side effects may also occur:

  • Infusion reactions may occur. Symptoms of this can resemble an allergic reaction, including fever, chills, flushing, rash, itchiness, dizziness, wheezing, and difficulty breathing. 

  • Autoimmune reactions: The immune system might start attacking different organs, leading to severe or life-threatening issues in the lungs, intestines, liver, glands, or other parts of the body.

Conclusion:

Pembrolizumab represents one of the pioneering efforts in the field of immunotherapy, showing remarkable effectiveness across a wide variety of cancers. By blocking PD-1, it enables the immune system to attack cancer more effectively. However, this also means that careful monitoring and management of immune-related side effects are essential. Its use continues to expand, and ongoing research is exploring its potential in combination with other therapies and in various settings and stages of cancer.

Targeted Therapies

Targeted therapy blocks specific enzymes, proteins, or molecules involved in cancer cell growth and spread. Your doctor may recommend biomarker tests to predict your response to targeted therapy drugs. 

Targeted therapies for bladder cancer include:

Erdafitinib (Balversa)

Erdafitinib is an oral drug approved to treat advanced urothelial carcinoma with specific genetic changes (FGFR3 or FGFR2) that has progressed after platinum chemotherapy. 

Side effects of erdafitinib may include increased phosphate level, mouth sores, fatigue, nausea, diarrhea, dry mouth/skin, nails separating from the nail bed or poor nail formation, and change in appetite and taste. 

Erdafitinib can cause rare but serious eye problems, including retinopathy and epithelial detachment, leading to visual field defects. Regular eye evaluations by an ophthalmologist or optometrist are needed monthly for the first 4 months, and then every 3 months thereafter. 

Sacituzumab govitecan (Trodelvy)

Sacituzumab govitecan is approved for treating advanced urothelial carcinoma that has been previously treated with platinum-based chemotherapy and a PD-1 or PD-L1 immune checkpoint inhibitor, which applies to many patients. Sacituzumab govitecan is another antibody-drug conjugate, but it has a distinct structure, components, and mechanism of action compared to enfortumab vedotin-ejfv. 

Side effects of sacituzumab govitecan may include neutropenia, nausea, diarrhea, fatigue, hair loss, anemia, vomiting, constipation, decreased appetite, rash, abdominal pain, and other less common effects.

Enfortumab vedotin-ejfv (Padcev)

Enfortumab vedotin-ejfv is approved for locally advanced or metastatic urothelial cancer in:

  • Patients who have received a PD-1 or PD-L1 immune checkpoint inhibitor and platinum-based chemotherapy.

  • Patients ineligible for cisplatin chemotherapy after prior treatment(s).

  • Combination with pembrolizumab for cisplatin-ineligible individuals.

Enfortumab vedotin-ejfv is an antibody-drug conjugate that targets Nectin-4 in urothelial cancer cells. Antibody-drug conjugates attach to cancer cells and release medication directly into them. 

Enfortumab vedotin-ejfv may cause side effects such as fatigue, peripheral neuropathy, rash, hair loss, changes in appetite and taste, nausea, diarrhea, dry eye, itching, dry skin, and elevated blood sugar.

Complementary Approaches

Curcumin

Curcumin regulates the p53 signaling pathway. Curcumin induces senescence in hepatic stellate cells by modulating p53 expression. Curcumin treatment increases p53 and p21 expression in gastric cancer. It restores the expression of tumor suppressor proteins p53, pRb, and PTEN13 in cervical cancer cells.

Paeonia lactiflora Pall (RPA) extract

Studies have shown that Paeonia lactiflora Pall (RPA) extract induces apoptosis and cell growth inhibition of human bladder cancer, bladder transitional cell carcinoma cells (TSGH-8301) cells in in vitro system and significantly inhibits tumor growth in in vivo N-butyl-N-(4-hydroxybutyl) nitrosamine (OH-BBN)-induced mouse mode. These effects are mediated through the Chk2 signaling.

