What’s known on the subject? and What does the study add?
Adjuvant intravesical therapies for the treatment of non-muscle invasive bladder cancers have been consistently recommended, which include intravesical immunotherapy with “bacillus Calmette-Guerin (BCG)” or intravesical chemotherapy with “mitomycin C (MMC), epirubicin, or doxorubicin.” BCG holds superiority over MMC, but the additional efficacy of the combination of pre-infusion of MMC in BCG protocol has been seldom studied. Thus, this study aimed to determine the differences between the two different protocols and show that combination therapy (MMC followed by BCG infusion) holds no advantage over BCG alone.
Introduction
Bladder cancer is one of the rare cancers that ranks ninth in the global list of cancers. In the majority of patients (approximately 80%), the cancer is superficial at presentation. However, despite being superficial [Ta, T1, or carcinoma in situ (CIS)], the outcome remains varied (1).
The usual initial management of non-muscle invasive (NMI) bladder cancers includes cystoscopy and transurethral resection (TUR). Despite this, the spread of cancers to the muscle tissue and the recurrence rate are high, which carries a poor prognosis (1).
Given this, the use of adjuvant intravesical therapies has been practically recommended, which include intravesical immunotherapy with “bacillus Calmette-Guerin (BCG)” or intravesical chemotherapy with “mitomycin C (MMC), epirubicin, or doxorubicin” (2). They have been proposed to delay the tumor progression and recurrence with minimal side effects (3).
The use of BCG in bladder cancer began after it proved efficacious in melanoma. The effect is based on the mechanism that BCG binds and internalizes in the bladder tumor cells and induces cell death by (1) apoptosis-inducing pathways and (2) stimulation of local inflammation and macrophage-induced destruction. Since an adequate host immunity is required for the BCG immunotherapy to be effective, BCG has been much used in NMI bladder cancers only, that is, with low cancer load and good host immunity (4). The dosage regime of BCG has been decided as per its delayed immunity effects, which begin to show in 3 weeks, and its side effects profile, which subsides within 1 week. Therefore, a weekly regime of 6 weeks has been practically unanimously agreed (5,6). This regime showed to reduce tumor progression and recurrence for up to 10 years (7), after which increased recurrence rates have been reported in a follow-up study of 15 years (8).
MMC, hydrophobic in nature, is an antitumor antibiotic, among others, like epirubicin and doxorubicin, which by local instillation, works as an immediate chemotherapy measure to provide a longer recurrence-free period (9,10). It is minimally absorbed in a dose of 40 mg in saline or water and thus carries minimal side effects (11,12). Unlike BCG multi-dosage regime, MMC shows no superiority in efficacy by multi-dosage in comparison to single immediate instillation (12,13). Thus unanimously, a single dose of 40 mg within 1 h of TUR has been accepted (11).
Among the two, BCG has shown superior efficacy in reducing the recurrence (14-19). With the ongoing medical advancements, combinations of therapies have been tried against monotherapy. However, no consensus was found as to combination therapies are safe and efficacious compared to monotherapy. Some studies showed that BCG in combination with MMC is far better in achieving tumor-free interval and lowering disease progression (20-22), whereas some studies fail to see any significant difference with the combination therapy (23,24).
Therefore, the present study was conducted to determine the benefits of a combination of BCG and MMC compared to BCG alone in the treatment of patients with NMI bladder cancer.
Materials and Methods
The randomized comparative study was conducted in the department of urology of a tertiary care hospital. The study recruitment period was of 1 year with a follow-up of 2 years. The institutional ethical committee approved the study (IEC/SNMC/1210/2010). All patients aged 18 years or older with freshly diagnosed and histologically proven stage pT1 transitional cell carcinoma of the bladder, whether papillary or solid, were included in the study. Any patient with muscle invasion, previous or ongoing treatment with intravesical agents, bladder capacity <2 L, a urethral stricture that would prevent endoscopic procedures and repeated catheterization, diseases of the upper urinary tract, history of tuberculosis, tumor recurrence, cardiac disease, other malignancies, psychiatric or neurological disorder, contraindications to spinal or general anesthesia as required for a TUR, and known hypersensitivity to BCG or MMC were excluded from the study.
Informed written consent was obtained from all patients before enrolling them into the study. The sample size calculation of the study was based on the research of Hurle et al. (25), who observed that in the BCG group, estimated recurrence-free survival was 58.1 months, whereas 34.6 months for the MMC group. Taking these values as a reference and assuming a standard deviation of 30 months, the minimum required sample size with 80% power of study and 5% level of significance is 26 patients in each study group. The total sample size taken is 27 (54 patients per group) to reduce the margin of error.
The enrolled patients underwent an investigative protocol of urine exfoliative cytology, ultrasonography of the upper urinary tract, intravenous urogram, cystoscopy, and biopsy. TUR of bladder tumor (TURBT) for all visible tumors was performed on cystoscopy. The detailed methodology of TURBT has been shown in Supplementary File 1.
