**1. Introduction**

Bladder cancer accounts for 3% of the total cancers diagnosed in the world. It is more prevalent in developed countries. The most potent risk factor is tobacco smoking. Seventy-five percent of bladder cancer cases present with non-muscle invasive disease. The five-year survival statistics in the US are 69.5% for localized disease, 36.3% for regional disease, and only 4.6% for metastatic disease [1]. Almost three-fourths of high-risk non-muscle invasive bladder cancer will have a recurrence within ten years, 33% will progress to invasive disease [2].

Clinical guidelines suggest a risk-stratified approach post TURBT for intravesical therapy instillation. BCG has been the gold standard for intermediate and high-risk diseases. However, 61% of all patients recur within one year [3, 4]. In low-risk patients, a single post-operative instillation is adequate. This is based on a meta-analysis by Sylvester et al., which showed that patients receiving post-operative chemotherapy had a decrease in 39% of odds of recurrence with chemotherapy. They also showed that in patients with multiple tumors single instillation was not successful. Patients with a single tumor had a recurrence of 35.8% vs. a recurrence of 65.2% in patients with multiple tumors. No difference in different chemotherapeutic agents was found. The instillation is recommended to be given within 6 hours after TURBT, but in any case, within 24 hours if there is no deep resection [5].

The intermediate-risk group of patients is the largest group of non-muscle invasive bladder cancer patients. Intravesical instillations are recommended to decrease the risk of recurrence. The combined analysis from the European Organization for Research and Treatment of Cancer [EORTC] and Medical Research Council [MRC] randomized clinical trials included 2535 patients of primary or recurrent, stage TaT1 transitional cell carcinoma compared transurethral resection alone with and without adjuvant intravesical therapy. It showed a significant difference in terms of the duration of diseasefree survival. No significant advantage in progression was seen. The median follow-up for survival was 7.8 years [6]. The guidelines recommend intravesical instillations of chemotherapeutic agents or BCG post TURBT in the intermediate-risk group [7, 8].

A second TURBT is mandatory within 2–6 weeks in the current guidelines in the high-risk group [7]. Guidelines recommend BCG intravesical therapy for high-risk patients. This is based on a meta-analysis by Sylvester et al., which included 24 trials with 4863 patients. The median follow-up was 2.5 years, and the maximum followup was of 15 years. In the BCG group, 260 out of 268 progressed [9.8%] while in the control group 304 out of 2205 progressed [13.8%]. There was a reduction of 27% in progression on BCG and the results were statistically significant. No significant benefit in disease-free survival was found [9]. No adjuvant chemotherapeutic regimens are included in the clinical guidelines as of now.

### **2. Advancements in low-risk disease**

#### **2.1 Gemcitabine**

#### *2.1.1 The rationale for using gemcitabine*

Gemcitabine is 2′2' – diflourodeoxycytidine and it has a broad spectrum of antitumor activity. It is phosphorylated and incorporated into DNA and RNA which results in apoptosis.

Many characteristics make gemcitabine a promising intravesical agent for bladder cancer. First, there has been a response rate of 27–38% during the systematic administration of gemcitabine against invasive bladder cancer. Second, the absorption of intravesical chemotherapeutic agents requires the size of the drug to be less than 300 Da. Gemcitabine has a molecular weight of 299 Da, which is lower than mitomycin and doxorubicin. It enables the drug to better penetrate the bladder mucosa and at the same time, the molecular weight is not too low so that systematic absorption of the drug occurs. The pKa of the drug is 3.6 and it results in a pH of 2.7–3.2 after reconstitution. Therefore, it results in low ionization of the drug at the acidic pH of the urine [10].

#### *2.1.2 Studies for intravesical gemcitabine*

Bohle et al. conducted a double-blind placebo-controlled randomized control trial in low and intermediate-risk patients for post-TURBT intravesical gemcitabine versus placebo in 355 patients in 24 urological centers. They used a single postoperative instillation of 2gm in 100 ml NS of gemcitabine with a 30–40 minutes retention time. The placebo used was 100 ml of normal saline. Both of these were followed by 20-hour bladder irrigation. The median follow-up was 24 months. Recurrence-free survival [12 months] was 77.7% in the gemcitabine group and 75.3% in the placebo group. There was no statistical significance between the two groups. The authors concluded that continuous irrigation and improved TURBT techniques might have led to high recurrence-free survival in both groups [11].