Cantharidin

After being treated with cantharidin, the active forms of caspase-3, -8, and -9 increased in numbers. Cantharidin caused apoptosis, which was linked to increased ROS and Ca(2+) production, DNA damage, and the release of Endo G and AIF from the mitochondria. The G0/G1 stop caused by cantharidin was linked to a big drop in the levels of cyclin E and Cdc25c proteins but an increase in the levels of p21 and p-p53.

Resveratrol

Resveratrol induces p53 phosphorylation at serine 20, activating p53-target genes like PUMA and BAX, restoring apoptosis in cisplatin-resistant MCF7 cells. Mutant p53 is inactivated by intracellular aggregation. Resveratrol reduces mutant p53 protein aggregation, not wild-type.

Polyporus polysaccharide

Studies have shown that Polyporus could improve the effect of N-butyl-N-(4-hydroxybutyl)-nitrosamine (BBN) on rats with bladder cancer. This may be due to the increased polarization of tumor-associated macrophages (TAM) toward M1. Homogeneous polyporus polysaccharide (HPP) may use the NF-B/NLRP3 signaling pathway to control TAM polarization and improve the inflammatory microenvironment of a tumor. Studies have also shown that HPP could be used to treat bladder cancer.

Guizhi Fuling Wan

GFW has demonstrated inhibitory effects on the growth of hepatocellular carcinoma and cervical cancer. Moutan Cortex, a prominent constituent of GFW (Generic Formula for Wellness), has demonstrated its ability to impede cellular proliferation and trigger apoptosis in hepatocellular carcinoma, a form of liver cancer that affects humans. The observed anticancer activity of GFW seems to be linked to its ability to impede the proliferation of cancer cells by triggering apoptosis and causing cell cycle arrest specifically in the G1 phase.

Berberine

Berberine causes cell cycle arrest in HTB-94 chondrosarcoma cells by affecting the expression of p53, p21, Rb, cyclin B1, cyclin-dependent kinase 1, and cdc25c.62 p53, Rb, PTEN, and APC are important tumor suppressor genes.

Lingzhi

Ethanol and water extracts of G. lucidum fruiting bodies and spores in an in vitro human urothelial cell (HUC) model made up of HUC-PC cells and MTC-11 cells showed that growth inhibition was linked to G2/M halt. At non-cytotoxic doses (40–80 g/ml), these extracts caused actin to stick together, which stopped both cell lines from migrating in response to the carcinogen 4-aminobiphenyl. Increased actin polymerization was linked to more stress fibers and focal adhesion complex formation. However, the expression of matrix metalloproteinase-2 and focal adhesion kinase (total and phosphorylated) remained the same, which suggests that other processes may be at play.

Traditional Chinese Medicine (TCM)

Genes Participate in Treatments Using TCM.

Impact on tumor suppressor genes: TP53 is a tumor suppressor gene. The mutant p53 protein is commonly found in many cancers. p53 can cause cell cycle arrest, apoptosis, or senescence, depending on factors like DNA damage, hypoxia, and oncogene activation.

Myc

Myc is a well-recognized oncogene, and studies have revealed that Myc expression in BxPC3 and gemcitabine-resistant BxPC3 cells can be suppressed by treatment with curcumin.

Silibinin

Silibinin promoted decreased proliferation and increased late apoptosis in TP53 mutated cells. Increased early apoptosis rates, primary DNA damage, and decrease of cell colonies in the clonogenic survival assay were detected in both RT4 and T24 cell lines. Down-regulation of FRAP/mTOR, AKT2, FGFR3, DNMT1, and miR100 expression occurred in RT4 cells. 

Resveratrol

Resveratrol has been shown to significantly decrease the phosphorylation of Her-2 and EGFR and the expression of Erk in ovarian cancer cell lines. A separate study demonstrated that resveratrol was able to enhance the expression of Caspase 3 and 9 and decrease the expression of Bcl2, Ras, Raf, MEK, and ERK1/2 in a dose-dependent manner in human colon cancer.

Berberine

In colon tumor cells, berberine treatment was demonstrated to suppress EGFR expression via enhancement of Cbl activity. As for the regulation of apoptosis regulators, curcumin, resveratrol, and berberine have all been shown to trigger apoptosis and increase the ratio of Bax/Bcl-2 expression. In fact, apoptosis has wide involvement in the antitumor effects of treating with CHM.

