Our principal fining is that both of Connaught strain and TICE strain BCG exhibited comparable 3-year RFS rates, and 3-year PFS rates. Besides, we found that adverse events occurred more often in the Connaught group, although most were not severe. Therefore, in the edge of BCG shortage, TICE strain is indeed another viable alternative to Connaught strain. However, further investigations comparing these strains are necessary so that medical professionals can confirm their effectiveness.
Nowadays, on the basis of EAU guideline, the principal of BC treatment is post-TURBt intravesical BCG instillation. Nonetheless, alternative therapeutic options, including intravesical chemotherapy instillation with agents like MMC and epirubicin, persist. Although, these therapies exhibit some effects on BC, they are not as good as the effectiveness of BCG. One meta-analysis showed that there was no significant difference in recurrence risk between BCG and MMC (RR 0.95, 95% CI 0.81–1.11); however, BCG with a maintenance course had lower recurrence risk than MMC (RR 0.79, 95% CI 0.71–0.87). Furthermore, BCG also displayed a lower recurrence risk than epirubicin (RR 0.54, 95% CI 0.40–0.74) 19. Besides, compared to TURBt alone therapy, adjuvant BCG therapy reduced risk of BC recurrence (RR 0.56, 95% CI 0.43–0.71, I2 = 0%) and progression (RR 0.39, 95% CI 0.24–0.64, I2 = 40%). Several other meta-analyses had similar findings, consistently highlighting that BCG is better than MMC, TURBt alone and epirubicin 20,21. Therefore, BCG indeed play an optimal role in the management of BC.
Nevertheless, owing to the shortage of Connaught strain, our institution had no choice but to switch to an alternate BCG strain, namely TICE strain, for BC treatment. As a consequence, we have to compare the difference between two of them. Prior study underscored that the Tice strain, when administered with a maintenance schedule, provided longer recurrence-free survival in NMIBC patients (HR 0.58, 95% CI 0.39–0.86) compared to the Connaught strain 16. Another analysis showed the same spectrum between Tice strain and Connaught strain with maintenance schedule; interestingly, in the absence of maintenance, Connaught strain had more effects on BC (HR 1.48, 95% CI: 1.20–1.82) than TICE strain 12. Yet, a study conducted by Chen et al. demonstrated different results that there were no differences in connection with 3-year recurrence-free survival and progression-free survival in patients with at least 1 maintenance course, which meant nine times of BCG therapy 17. The aforementioned reports demonstrated that TICE strain with maintenance program could hold an advantageous position over Connaught strain. Conversely, in the context of an induction program, TICE strain would be inferior to Connaught strain.
Despite the above, we focused on the patients whether they received an entire induction cycle or not (Table 2), and the comparison between the two groups did not reveal any significant differences. Moreover, our investigation illustrated that the analyzed three-year RFS and PFS rates were somewhat higher for Connaught strain compared to TICE strain. Over a 5-year span, the TICE group exhibited slightly higher overall death and cancer-specific death compared to the Connaught group. The results indicated that there were no significant differences in terms of clinical efficacy between the TICE group and the Connaught group, used in T1 high grade BC patients. While our findings imply that the Connaught group exhibits an extended PFS in comparison to the TICE group, it should be noted that the median PFS duration could not be definitively determined. This observation suggests that the data might be incomplete or insufficient, as aspect that is further substantiated by the COX regression analysis.
In our study population, the Tice group underwent immediate intravesical chemotherapy instillation more frequently compared to the Connaught group (MMC 38.30% vs 37.74%, epirubicin 25.53% vs 7.55%; p = 0.012). According to a research and guideline from the EAU, immediate intravesical chemotherapy is recommended for reducing recurrence rates in certain low-risk patients 4,22. However, the patients in our study belong to a high grade (high risk) category, which makes them less likely to be affected by the benefits of immediate intravesical chemotherapy.
Earlier studies have indicated that SE were reported in comparable numbers of patients receiving both Tice and Connaught strains, ranging from 13.5–42% in frequency 18. A meta-analysis also showed that reducing the amount of BCG administered results in a lower likelihood of experiencing SE when compared to the standard BCG dosage. Furthermore, their discovery also uncovered that lower doses of BCG might be less effective in preventing cancer recurrence 23.
The aforementioned researches showed the relationship between different BCG strain and SE. Moreover, our study showed a resemblance to the aforementioned researches. Compared to the Connaught group, the TICE group exhibited a significantly lower frequency of adverse effects, including cystitis, UTI and hematuria. However, differences in BCG infection and the complications category were not statistically significant between the two groups. Consequently, we could conclude that TICE strain had a lower incidence of SE than Connaught strain, although there was no distinction in the severity of SE.
Our observations were in alignment with the conclusions drawn in prior studies. Nevertheless, several limitations are present within this study. Primarily, the sample size in both the Connaught and Tice groups was relatively small, with the TICE group's size being nearly twice as large as that of the Connaught group. Besides, the duration of follow-up was uneven with the p-value < 0.0001. The incorporation of TICE strain into our institution was prompted by the global scarcity of Connaught strain. Given the prevailing clinical circumstances, the relatively shorter follow-up duration for TICE strain was considered reasonable. Nonetheless, the median follow-up period for Tice was 28 months, a duration deemed adequately extensive to detect occurrences of recurrence and progression among patients diagnosed with T1 high grade BC.
Secondary, according to the research conducted by J Alfred Witjes et al., the clinical efficacy of TICE strain would be different from cooperating with maintenance course to without course when comparing to Connaught strain 12. However, in our experiment, the results did not show any significantly different predictors in recurrence and progression between TICE strain and Connaught strain. The outcomes in our study differing from the research could be owing to the classification of BCG completion rate (Table 2). We did not differentiate the patients based on whether they achieved maintenance or not. Instead, we just classified the patients into categories based on completion or non-completion of the entire BCG induction cycle. Therefore, this factor could potentially hinder our ability to differentiate between the superior strain concerning tumor recurrence and progression. Alternatively, it remains plausible that both strains of BCG demonstrated comparable outcomes in terms of recurrence and progression. Moreover, another point that should be considered is the difference in dosage between Connaught and Tice, which could affect their effectiveness and SE. However, surprisingly, seldom of researchers had been interest in addressing this issue so far.
Finally, according to a previous study by Rausch S. et al. 24, it revealed that eGFR (< 60 ml/min) was one of the significant predictive determinants for recurrence, overall progression. Typically, the more severe the tumor, the higher the likelihood of causing obstruction that affects kidney function, consequently leading to progression. As for our study, the data also showed a similar tendency in tumor progression; the results showed that creatinine would impact the occurrence of tumor progression through univariate regression with the p-value of 0.0048 (Table 5). Although creatinine values were not significantly different between the two strains of BCG (p = 0.097) (Table 1), the mean value for the TICE group (1.50) exceeded the normal range (0.7–1.2), whereas the mean value for the Connaught group (1.16) did not. Therefore, this result might influent the overall tumor progression causing the statistically significant difference between the two groups with the p-value of 0.048 (Fig. 2).