**4. Advancements in BCG failure cases**

## **4.1 Hyperthermia in BCG unresponsive cases**

The HYMN trial was an open-label, two-arm, phase III randomized control trial in which 104 patients with BCG unresponsive non-muscle invasive bladder cancer were randomized to hyperthermia plus mitomycin or a second course of BCG. In the hyperthermia arm Synergo SB-TS 101 System was used and two 30 min cycles, each with 20 mg mitomycin at 420 +/− 20 . Patients allocated to the BCG arm received six consecutive weekly BCG instillations [in 50 ml normal saline] followed by maintenance therapy [three consecutive weekly instillations at 3, 6, 12, 18, and 24 months]. Primary outcomes were disease-free survival [DFS] and three months complete response for CIS patients at randomization. The median follow-up was 35 months. No statistically significant difference was observed between the two arms. The hyperthermia arm had 35% DFS, and the BCG arm had 41% DFS. [HR 1.33, 95% confidence.

interval [CI] 0.84–2.10], p = 0.23; adjusted p = 0.49]. There was a nonsignificant higher DFS favoring hyperthermia group than BCG group in non-CIS patients at baseline [HR 0.50, 95% CI 0.22–1.17, p = 0.11] [25].

The most adverse events in this study were grades 1–2. There was two grade 4 toxicities in the BCG arm due to arthritis, and the other BCG-related sepsis resulted in death. No difference in health-related quality of life [HRQoL] was observed between the two treatment arms, although hyperthermia group patients reported their HRQoL higher than BCG group patients at 3,6 and 9 months [25].

### **4.2 Docetaxel**

Docetaxel as a sole agent was studied in a phase I/II trial in 54 BCG refractory NMIBC between 2003 and 2012. A dose-escalation scheme was used in the first 18 patients treated with doses ranging from 5 to 75 mg for a final concentration of 0.125 to 0.75 mg/ml for administration. All subsequent patients received the maximum dose of 75 mg/100 ml of normal saline. All patients received six weekly instillations of intravesical docetaxel. After the phase I trial, those with a complete response to induction treatment were offered single dose monthly maintenance treatments for a total of up to 12 months of docetaxel therapy. The Median followup was 39.1 months. A complete initial response was seen in 32 patients [59%]. One year and the three-year recurrence-free rate was 40% and 25%, respectively. The authors concluded that intravesical docetaxel appears to be an efficacious agent, but large trials are needed to fully characterize this agent's benefits [26].

## **4.3 Gemcitabine and associated combinations**

#### *4.3.1 Gemcitabine as a sole agent*

Gemcitabine has been studied in BCG refractory cases in two trials. Lorenzo et al. conducted a multi-center prospective randomized phase 2 trial in which 80 patients failing one course of BCG were randomly allocated to Gemcitabine arm and 2nd course of BCG arm. Kaplan Meier statistics of 2-year recurrence-free survival showed a significant difference between the gemcitabine and BCG group [19% and 3%, respectively, P < 0.008]. Seven of 21 [33%] patients in gemcitabine group and 13 of 35 [37.5%] patients in group had disease progression and underwent radical cystectomy [P = .12]. No significant safety concern was seen in both groups. The authors concluded that gemcitabine might be considered a second-line treatment after BCG failure in a high-risk non-muscle-invasive group [27].

Addeo et al. conducted a phase III randomized control trial in 120 high-risk NMIBC patients previously treated with BCG from march 2003 to November 2005. They received 40 mg of mitomycin C or 2000 mg of gemcitabine diluted in 50 mL of normal saline. The median follow-up was 36 months. In the gemcitabine arm, 39 of 54 patients remained free of recurrence versus 33 of 55 in the mitomycin C arm. Progression was seen in 10 patients in the mitomycin C arm and 6 in the gemcitabine arm. The incidence of chemical cystitis in the mitomycin C arm was statistically higher than in the gemcitabine arm [P = .012] [28].

These studies show that gemcitabine alone or combined can be considered in BCG refractory high-grade disease if cystectomy is contraindicated or refused [29].

#### *4.3.2 Gemcitabine plus cabazitaxel plus cisplatin*

A phase I trial studied the effect of this combination therapy. The trial was a dose-escalation, drug escalation study in patients of high-risk BCG failure NMIBC. A total of 18 patients were included, and the median follow-up was 27.8 months. The schedule used was


The dosing used in this study was:

1.Gemcitabine- 2 g/100 ml, Cabazitaxel – 5 mg/100 ml, Cis – 66 mg/100 ml

2.Gemcitabine- 2 g/100 ml, Cabazitaxel – 5 mg/100 ml, Cis – 80 mg/100 ml

3.Gemcitabine- 2 g/100 ml, Cabazitaxel – 5 mg/100 ml, Cis – 100 mg/100 ml

A complete response rate of 94% was observed, and a DFS of 78% was observed at 9.5 months. No Dose-limiting toxicity till the last follow-up. Further studies need to be done to evaluate the efficacy of this combination.