Regulation of oncogene expression

An oncogene, the mutation and/or overexpression of which is often observed in cancer, has the potential to cause cancer. Chromosomal rearrangements, mutations, and gene amplification can activate oncogenes, conferring a growth advantage or increased survival to these cells. Studies of the changes in Myc, Ras, and Bcl2 oncogenes provided the first wave of evidence that cancer arises from somatic genetic aberrance. 

Oncogenes can be classified into several categories, comprising transcription factors (eg, Myc), growth factors (eg, PDGF), growth factor receptors (eg, VEGFR, EGFR), signal transducers (eg, PI3K, Akt, mTOR), cytoplasmic tyrosine kinases (eg, Src family), cytoplasmic serine/threonine kinases (eg, Raf kinase), or regulators of apoptosis (eg, Bcl2).

Here are some other complementary methods that can be helpful and safe when used with standard medical treatment. Consult your cancer care team before attempting any of these.

  • Acupuncture

    Acupuncture is a medical intervention in which fine metallic needles are inserted into anatomical locations of the body to stimulate the peripheral and central nervous system. Giving acupuncture before each intravesical BCG treatment may help to reduce the side effects of intravesical BCG, and help patients complete treatment.

    In Phase I/II trials, there were observed reductions in pain and a trend towards improved urinary function scores over successive treatments among patients undergoing in-clinic pre-BCG instillation acupuncture. Patients receiving acupuncture reported high degrees of satisfaction with treatments.

  • Acupressure

    Applying pressure to specific body parts to alleviate symptoms. Acupuncture is a technique that uses thin needles to treat symptoms like pain and nausea.

  • Aromatherapy

    Using essential oils from plants to improve mood and alleviate symptoms like stress or nausea. These oils can be inhaled or applied topically.

  • Art therapy

    Helping people express emotions through creative activities.

  • Biofeedback

    A technique that uses monitoring devices to help people gain conscious control over physical processes like heart rate, blood pressure, temperature, sweating, and muscle tension.

  • Labyrinth walking

    A meditative walk along a circular pathway. Labyrinths can be “walked” online or on a grooved board with a finger.

  • Massage therapy

    Involving manipulating and rubbing the body's muscles and soft tissues. It may reduce stress, anxiety, depression, and pain and increase alertness.

  • Meditation

    A process of using concentration or reflection to relax the body and calm the mind.

  • Music therapy

    Using music to promote healing and improve quality of life.

  • Spirituality and prayer

    Involving the awareness of something greater than oneself. Expressed through religion, prayer, and other spiritual paths.

  • Tai chi

    A mind-body system that improves health and well-being through movement, meditation, and breathing. It improves strength and balance in some people.

  • Yoga

    A non-aerobic exercise that includes precise postures and breathing activities.

Other Theories of Cancer Applied to Bladder Cancer & Survivorship

Multiple and complex chromosomal alterations in bladder TCC have led to the development of the "clonal" theory of bladder cancer pathogenesis. This theory suggests that multifocal and recurrent tumors originate from a single transformed cell with identical genetic mutations. The traditional "field cancerization" theory assumes overall changes in the urothelium, with independently evolving cells forming genetically unrelated tumors. Both theories have compelling evidence. Both theories are equally valid and can occur simultaneously in the same patient.

Two theories explain the recurrence of BC: field cancerization and intraluminal seeding and implantation. The field-cancerization theory suggests that multi-focal tumors result from carcinogen exposure of the entire urothelial layer. Molecular data support the theory that multi-focal tumors result from the clonal evolution of a single transformed cell.

  • Bladder cancer patients may face financial challenges. Bladder cancer patients may experience financial issues due to the need for regular surveillance to detect disease recurrence or progression.

  • Cystectomy recovery may involve discussions about sexual function. Cystectomy patients may experience sexual discomfort. More common in men. Non-cystectomy patients may have improved sexual function. Patients worry about infecting partners.