Following TURBT, patients were randomly grouped into two using a sealed envelope system. In this, ten sealed opaque envelopes were prepared, assigning A and B in 5 envelopes each, where A is represented by perioperative MMC and BCG and B by BCG alone. Once a patient consented to enter a trial, an envelope was opened, and the patient was then offered the allocated group. In this technique, patients were randomized in a series of blocks of 10. Once 25 patients were allocated to each group, then we used four sealed opaque envelopes, assigning A and B in 2 envelopes each.
Group A (n=27) included patients who received postoperative MMC at 40 mg diluted in 50 mL of NS within 6 h of operation, followed by intravesical BCG at 60 mg per week for 6 weeks followed by monthly BCG for 1 year. BCG therapy was begun 2-4 weeks after the tumor resection to allow time for re-epithelization.
Group B (n=27) included patients who received intravesical BCG at 60 mg postoperatively (after 2-4 weeks) per week for 6 weeks, followed by BCG monthly for 1 year.
The detailed steps of drug instillations are shown in Supplementary File 2, and the procedural flow is shown in Figure 1.
Follow-up
All patients were properly followed for the next 2 years to fulfill the objectives of the study. Adverse events were recorded according to the World Health Organization toxicity grading (26) after each instillation and a week after the 6th dose. In case of persistent fever for >72 h and sterile urine culture, antitubercular treatment was started depending on the severity of the symptoms, and all records were maintained of the total dose and duration. Follow-up cystoscopy with three urine cytology was done every 3 months for 2 years. Histopathological types and grades were recorded for each recurrence.
The outcome measures were time to recurrence, progression of the disease to muscles or other organs, overall survival, and treatment-related side effects. Recurrence (or persistent disease) was defined as biopsy confirmed CIS or non-invasive papillary carcinoma, or malignant cytology and progression defined as pT1 tumor or more advanced disease. Patients were considered to have a complete response at 1 year if they had no progression during the first 9 months and no recurrent/persistent disease or progression at 12±3 months. The treatment failure was defined as progression or change in therapy resulting from recurrence or side effects during the first year or as recurrence, progression, or change in therapy after the first year.
Statistical Analysis
The categorical variables were presented in the form of numbers and percentages (%). Contrarily, the continuous variables were presented as mean ± standard deviation and median values. Mann-Whitney U test was used to compare quantitative variables, and the chi-square test and Fisher’s Exact test were used to compare qualitative variables. The data entry was done in the Microsoft Excel spreadsheet, and the final analysis was done with the use of Statistical Package for Social Sciences software version 21.0. For statistical significance, a p-value of <0.05 was considered significant.
Results
The demographic distribution of the two groups was comparable (Table 1). The median age in the group of perioperative MMC with BCG was 65 years and in BCG alone was 67 years (p=0.361). The gender distribution showed slight male predominance in both groups (p=0.573). All patients were of NMI bladder cancer with T1 stage in both the groups (p=0.967). The majority of tumors were the papillary type of transitional cell carcinoma (88.89% in group A and 92.59% in group B) with others being the solid type of transitional cell carcinoma, with no significant difference (p>0.05). The tumors were majorly low grade (85.19% in group A and 88.89% in group B) with well-differentiated morphology. Among all the cases belonging to T1, 2 cases in group A and 3 cases in group B were CIS.
Compared to BCG alone, perioperative MMC in combination with BCG had comparable disease-free survival (85.18% vs. 66.66%, p=0.202), disease recurrence (14.81% vs. 33.33%, p=0.202), and progression rate (11.1% vs. 25.9%, p=0.293) (Table 2).
The side effects profile of the study participants was comparable in both the study groups (Table 3). The side effects included dysuria, bacterial cystitis, drug-induced cystitis, macroscopic hematuria, prostatitis, epididymitis, fever, influenza-like symptoms, and fatigue, due to which treatment had to be temporarily stopped in 5 patients in group A and 4 patients in group B. However, overall, they were minor side effects and were effectively managed without any mortality.
Discussion
The present study was a randomized comparative trial on 54 patients (27 patients in each group), where we determined the benefits of a combination of BCG and MMC in comparison to BCG alone in the treatment of patients with NMI bladder cancer by comparing progression-free survival rates in patients.
The randomization ensured that age, gender, and cancer stage were comparable among the two groups and that any difference in outcome is purely due to differential intervention and not due to chance bias (27).
Despite the developments in diagnosis and treatment modalities, a high recurrence rate in bladder tumors is reported. Generally, the progression from non-muscle to muscle-invasive urinary bladder cancer results in metastasis and is considered a bad prognosis. Approximately 70-80% are NMI, which usually recur without aggressive histopathological features, and a subgroup of high-risk lesions that usually progress to invasive forms (MI). Recurrent relapses, disease progression, and chemoresistance lead to urinary bladder cancer that becomes difficult to manage from the diagnosis till death (28).
