For non-muscle invasive bladder cancer, bacillus Calmette-Guerin (BCG) instillation is the most effective intravesical bladder instillation therapy, which is effective in reducing recurrence and delaying tumor progression. However, there are drawbacks, with a higher recurrence rate for intermediate- and high-risk patients. It has been suggested that the effectiveness of BCG could be improved by increasing the inflammatory response. However, previous studies have not shown evidence of this, and drug combinations do not appear to have better efficacy than BCG perfusion alone. Recently, European Urology published a study suggesting that sequential use of mitomycin C (MMC) and BCG over 24 hours may reduce tumor recurrence. An accompanying commentary by Dr. Oosterlinck et al from Ghent University School of Medicine in Belgium describes the two treatment options, compiled below. Study Background In a 2012 meta comparing the efficacy of chemotherapeutic agents and BCG sequential therapy with BCG infusion alone, the authors concluded that adding chemotherapeutic agents to maintenance BCG therapy did not reduce tumor recurrence or progression. But the toxicity of both was similar. However, another meta-analysis that included more studies found that the combination of epirubicin and BCG may be more effective than BCG alone. However, a review of the raw data from these studies revealed that this conclusion was simply not valid. In addition, in all of these studies, the chemotherapy drug was given one week before BCG treatment. In the current issue of European Urology, a randomized clinical trial with high statistical validity has finally demonstrated that intravesical instillation of MMC one day prior to BCG treatment improves the disease-free interval in patients with non-muscle-invasive bladder cancer (NMIBC) compared with that of non-muscle-invasive bladder cancer (NMIBC) alone. intervals than BCG alone in patients with NMIBC. The study included 407 patients with NIMBC, and the trial group used MMC and BCG perfusion sequentially over 24 hours. The results found that sequential use of MMC and BCG increased the tumor-free interval and reduced recurrence compared to BCG perfusion alone. Comparison of previous studies reveals that these differences in outcomes can be explained only by differences in treatment schedules. History and rationale for sequential treatment with chemotherapeutic agents and BCG In the early 1990s, intravesical instillation of chemotherapeutic agents and BCG became the standard of care for NMIBC. Logically, the two drugs have different anticancer mechanisms, and thus combining them may further reduce the recurrence rate, but may also lead to higher local toxicity. Early studies found that the combination of epirubicin and BCG (once weekly for 6 weeks, then once monthly for 6 months) reduced the recurrence rate to 11%; however, as with current studies, the toxicity of the drugs was high, resulting in delayed perfusion in nearly half of the patients. In 1995, the Finnish Bladder Group published his findings that alternating monthly MMC and BCG infusions did not show better efficacy than BCG infusions alone. Therefore, it can be assumed that BCG infusion every 2 months in an alternating regimen is not optimal for producing results. Subsequent clinical trials in the Nordic study of carcinoma in situ (CIS) used the same treatment program and confirmed these results. Even longer tumor-free intervals were seen in the BCG-perfusion-alone group, while the Mansoura study used epirubicin and BCG-perfusion and, again, did not find any better efficacy with the drug combination. In 1996, a study by the European Organzation for Research and Treatment of Cancer (EORTC) showed that the readmission rate for the combination of total MMC and BCG was 50%, which was not higher than that of BCG alone.In this study, 40 mg of MMC was infused weekly for the first 3 weeks, followed by 6 weeks of BCG infusion. In this study, 40 mg of MMC was infused weekly for the first 3 weeks, and BCG was infused weekly for the next 6 weeks; however, the toxicity of the drug combination was tolerated by the patients and was not greater than that of BCG infusion alone. This treatment program was subsequently used in a clinical trial for the treatment of CIS. Surprisingly, the results of the study did not show that the drug combination was more effective. No one even recommended drug combinations, and there was no trend toward combining drugs. Based on these results, there are currently no guidelines recommending the combination of chemotherapy drugs and BCG; however, this treatment option is currently reported in this article. Mechanism of Action Clinical studies have found that cases resistant to BCG are difficult to treat with MMC or epirubicin remediation. Therefore it is to be expected that the combination of drugs does not increase efficacy unless there is a synergistic effect between them. It is now clear that synergistic effects can only be produced when both drugs are administered within 24 hours of each other. A review of the literature shows that synergistic effects have been demonstrated only in studies in which the drugs were administered sequentially over such a short period of time; however, at the same time, the toxicity of the drugs increased. The one-week dosing interval between chemotherapeutic agents and BCG was too long to produce synergistic effects. However, the synergistic effect of the drugs does not arise from the anticancer effect of the chemotherapeutic agent itself, but more from the preparation of the tumor for immunotherapy. 10 mg of MMC is not sufficient to stimulate the chemotherapeutic effect. Is drug combination worth advocating? And for whom? As discussed in the original article, such an intense and toxic regimen should only be used for highly recurrent and high-grade tumors with high progression (including CIS); however, it can be extended to patients with a strong desire for bladder preservation or who are at high risk for surgery. This regimen occupies a place among the remedial options for treatment-difficult patients. It has the definite advantage that these drugs are available in every urology department and are not particularly expensive for the patient. But no matter how you look at it, this treatment option will not become routine. The study’s conclusions would have been more compelling if it had included more CIS and stage T1G3 bladder cancers with high recurrence rates. Why did the investigators stop their trial? Demonstrating that sequential therapy is effective against tumor progression makes sense for these populations; maintenance therapy with the same drugs is also necessary. But more evidence is needed to include this treatment option in guidelines.