  • Quality of life for bladder cancer patients varies by gender. Men may have a better sexual function but also experience discomfort with intimacy and fears of contaminating their partners. Women may have higher levels of constipation and diarrhea.

  • Low-risk bladder cancer has less impact on quality of life compared to high-risk bladder cancer. They had better physical and social functioning, less fatigue, and fewer financial problems. 

Recurrence Monitoring

Noninvasive bladder cancer cases usually don't require much urologic intervention. Cases progress and patients often experience recurrence, requiring accurate tumor surveillance.

The American Urological Association/Society of Urologic Oncology guidelines recommend the following surveillance recommendations:

  • Perform the first surveillance cystoscopy 3-4 months after the initial evaluation and treatment of non-muscle invasive bladder cancer (NMIBC) patients.

  • Perform surveillance cystoscopy 6-9 months after the first negative cystoscopy for low-risk patients. After that, perform annual surveillance cystoscopy. After 5 years without recurrence, decide on further surveillance based on shared decision-making between patient and clinician.

  • Do not routinely do upper tract imaging for asymptomatic patients with low-risk NMIBC.

  • Perform cystoscopy with cytology every 3-6 months for 2 years after negative initial surveillance cystoscopy, then every 6-12 months for years 3 and 4, and annually thereafter.

  • Perform surveillance cystoscopy with cytology every 3-4 months for 2 years after a negative initial cystoscopy in high-risk patients. Then, perform it every 6 months for years three and four, and annually thereafter.

  • Perform surveillance upper tract imaging every 1-2 years for intermediate- or high-risk patients.

The NCCN advises individualized follow-up plans based on risk levels:

  • For low-risk NMIBC, have cystoscopy at 3 and 12 months, then annually for years 2-5, and as needed afterward.

  • For intermediate-risk NMIBC, do cystoscopy and urine cytology every 3, 6, and 12 months in year 1, every 6 months in year 2, annually in years 3-5, and as needed after that.

  • For high-risk NMIBC, have a cystoscopy and urine cytology every 3 months in years 1 and 2. Consider measuring urinary epithelial tumor markers. Then, have them every 6 months in years 3-5, annually in years 5-10, and as needed thereafter.

NCCN recommends baseline imaging in year 1 for all NMIBC risk levels, followed by imaging as needed.

Patients who had radical cystectomy need regular surveillance to monitor for local recurrence or metastatic disease. Annual abdominal and pelvic CT scans and chest radiographs are recommended. Patients with advanced disease may need more frequent imaging after cystectomy.

Follow-Up Care

Care for bladder cancer patients continues after treatment. Your healthcare team will conduct follow-up care which involves monitoring your health, checking for cancer recurrence, and managing side effects. 

Follow-up care may include physical exams and medical tests. Doctors need to monitor your recovery in the future. Follow-up care for bladder cancer patients includes a physical examination, cystoscopy (if the bladder is not removed), urine cytology, x-rays, and routine blood and urine tests to monitor bladder function and detect cancer recurrence.

Follow-up care for individuals with urinary diversion may involve urine tests to check for infection, addressing issues with urination control, monitoring for recurrent upper urinary tract cancer, and assessing kidney function through blood and urine tests and x-rays.

Inform your doctor of any new symptoms, including painful urination, blood in urine, frequent urination, urgent need to urinate, and any other symptoms. These symptoms may indicate cancer recurrence or another medical condition.

Cancer rehabilitation and survivorship care may include physical therapy, occupational therapy, career counseling, pain management, nutritional planning, financial counseling, and emotional counseling. Rehabilitation aims to restore control and independence in various aspects of life.

Survivors may continue seeing their oncologist or urologist, or transition to their primary care doctor or another healthcare professional. The decision depends on bladder cancer type, stage, side effects, insurance rules, and personal preferences, expectations, and beliefs.

Additional Treatments (other than CAM)

Valrubicin

Valrubicin rapidly passes through the cytoplasmic membrane and accumulates in the cytoplasm, causing cytolytic cell death. It is directly given into the bladder as a treatment for non-responsive carcinoma in situ after BCG treatment and is used for non-surgical patients.

