Worldwide, bladder cancer is the seventh most commonly diagnosed cancer in the male population and is the eleventh in the whole population (males and females).
Tobacco smoke contains the carcinogenic aromatic amines and polycyclic aromatic hydrocarbons. Therefore, tobacco smoking is the most important risk factor for bladder cancer, accounting for approximately 50% of cases. Exposure to tobacco smoke ("passive smoking”) is also associated with an increased risk for the disease. Occupational exposure to aromatic amines, polycyclic aromatic hydrocarbons and chlorinated hydrocarbons is the second most important risk factor for bladder cancer, accounting for about 10% of all cases. This type of occupational exposure occurs mainly in industrial plants, which process paint, dye, metal, rubber and petroleum products. Today, in developed industrial settings, these risks have been reduced by work-safety guidelines. Therefore, chemical workers in these industrial settings no longer have a higher incidence of bladder cancer compared to the general population
Tumors Classifications and Definitions
Bladder cancer tumors are classified by stage and grade:
Stage: degree of tumor invasion into the bladder wall. It can be:
- NMIBC: non-muscle-invasive Bladder cancer - where the tumor does not invade the muscle and includes Ta, T1, and CIS or,
- MIBC: muscle-invasive Bladder cancer where the tumor invades the muscle and includes T2, and higher stages as T3 and T4
Grade: malignancy of the tumor that can be:
- Low Grade (LG)
- High Grade (HG)
All tumors must be defined according to their Stage and Grade.
Bladder tumors can present as solitary tumor or multiple tumors.
Bladder tumors can present as Primary (first time) or Recurrent.
Bladder tumors can present as Small (<3cm) or Large (>3 cm)
Recurrence of bladder tumors can be expressed by the term recurrence-free-interval (RFI). It can be Low (RFI is equal or longer than 12 months) or High (RFI is shorter than 12 months)
Bladder tumors can progress to higher stage (and even progress from NMIBC to MIBC) and/or progress from Low grade to High grade
Approximately 75% of patients with Bladder cancer present with a disease confined to mucosa (the innermost layer of the bladder lining) including the stage Ta and CIS or confined to submucosa - stage T1.
Patients with NMIBC (Ta, T1 and CIS) have a high prevalence due to long-term survival in many cases and lower risk of cancer-specific mortality compared to patients with MIBC (T2 and higher stage tumors)
Risk group stratification in NMIBC
CIS (Carcinoma In Situ) = a flat, high-grade tumor that is confined to the mucosa
Ta = a tumor confined to the mucosa
T1 = a tumor that invades the lamina propria (submucosa)
Low-grade (LG) papillary urothelial carcinoma
High-grade (HG) papillary urothelial carcinoma
Urothelial CIS is always high-grade.
- Low-risk tumors
All the following features must be present:
Primary, Solitary, Ta, LG, Small (<3cm), no CIS
- Intermediate-risk tumors
All tumors not defined as Low- or High-risk
- High-risk tumors
Any of the following: T1 tumor; HG tumor; CIS; Multiple, recurrent, large (>3 cm) - all features must be present.
Trans urethral resection of bladder tumor(s) - TURBT surgery is performed to eradicate the bladder tumor(s) as completely as possible
Intravesical is a way in which liquid drugs are put directly into the bladder through a catheter and is also called bladder instillation.
Although TURBT by itself can eradicate a Ta or T1 tumor completely, these tumors commonly recur and can progress to MIBC. The high variability in the three-month recurrence rate indicates that the TURB was incomplete or provokes recurrences in a high percentage of patients. Therefore, it is necessary to consider adjuvant therapy in all patients
Intravesical chemotherapy instillations
- Single, immediate chemotherapy instillation
Immediate post-operative, single chemotherapy bladder instillation (usually with mitomycin C – MMC) has been shown to act by destroying circulating tumor cells after TURBT, and by an ablative effect (chemo resection) on residual tumor cells at the resection site and on small overlooked tumors. This single post-operative instillation cannot perform if there is an overt or a suspected bladder perforation. Therefore, in such circumstances it is avoided
- Additional adjuvant intravesical chemotherapy instillations
The need for further adjuvant intravesical therapy depends on prognosis. In low-risk patients an Immediate post-operative, single chemotherapy bladder instillation reduces the risk of recurrence and is considered to be the standard and complete treatment. For other patients, however, a single post-operative instillation remains an incomplete treatment because of the considerable likelihood of recurrence and/or progression. The length and frequency of repeat chemotherapy instillations is still controversial and ideal duration and intensity of the schedule is yet undefined
- Device-assisted intravesical thermo-chemotherapy instillations
It was shown that intravesical thermo-chemotherapy instillations in patients with intermediate-risk and high-risk tumors, are more effective than stand-alone intravesical instillations. Promising data have been presented on enhanced efficacy of MMC instillations combined with hyperthermia (hyperthermia = non-ablative temperatures ranged 40OC to 45OC). It was also shown that the higher treatment temperatures within the hyperthermia range (yet with no burns or thermal effects) resulted in higher treatment efficacy and longer recurrence-free intervals.
Different technologies which increase the temperature of instilled MMC are available and are mainly divided into two groups: microwave-heat based system and conductive-heat based systems (conductive-heat systems were pioneered by Elmedical Founders since 1990). Conductive-heat is better controlled than microwave and provides uniform heating while in microwave the radiated energy transforms into heat in a difficult to control manner which can create "cold spots” (lower than optimal treatment temperature) or "hot spots” (too high temperature above the hyperthermia range which can result in burns or thermal side-effects)
Intravesical BCG instillations
BCG (bacillus Calmette-Guérin) is a bacterium similar to that which gives rise to tuberculosis and is used to vaccinate people against tuberculosis and as intravesical immunotherapy to treat NMIBC. Immunotherapy works by encouraging a person's immune system to attack and destroy cancer cells.
Although BCG is very effective, there is consensus that not all patients with NMIBC should be treated with BCG due to the risk of toxicity.
BCG intravesical treatment is associated with more side effects requiring treatment stoppage compared to intravesical chemotherapy and include, inter alia, fever, chills, aches, weakness, flu-like symptoms, cough or trouble breathing, pain or burning when urinating, upper stomach pain (https://www.drugs.com/mtm/bcg-intravesical.html).
Major complications can appear after systemic absorption of the drug.
BWT - UniThermia