*4.3.3 Gemcitabine plus mitomycin*

This combination was first used in 2006, and it showed promising results in BCG failure patients. There were 20 months of median disease-free survival in the study by Maymi et al. [30].

In a retrospective study conducted by Cockerill et al., 27 patients with BCG failure were identified and had received gemcitabine plus mitomycin combination therapy. With a median follow-up of 22.1 months, ten patients had no recurrence. The authors concluded that this combination could offer durable recurrence-free survival to patients with recurrent NMIBC who are not candidates for, or refuse, cystectomy [31].

Similarly, Lightfoot et al. showed in a retrospective review of 47 patients who received six weekly treatments with sequential intravesical gemcitabine [1 g] and MMC [40 mg] chemotherapy for NMIBC. The median time for follow-up was 26 months. Fourteen of 47 patients [30%] remained free of recurrence. These studies show that gemcitabine plus mitomycin combination can be helpful in high-risk BCG failure NMIBC cases.

## *4.3.3.1 Administration of gemcitabine plus mitomycin combination*

Patients should be pre-treated with an oral urinary alkalization agent [such as sodium bicarbonate the night before and the morning of installation]. Gemcitabine does not directly irritate the bladder, but its solution is very acidic [pH - 2.6], whereby Mitomycin C is inactivated under acidic conditions, and it irritates the bladder.

Patients receive six weekly intravesical installations for induction, which includes administration of the following:


Monthly maintenance administrations are generally given for 1 to 2 years or until recurrence [31, 32].

### *4.3.4 Gemcitabine plus docetaxel*

Docetaxel inhibits mitosis and cell division by inhibiting the microtubular assembly [33]. Preclinical studies have shown that gemcitabine acts as an exfoliant for urothelial cells. This increases the penetration of docetaxel and therefore has enhanced efficacy [34].

Retrospective studies have shown that this combination is a promising intravesical combination in BCG failure cases. Milbar et al. showed in a retrospective analysis of 33 BCG unresponsive patients that 1-year recurrence-free survival [RFS] is 49% and 34% in 2 years [35]. Steinberg et al., in another retrospective analysis of 45 patients, showed treatment success of 66% at first surveillance, 54% at one year, and 34% at two years [36].

Steinberg et al. presented the preliminary results from a multi-institutional retrospective study of 276 BCG failure patients. The median follow-up was 22.9 months. Recurrence-free survival after 1 and 2 years was 60% and 46%, respectively. High-grade recurrence-free survival rates were 65% and 52%, respectively [37].

#### *4.3.4.1 Administration of gemcitabine and docetaxel*

The patient should be pre-treated with an oral alkalinizer. Pre-treatment with ondansetron helps to control gemcitabine-induced vomiting. Six intravesical instillations are given for induction as follows:


Monthly maintenance is given 1–2 years [36, 37].

#### **5. Nanoparticles**

One nanometer is the scale at which many of the biological molecules operate inside the living cells. Nanoparticles accumulate in tumor tissues. This occurs via the enhanced permeability and retention [EPR] effect because the tumor tissues have a more permeable vascular supply, and this allows the nanoparticles to enter the cell. Nanoparticles can be used for the encapsulation of poorly soluble drugs [38].

Abraxane - nanoparticle albumin-bound version of paclitaxel. Nanoparticle albumin bound-paclitaxel has five times higher solubility as compared to docetaxel. Mckiernan et al. have studied this nanoparticle albumin-bound paclitaxel in 28 patients in a phase I single-center trial. Complete response was seen in 10 patients. The Median follow-up was 21 months. There was no progression in 19 out of28 patients. Their adverse events were limited to grades 1 and 2. The authors concluded that intravesical nab-paclitaxel had a 35.7% response rate in patients with NMIBC and BCG failure.

#### **6. Future directions**

After many years of stagnation, multiple new therapies are being investigated as potential intravesical agents for NMIBC. Strict criteria to define the disease have encouraged trials for patients with NMIBC. Most active trials focus on high-risk NMIBC in BCG naïve and BCG failure settings [39]. Multiple combination therapies continue to emerge. **Table 2** shows the various ongoing trials based on intravesical chemotherapy.

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



#### **Table 2.**

*The ongoing clinical trials based on intravesical chemotherapeutic agents.*

Food and drug administration gave guidelines on designing trials in NMIBC as follows: [40].

• High-risk NMIBC

1.Trials can include a mix of high risk and CIS cases

	- 1.No standard of care in this group.
	- 2.Single-arm trials can be used if they provide robust results
	- 3.Patients having BCG refractory CIS should have a complete response rate of 40–50% at six months and at least 30% response rate at 18–24 months.

These can be used in low-risk patients.

	- 1.Time to event analysis should be used
	- 2.Follow-up of at least two years
	- 3.The clinically meaningful result is defined as a 15% event rate reduction or a hazard ratio of 0.7.

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