Taxanes

Taxanes like docetaxel and paclitaxel stabilize microtubules, leading to cell cycle arrest and death. Taxanes and other high-molecular-weight chemotherapeutics have low solubility in water, resulting in poor drug uptake in bladder tissue. Researchers synthesize substances to increase taxanes' water solubility. PMB30W greatly increases paclitaxel solubility compared to water. 

Mycobacterium phlei cell wall-nucleic acid complex (MCNA)

MCNA is a complex of mycobacterial cell wall fragments and nucleic acid oligomers from Mycobacterium Phlei or other mycobacteria species. Using BCG structural extracts instead of live mycobacterium can help avoid side effects like BCG cystitis, reactive arthritis, and interstitial pneumonitis. MCNA has antitumoral activity through direct cytotoxic and immune-mediated mechanisms. MCNA negatively affects cell proliferation and viability, leading to tumor cell death. Additionally, it stimulates IL-12 production, which also has anti-cancer activity.

Chemothermotherapy

Using heat for treating cancer is not new, but recently there has been an evaluation of combining chemotherapy and heat, known as "chemothermotherapy" (CHT), for patients with high-risk diseases and failed BCG treatments. The MMC concentration decreases by half over 500 microns. The MMC concentrations for urothelium, lamina propria, and detrusor muscle are 5.6 mcg, 2.7 mcg, and 0.9 mcg, respectively. CHT relies on enhancing the effectiveness of MMC through tumor cell toxicity, altered blood flow, and localized immune response.

This technology was most rational for patients who had failed BCG treatment. In a study of 111 patients, the DFS rates were 85% at 1 year and 56% at 2 years. This is the best treatment alternative for BCG failures so far. Questions about session number, duration, and maintenance therapy remain unanswered despite promising outcomes. The high cost of disposable catheters is a challenging issue.

Gemcitabine

Gemcitabine (GEM) inhibits DNA synthesis and is used in chemotherapy for muscle-invasive BC (MIBC). Standard intravesical concentrations (2000 mg/day) are relatively safe with minimal absorption to the systemic circulation. 

Combination chemotherapeutics

These include doxorubicin-BCG, MMC-doxorubicin, and cisplatin. Intravesical delivery of combination chemotherapy is attractive for preventing disease progression to MIBC. Single agents in NMIBC are not effective enough to control the disease. GEM was the most effective chemotherapy for preventing disease progression to a muscle-invasive state. In-vitro studies suggest that paclitaxel plus cisplatin and doxorubicin plus mitomycin could be effective combinations.

Mistletoe lectin (ML)

Mistletoe lectin (ML) is a European plant used for various diseases. In vitro studies have shown its cytotoxic effects on cancer cells, including antiproliferative, antimetabolic, cytotoxic, and immunomodulatory effects. Mistletoe has been studied as a cancer treatment. Many studies on improved survival and quality of life have weaknesses that cast doubt on their reliability.

Electromotive drug administration (EMDA)

EMDA uses electrical current to enhance drug penetrance through the bladder wall. EMDA increases MMC delivery by 4-7 times in vitro. Intravesical EMDA is administered using a battery-operated generator that delivers controlled electric current from the urethral catheter to the skin electrodes on the patient.

IFN-α2b producing adenoviruses

Another application is using a genetically engineered adenovirus to produce interferon α2b (IFN-α2b) and stimulate the local immune system. A study conducted a phase I study using intravesical recombinant adenovirus-mediated IFN-α2b gene therapy in 17 BCG unresponsive patients. Out of 14 patients, 6 (43%) had a complete response lasting an average of 31 months, and 2 patients were disease free at the last follow-up. 5 out of 7 patients were disease-free after a minimum follow-up of 23.9 months, with 2 patients receiving additional treatment at 3 months.

IFN-2α

Interferon (IFN) boosts local immune response and may enhance the antitumoral activity of immunotherapeutics. IFNα gene therapy is a new treatment for NMIBC. Adenoviral vectors with IFNα effectively treat BCG-unresponsive bladder cancer. 

