A new randomized controlled trial has found that neoadjuvant electromotive drug administration (EMDA) of mitomycin C before transurethral resection of bladder tumor (TURBT) may reduce recurrence rates and prolong disease-free intervals in patients with non-muscle-invasive bladder cancer (NMIBC) compared to standard treatment with bacillus Calmette–Guérin (BCG) alone.
The study, published in October 2023 in Investigative and Clinical Urology, was conducted by researchers at the National Cancer Institute, Cairo University in Egypt. It aimed to assess the efficacy and safety of immediate neoadjuvant EMDA of mitomycin C before TURBT compared to TURBT followed by intravesical BCG alone in patients with NMIBC.
Non-muscle-invasive bladder cancer accounts for about 70% of bladder cancer cases at initial presentation. While treatable with TURBT and intravesical therapies, NMIBC is characterized by high recurrence rates and potential for progression to muscle-invasive disease. Finding ways to reduce recurrence and progression remains an important goal in managing these patients.
The randomized trial included 50 patients with histologically proven NMIBC (stages pTa, pCIS, pT1) who were treated at the Department of Urologic Oncology at the National Cancer Institute in Cairo. Patients were randomly assigned to two groups of 25 each:
Group I received neoadjuvant EMDA of 40 mg mitomycin C for 30 minutes before TURBT, followed by intravesical BCG weekly for 6 weeks starting 2-4 weeks after TURBT.
Group II received TURBT followed by intravesical BCG weekly for 6 weeks starting 2-4 weeks after TURBT (standard of care).
The study excluded patients with muscle-invasive disease, non-urothelial histology, cardiac disease, pregnancy, immunocompromised status, bleeding disorders, other malignancies, and known hypersensitivity to BCG or mitomycin C.
Patients were followed for at least 18 months with cystoscopy at 3, 6, 12 and 18 months. The primary outcome measures were disease-free interval, time to recurrence, recurrence rate, progression to muscle-invasive disease, and treatment-related adverse effects.
The two groups were well-matched in terms of age, gender, pathological stage and risk group. About 60% of patients in both groups had multifocal disease and invasion of the lamina propria (pT1). Intermediate and high-risk groups were predominant.
Key results of the study included:
- Recurrence rate was significantly lower in the neoadjuvant EMDA group compared to the BCG alone group (12% vs 48%, p=0.012)
- Disease-free interval was significantly longer in the neoadjuvant EMDA group (88% vs 52%, p=0.012)
- Median time to recurrence was 18 months in the EMDA group vs 12 months in the BCG alone group
- No recurrences occurred in the EMDA group within the first 12 months, compared to 9 recurrences in the BCG alone group
- 4 patients (16%) in the BCG alone group progressed to muscle-invasive disease, compared to none in the EMDA group, though this difference was not statistically significant (p=0.516)
- Adverse effects were comparable between groups, with no cases of electrical burns or systemic side effects in the EMDA group
The researchers concluded that neoadjuvant EMDA of mitomycin C before TURBT appears to be safe and effective in reducing recurrence rates and prolonging disease-free intervals in NMIBC patients compared to standard BCG therapy alone.
They hypothesized that the high concentrations of mitomycin achieved in the bladder tissue through EMDA may destroy or inhibit implantation of viable cancer cells released during TURBT, leading to lower recurrence. An alternative explanation is that EMDA of mitomycin before TURBT may treat residual tumors and deeper tissue exposed after resection.
The authors noted some limitations of the study, including its single-center design, relatively small sample size, and lack of long-term follow-up beyond 18 months. They acknowledged that the ideal therapeutic regimen in terms of timing, number of instillations, and duration of treatment still needs to be better defined.
Nevertheless, the researchers concluded that their findings suggest EMDA of mitomycin C can be used safely and effectively in NMIBC patients. They called for further research with larger samples and longer follow-up to confirm the results.
If validated in larger trials, this approach could potentially impact clinical practice by offering a new neoadjuvant treatment option to reduce recurrence risk in NMIBC patients undergoing TURBT. The technique may be particularly beneficial for intermediate and high-risk patients who have higher rates of recurrence and progression with standard therapy.
The study adds to a growing body of research on electromotive drug administration for bladder cancer. Previous studies have shown EMDA can increase tissue concentrations of mitomycin C compared to passive diffusion. A 2011 randomized trial by Italian researchers found neoadjuvant EMDA of mitomycin before TURBT prolonged disease-free intervals compared to mitomycin after TURBT or TURBT alone.
However, this is one of the first trials to directly compare neoadjuvant EMDA of mitomycin to the current standard of care with BCG. The results suggest it may offer advantages over BCG alone, particularly in delaying or preventing early recurrences.
Several questions remain to be addressed in future research:
- What is the optimal timing and dosing schedule for neoadjuvant EMDA of mitomycin?
- How does this approach compare to other emerging intravesical therapies for NMIBC?
- Are there specific subgroups of patients who benefit most from this technique?
- What is the long-term efficacy and safety beyond 18 months?
- How cost-effective is this approach compared to standard therapy?
Larger multi-center trials with longer follow-up will be needed to definitively answer these questions and determine if neoadjuvant EMDA of mitomycin should be incorporated into clinical guidelines for NMIBC management.
In the meantime, this study provides promising early evidence that the technique is feasible and may improve outcomes compared to BCG alone. For urologists and oncologists treating bladder cancer patients, it highlights a potential new treatment strategy to consider, particularly for higher-risk NMIBC cases.
The researchers did not report any specific funding sources for this investigator-initiated study. As it was conducted at a single academic medical center in Egypt, the generalizability of results to other healthcare settings and patient populations will need to be evaluated.
It's important to note that while the results are encouraging, they are not practice-changing at this point. BCG remains the standard of care for intermediate and high-risk NMIBC based on established evidence. However, this study opens up an interesting avenue for further research that could eventually lead to changes in treatment paradigms if the findings are replicated in larger trials.
For patients with NMIBC, particularly those at higher risk of recurrence, these results offer hope for potentially improved outcomes with a new treatment approach. However, patients should be aware that more research is needed before this technique could become widely available in clinical practice.
As bladder cancer is a chronic disease requiring long-term management, any new approaches that can reduce recurrence risk and prolong disease-free intervals could significantly impact quality of life for patients. This study represents an important step in exploring novel intravesical treatment strategies to improve outcomes in NMIBC.
In conclusion, this randomized trial provides early evidence that neoadjuvant EMDA of mitomycin C before TURBT may reduce recurrence rates and prolong disease-free intervals in NMIBC patients compared to BCG alone. While larger studies are needed to confirm the findings, it highlights the potential of this technique to enhance current treatment approaches for non-muscle invasive bladder cancer. Clinicians treating these patients should be aware of this emerging strategy as research in this area continues to evolve.
References
El Azab A, Abdelbary A, El Faqeh M Okasha A, et al. The effect of immediate neoadjuvant electromotive instillation of mitomycin C with Bacillus Calmette-Guérin versus BCG alone in non-muscle-invasive bladder cancer: A randomized controlled trial. Investig Clin Urol. 2023;64(6):554-560. doi:10.4111/icu.20230161