*Advancements in Intravesical Chemotherapy in Non-Muscle Invasive Bladder Cancer DOI: http://dx.doi.org/10.5772/intechopen.99441*

The SWOG SO337 randomized control trial was conducted at 23 US centers, and it assessed the effect of single post-operative instillation of intravesical gemcitabine versus saline in low-risk NMIBC cases. They used 2gm gemcitabine in 100 ml NS and 100 ml saline with a retention time of 1 hour in both groups. A total of 215 patients with low-risk NMIBC were randomized. The median follow-up was four years. In the gemcitabine group, 34 recurred out of 102, and in the saline group, 59 recurred out of 113 patients. There was a statistically significant difference between both groups [P = 0.001]. There were no grade 4 or 5 adverse events. The authors concluded that in low-risk non muscle-invasive bladder cancer patients, immediate intravesical instillation of gemcitabine significantly reduced the recurrence rate over a median of 4 years [12].

#### **2.2 Apaziquone**

Apaziquone is a mitomycin derivative and chemically 5-[aziridin-1-yl]-3- [hydroxymethyl]-2-[[1E]-3-hydroxyprop-1-enyl]-1-methyl-1H-indole-4,7-dione. It has a molecular weight of 288.30 Da. The drug product is called EOquin, and it has a storage temperature of 2–8 degrees Celsius. Before intravesical instillation, the EOquin vial is reconstituted with 20 ml of Diluent [a propylene glycol solution for intravesical instillation] to yield 0.2 mg/ml of apaziquone. This solution is further diluted with 20 ml of sterile water for injection, USP, resulting in 40 ml of the instillation solution containing 0.1 mg/ml of apaziquone [13].

It is the most potent intravesical agent in vitro. It is a prodrug and enzymatically activated by DT diaphorase [DTD] to generate cytotoxic species [13].

Karsh et al. reported two phases 2 multinational, double-blind placebocontrolled trials in patients with Ta, G1-G2 NMIBC to evaluate the efficacy of single instillation of apaziquone post TURBT. These two trials [SPI -611 and SPI 612] were conducted between April 2007 to January 2012. A single intravesical instillation of apaziquone [4 mg/40 mL] or placebo was administered within 6 hours post-TURBT. The primary endpoint was a 2-year recurrence-free rate, and the secondary endpoint was time to recurrence. A total of 1614 patients were enrolled.

Individually the two studies did not meet any statistical significance for a 2-year recurrence-free rate [38.0% vs. 44.6%, 39.7% vs. 46.3%]. When the pooled analysis was presented, it showed a 6.7% reduction in the 2-year recurrence-free rate. [OR – 0.76, P – 0.0218]. In both the studies, time to recurrence showed improvement, which was statistically significant in the SPI-611 study. Pooled data for time to recurrence also showed a significant improvement of time-to-recurrence [hazard ratio [HR] 0.79; P5.0096]. Apaziquone is rapidly metabolized in the blood. Therefore, a post hoc analysis was conducted by the time window of drug instillation post TURBT. Patients who had drugs instilled in the time window 60 ± 30 minutes post-TURBT demonstrated 20.3% and 20.8% reduction in 2- in the two studies, respectively.

These studies reported the safety of this drug for intravesical instillation, but further studies are required for determining the efficacy of this drug [14].

#### **3. Advancements in intermediate and high-risk disease**

#### **3.1 Heated intravesical chemotherapy**

Hyperthermia is the application of mild heat [40–44-degree Celsius]. Thermal ablation is having a higher temperature range of 600 to 900 Celsius. Hyperthermia helps in triggering the immune anti-cancer response. It also helps to improve drug delivery and is itself also directly cytotoxic to the cancer cells [15, 16].

#### *Modern Approach to Diagnosis and Treatment of Bladder Cancer*

The warm temperature results in local vasodilation and causes the leaky tumor vasculature to become leakier, resulting in improved drug delivery to the tumor cells. This is called the enhanced permeability and retention effect [17]. Hyperthermia can be provided by external devices and internal devices. Internal devices are most commonly used. **Table 1** describes the various devices which are used.

Heated intravesical chemotherapy has been used in neoadjuvant and adjuvant settings.