Keyhole limpet hyocyanin (KLH)

KLH is an immune stimulant in animals and humans. It is filtered from the hemolymph of Megathura cranulata, a sea creature found in Southern Carolina and Mexico. KLH is linked to more recurrences in patients with intermediate-high BC without CIS. No reduction in stage-adjusted disease progression.

Apaziquone

Apaziquone is a synthetic alkylating agent activated by deoxythymidine-diaphorase. Apaziquone is a promising intravesical agent due to its pharmacodynamics and safety profile. Evidence supports adjuvant chemo ablative therapy and post-transurethral resection of bladder (TURB) single-dose regimen. New phase III trials are needed to evaluate the efficacy of the therapy as an adjuvant treatment for intermediate- to high-risk non-muscle invasive bladder cancer and to determine the best candidates and treatment schedule. 

Oncolytic viruses

Oncolytic viruses have been modified to replicate in cancer cells without harming normal cells. This concept differs from gene therapy, which uses a virus as a carrier for delivering transgenes. BC used an oncolytic virus (CG0070) armed with GM-CSF to treat recurrent NMIBC by destroying RB pathway defective cells. A recent in vitro study shows BC tissue-specific adenovirus enhances radiotherapy's antitumor efficacy.

Nanoparticle albumin-bound paclitaxel (nab-paclitaxel)

Nab-paclitaxel is commonly used for metastatic breast and pancreas cancers due to its effective drug delivery mechanism using albumin receptor-mediated transport. Nanotechnology is being studied for delivering drugs like paclitaxel and docetaxel more efficiently to the endothelium using hydrophobically derivatized hyperbranched polyglycerols or mucoadhesive polymers.

Checkpoint inhibitors

Checkpoint inhibitors like atezolizumab and nivolumab are now commonly used to treat advanced and metastatic BC that has not responded to platinum-based therapy. They target PD-L1 on both the tumor and T cells. Studies are recruiting patients for atezolizumab (NCT02792192, NCT02844816) and pembrolizumab (NCT02625961) of which results are pending.

Vaccines

Vaccines target specific tumor-associated proteins. Three immunomodulators (Vesigenurtacel-L [HS-410], ALT-801, and PANVAC) are currently being investigated, but no clinical data is available yet. Vesigenurtacel-L is an allogeneic cell line selected for high expression of bladder tumor antigens to induce an immune response in CD+ cytotoxic t-lymphocytes. ALT-801 is a fusion molecule of IL-2 and T-cell receptors that boosts immune response by presenting target peptide/HLA complexes. PANVAC is a vector vaccine with tumor antigens (carcinoembryonic antigen and mucin-1) and costimulatory proteins (B7-1, ICAM-1, LFA-3) to enhance CD4 and CD8 immune response. 

Remaining Challenges

Lack of Predictive Biomarkers: First Cause of Treatment Failure

The main problem for NMIBC is high recurrence and early identification of potentially progressing tumors.

BCG therapy's mechanism of action is still being investigated despite being used for over 30 years. 40% of patients experience tumor recurrence within 2 years after BCG therapy. Factors causing BCG failure include metastasis, inappropriate immune response, and overexpression of exhaustion markers (PD-1 and PD-L1). Radical cystectomy is the preferred treatment for patients after BCG failure. Immune checkpoint inhibitors targeting PD-L1 or PD-1 have been considered as a therapy in combination with BCG due to the role of exhaustion markers in BCG resistance and relapse. Efforts to identify patients who will benefit from BCG, combination therapies, or radical cystectomy are needed.

Treatment failure is common in NMIBC and MIBC. Current classification systems may not accurately represent the heterogeneity of BLCa, and treatment may not take this heterogeneity into account. Current pathological assessment is inaccurate, leading to inadequate treatment choice for around 40% of tumors. Patient stratification can be improved by using molecular classifications, such as molecular subtypes, to guide treatment options for BLCa patients. Understanding the biological roles and therapy response is crucial for clinical implementation.

