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Information for Patients and the General Public

Bladder Cancer

Bladder cancer is defined as abnormal (malignant) tissue growth in the bladder lining. If it is diagnosed in an early disease stage the chances for its cure are good and most patients do not die as a result of the cancer. When the disease is diagnosed at later stages, it may have grown into deeper layers of the bladder, more specifically the muscle layer, and may have spread across the body. In such cases treatment options are limited and the patients' probability to die as a result of the disease, is high. Therefore, early diagnosis is one of the most important requirements for an auspicious bladder cancer treatment. At the present time, 70% of bladder cancer cases are diagnosed at an early stage of the disease.

The average patient age of bladder cancer appearance is about 70 years. Men are more often affected than women, resulting in bladder cancer being the fourth most common cancer in men with an associated incidence rate of 27 cases per 100,000 citizens in the European Union and the seventeenth most common cancer among women with an incidence rate of 6 cases per 100,000 citizens in the European Union. Bladder cancer is the most common malignant transformation of the urinary tract.

Causes of Bladder Cancer

It is not always known what external factor causes the cell mutations, which lead to bladder cancer development, but many risk factors were identified over the last century. These include the following:

1. Smoking

Smoking is the primary risk factor for bladder cancer, since tobacco smoke contains many cancer-causing chemicals, also known as carcinogens. While smoking, these carcinogens pass into the bloodstream and are delivered for urinary filtration to the kidneys. The carcinogen containing urine is then stored in the bladder for many hours and can therefore cause alternations in the cells of the bladder lining that may ultimately lead to aggressive tumor development. It is accepted that smoking causes about 50% of all bladder cancer cases.

2. Exposure to chemicals

The second most important risk factor for bladder cancer is the exposure to cancer-causing chemicals, such as aromatic amines and polycyclic aromatic hydrocarbons. These chemicals are often used in industrial processes relating to textile dyes and rubber. Therefore individuals working in the dye, textile, rubber, paint, plastic or leather tanning industries at increased risk for developing bladder cancer. In addition it is supposed that truck and bus drivers are also more affected since the above mentioned carcinogens are also found in diesel fuel.

3. Genetic Predisposition

It has been found out that genetic predisposition has a significant influence on bladder cancer development, especially in combination with other risk factors like smoking.

4. Other Risk Factors

It is known that other factors also increase the risk of bladder cancer development including:

  • Chronic urinary tract infections.
  • Untreated schistosomiasis, an infection caused by a parasite.
  • Previous radiotherapy for treatment of cancers located nearby the bladder.
  • Previous chemotherapy with cyclophosphamide and cisplatin.

Bladder Cancer Related Symptoms

Blood in urine – medical term: haematuria – is the most common symptom of early stage bladder cancer. If the tumor increases in size, less common symptoms such as the sudden need to urinate, a burning sensation while urinating, and the demand of urinate more frequently may apply beyond haematuria. In advanced disease stage, namely when the tumor invades the bladders muscle layer and begins to spread throughout the body, symptoms like pelvic pain, unexplained weight loss, bone pain and swelling of the legs occur. It is noted that haematuria is also a common symptom of several other diseases, and therefore it is advised to visit a doctor when detecting blood in urine.

State of the Art in the Diagnosis of Bladder Cancer

If encountered with bladder cancer related symptoms the first step in bladder cancer diagnosis involves the record of the patient's history, including detailed information with possible connection to BCa. Moreover the presence of haematuria is controlled by urine analysis. In the case that the suspicion of bladder cancer is hardened by the preliminary diagnostic record the patient is subjected to an invasive cystoscopic examination of the bladder. During this procedure a thin tube with camera and light (cystoscope) is inserted into the bladder through the urethra while the patient is under local anesthesia. If abnormalities are found in the patient's bladder during this process a second cystoscopic examination of the bladder under general anesthesia is carried out. During this second cystoscopic examination, the abnormal bladder tissue is removed (also known as biopsy), which is subsequently analyzed by specialists to determine its malignant potential.

Although the cystoscopic examination of the bladder is the current gold standard in bladder cancer diagnostics, other methods are also used for initial diagnosis, including cytology and computerized tomography (CT) scan. During cytology the patient's urine is analyzed for abnormal cells that have been released by a malignant tumor. The accuracy of this examination is dependent on the malignancy of the tumor, being high for aggressive tumors but low for less aggressive tumors. During the CT scan a series of X-ray images are taken to create a detailed picture of the bladder and adjacent organs by a computer. This method is best suited for progressed disease stages where larger tumors and metastases are found.