Future Directions

Future of diagnosis

AI technology in BCa diagnostics and prognostics can improve patients' quality of life by preventing unnecessary radical cystectomies and reducing the financial burden of BCa as the most expensive malignancy to treat over the patients' lifetime. More research is needed, including observational studies and clinical trials. Most studies using machine-learning (ML) algorithms for cancer diagnosis and outcome prediction, including BCa, have been retrospective. The clinical efficacy of diagnostic technologies should be established through prospective randomized phase 3 clinical trials.

Future of treatment

A study from the University of Iowa shows that a safe and inexpensive combo-chemotherapy is better tolerated and more effective in preventing high-grade cancer recurrence in patients with non-muscle invasive bladder cancer (NMIBC) compared to BCG. Gem/doce was found to improve recurrence-free survival in high-risk NMIBC patients compared to BCG. Additionally, fewer patients on gem/doce discontinued treatment compared to those on BCG. 

Future of recurrence monitoring

Artificial neural networks using tumor markers may be more cost-effective for detecting recurrence and progression than cystoscopy and conventional cytology. Using better markers could improve the scheduling of cystoscopy to be more logical and targeted than the current default.

Nonlinear surveillance strategies can decrease tumor recurrence detection time and optimize resource utilization. In nonlinear surveillance, follow-up schedules are based on patients' risk profiles, with longer intervals for low-risk patients and shorter intervals for high-risk patients. The risk profile is determined by the patient's previous recurrence rate and tumor stage and grade.

Future surveillance may benefit from advancements in endoscopic techniques and molecular diagnostic tests to detect hidden malignancies and identify malignant changes before they become visible. For now, cystoscopy with cytology (either conventional or molecular cytology, like FISH) will continue to be the main method for surveillance at accepted intervals.

https://www.cancer.net/cancer-types/bladder-cancer/statistics https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6372534/ https://www.ncbi.nlm.nih.gov/books/NBK304408/ https://www.cdc.gov/niosh/docs/90-116/default.html https://pubmed.ncbi.nlm.nih.gov/27352265/ https://www.cancercenter.com/cancer-types/bladder-cancer/risk-factors https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4315315/ https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6334926/ https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5642604/ https://bcan.org/facing-bladder-cancer/bladder-cancer-types-stages-grades/ https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2684228/ https://www.cancer.org/cancer/types/bladder-cancer/detection-diagnosis-staging/signs-and-symptoms.html https://www.cancer.gov/types/bladder/treatment https://www.cancer.org/cancer/managing-cancer/treatment-types/complementary-and-integrative-medicine/complementary-and-alternative-methods-and-cancer/which-methods-are-likely-safe.html https://bjui-journals.onlinelibrary.wiley.com/doi/full/10.1111/bju.14934 https://emedicine.medscape.com/article/458825-overview?form=fpf https://www.sciencedirect.com/science/article/pii/S1040842822000257#sec0060 https://medicine.uiowa.edu/content/alternative-bladder-cancer-treatment-emerges-amid-worldwide-shortage-standard-care-bcg https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7461199/ https://www.cancer.gov/about-cancer/treatment/drugs/valrubicin https://www.sciencedirect.com/science/article/pii/S2372770522000833 https://pubmed.ncbi.nlm.nih.gov/29034722/ https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5687201/ https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3401896/ https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3175393/ https://onlinelibrary.wiley.com/doi/10.1002/cam4.2108#cam42108-bib-0019 https://bmccomplementmedtherapies.biomedcentral.com/articles/10.1186/1472-6882-13-44 https://www.sciencedirect.com/science/article/abs/pii/S0378874111001449?via%3Dihub https://www.frontiersin.org/articles/10.3389/fimmu.2022.839460/full https://www.sciencedirect.com/science/article/abs/pii/S030438350400432X?via%3Dihub https://pubmed.ncbi.nlm.nih.gov/20878071/ https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5004708/ https://www.urotoday.com/conference-highlights/asco-2023/asco-2023-bladder-cancer/144851-asco-2023-phase-i-ii-randomized-clinical-trial-of-in-clinic-acupuncture-prior-to-bcg-in-patients-with-high-risk-non-muscle-invasive-bladder-cancer.html https://www.cancer.org/cancer/types/bladder-cancer/treating/radiation.html