Improving Bladder Cancer Diagnosis with Biomarkers – Reducing the Amount of Necessary Cystoscopies

One aim of the TransBioBC project is the development of a biomarker classifier for bladder cancer detection. A biomarker is defined as a traceable and measureable substance in the body, which reflects an individual's health or disease state. A famous example for a biomarker is the pregnancy test, which detects human chorionic gonadotropin, a protein that is normally only produced during pregnancy. Therefore, a positive test displays a pregnancy with a sensitivity (true-positive rate) higher than 99.9%. A biomarker classifier is composed of more than one biomarkers, that means of more than one measureable substance. Since urine is stored in the bladder for many hours and is in addition easily assessable, it is our goal to establish a urine based biomarker classifier for bladder cancer detection. The measurement method of choice for urine is capillary-electrophoresis coupled to mass spectrometry (please find more information in the CE-MS based biomarkers panel) and/or state-of-the-art antibody-based micro-ELISA tests.

The aim of the TransBioBC project is that the newly developed biomarker classifier is used as the initial step of diagnosis before the cystoscopic examination of the bladder. The non-invasive urine test, that is predicted to take about one day, is carried out and the patient is afterwards directly transferred to a cystoscopy combined with a biopsy under general anesthesia, if the biomarker classifier scored positive. Current health-economic calculations predict that the average number of invasive and unpleasant cystoscopies can be significantly reduced by using such biomarker classifier. In detail it was calculated that the average number of 2.12 cystoscopies per patient in the cystoscopy-based diagnosis could be reduced to 0.56 cystoscopies per patient in the biomarker classifier based diagnostic procedure, notably reducing the discomfort during bladder cancer diagnosis. In the calculations, it was assumed that 10 percent of the patients, which possess bladder cancer specific symptoms, definitely harbor the disease.

Bladder Cancer Treatment and Follow-Up

The treatment of bladder cancer depends on the disease stage at the time of diagnosis. Bladder cancer can be roughly classified into two categories: first non-muscle invasive bladder cancer (NMIBC) and second muscle invasive bladder cancer (MIBC). Since the disease is more aggressive in the muscle invasive stage and in addition features the ability to form metastases, the treatment of choice in this case is the radical removal of the bladder. On the other hand non-muscle invasive bladder cancer can be removed by a more conservative treatment. Thereby only the tumor is trimmed out of the bladder lining during a cystoscopic examination of the bladder. Unfortunately, patients, who suffer from NMIBC have a moderate to high probability for disease reappearance (recurrence). Therefore, bladder cancer patients have to attend an intensive follow-up schedule.

The recommended follow-up scheme depends on the probability of recurrence in the specific patient that is calculated by the so-called EORTC table. Based on this table the patients are classified into three different risk-groups for bladder cancer recurrence: the low-risk, the intermediate-risk, and the high-risk group. The European Association of Urology recommends standardized follow-up schemes for low- and high-risk group patients in their guidelines. The follow-up of patients with a low-risk of recurrence include six cystoscopic examinations of the bladder. The first cystoscopy is carried out three months after the surgery to control the healing process. Afterwards, the second cystoscopy is executed one year after the tumor removal, followed by annual cystoscopic examinations of the bladder for a total of five years. In the follow-up of the high-risk group of bladder cancer recurrence, the cystoscopic examinations are conducted more frequently. In the first two years after successful excision of the tumor, cystoscopies are carried out every three months. Afterwards they are conducted every six months for three years. If no recurrence is detected in the aforementioned period, subsequent cystoscopic examinations are executed annually for the rest of the patient's life. In addition to the cystoscpic examination of the bladder, cytologic examinations of the patient's urine are undertaken along with each cystoscopy. The follow-up of patients with an intermediate risk of bladder cancer recurrence is located in between the aforementioned follow-up procedures. Based on the high numbers of cystoscopies that are carried out during the follow-up period, bladder cancer remains one of the most expensive and most uncomfortable cancer type humankind is currently facing.

Improving Bladder Cancer Follow-up with Biomarkers – Reducing the Amount of Necessary Cystoscopies

The second aim of the TransBioBC project is the development of a biomarker classifier that is able to detect recurrent bladder cancer after successful surgical removal of non-muscle invasive bladder cancer. The goal of the project is that the biomarker classifier replaces the cystoscopies - apart from the first three months after surgery - during the follow-up and therefore significantly reduces the number of necessary cystoscopies, while keeping at least the same accuracy in detecting bladder cancer recurrence. Ongoing calculations shows that the average number of cystoscopies could be reduced from 4.37 to 1.34 in the low-risk and from 7.57 to 3.66 in the high-risk group of bladder cancer recurrence by using a biomarker classifier. This decrease in invasive diagnostic procedures clearly reduces patients' discomfort during the follow-up and remarkably increases the patients' quality of life.