Our study revealed a comparable progression rate in perioperative MMC in combination with BCG compared to BCG alone (11.1% vs. 25.9%, p=0.293). Among the previous studies that compared the combination therapy with BCG alone, similar findings were reported by Solsona et al. (29), who found no statistically significant difference between MMC + BCG and BCG alone in terms of 5-year PFI (12.3% vs. 12.2%; hazard ratio: 1.05; 95% confidence interval, 0.61-1.83; p=0.852). Even Oosterlinck et al. (30) reported that alternating chemoimmunotherapy schedules with MMC and BCG demonstrated comparable efficacy compared to BCG alone in reducing the rate of progression. In contrast, Di Stasi et al. (23) reported that sequential BCG in combination with electromotive MMC showed lesser progression of the disease than BCG alone [9.3% (3.8-14.8) vs. 21.9% (17.9-25.9); p=0.004].
Disease-free survival is an important landmark in cancer treatment. Our study revealed a comparable disease-free survival in perioperative MMC in combination with BCG compared to BCG alone (85.18% vs. 66.66%, p=0.202), as well as in disease recurrence (14.81% vs. 33.33%, p=0.202). The findings were comparable to Oosterlinck et al. (30), who found that alternating chemoimmunotherapy schedules with MMC and BCG had similar efficacy compared to BCG alone in reducing the rate of recurrence. Contrary to the present study, Di Stasi et al. (23) found a combination of the sequential BCG with electromotive MMC to be superior to BCG alone, as sequential BCG and electromotive MMC had lower recurrence [41.9% (32.7-51.5) vs. 57.9% (48.7-67.5); p=0.0012]. Solsona et al. (29) also reported similar findings as a combination of sequential BCG with MMC significantly reduced the disease relapse at 5 years compared to BCG alone (20.6% vs. 33.9%, p<0.05).
The side effects of both protocols were minor without any mortality. They were mainly macroscopic hematuria, dysuria, and drug-induced cystitis in the BCG + MMC group and macroscopic hematuria, fatigue, and drug-induced cystitis in the BCG alone group (p>0.05). A similar comparable side-effect profile was observed in the study by Di Stasi et al. (23). Kaasinen et al. (31) found significantly more local side effects with BCG monotherapy, which also resulted in premature cessation of instillation treatment compared to the MMC + BCG. However, the difference in serious side effects in both groups was not significantly different. Contrarily, Solsona et al. (29) found that the MMC + BCG had significantly more local toxicity compared to BCG alone (80.4% vs. 69.7%, p<0.05). Even after reducing the dose of MMC to 10 mg, toxicity was still higher compared to BCG alone, specifically in local side effects grade 3 (28.4% vs. 10.9%; p<0.001).
Overall, we found that both protocols were comparable in safety and efficacy in reducing the progression and recurrence of NMI bladder cancers without any significant superiority of MMC in combination with BCG compared to BCG alone. Our findings were in line with the studies by Solsona et al. (29), who found comparable PFI, and were in contrast to the studies by Oosterlinck et al. (30) and Di Stasi et al. (23), who showed that combination is a better protocol compared to BCG alone in terms of recurrence, progression, and disease-free survival. Among other studies, Kaasinen et al. (31) found that 1-year BCG monotherapy was more effective than the alternating therapy of BCG and MMC for reducing recurrence rates and disease-free survival and similar progression rate.
The difference in the results of various studies could be due to the difference in the schedule of instilling MMC with BCG. In studies by Oosterlinck et al. (30) and Kaasinen et al. (31), MMC plus BCG was administered on a weekly alternating schedule. In a study by Solsona et al. (29), MMC was administered sequentially, 1 d before the BCG instillation. In the study by D i Stasi et al. (23), patients who were assigned to BCG + MMC had electromotive MMC once a month. The comparable reduction in the progression and recurrence of NMI bladder cancers noted in the present study might be because MMC was given only once immediately after the TURBT, whose effect might be overpowered by the continuous instillation of BCG for 1 year given in both the groups.
Thus, combination therapy is proposed to depend specifically on the infusion timing. In contrast to the present study, where MMC was given initially and followed by BCG in due course, better outcomes have been seen with initial treatment with BCG followed by MMC. With the initial treatment with BCG, the immune response is initiated, and the tumor cells get exposed to infiltration of cytokines (some of which exert an antiproliferative action), cytotoxic T-lymphocytes, helper T-lymphocytes, and specifically, non-specific BCG-induced responses. These cascades play an important role for MMC introduction, which by enzymatic reduction, enhances the anticancer effects by crosslinking of DNA to all tissue layers of the bladder wall, which are affected by NMI bladder cancer (such as urothelium and lamina propria). In addition, MMC attacks cancer cells that are resistant to BCG (23).
Study Limitations
One of the limitations of the study was the insufficient long-term maintenance schedule, which is recommended as per the guidelines (32). Another limitation was that this study was conducted at a single center; thus, results cannot be generalized. Lastly, no comparison was made on BCG infusion followed by MMC on the disease-free interval in NMI bladder cancers.
Conclusion
Perioperative MMC in combination with BCG was comparable to BCG alone in the effectiveness in terms of disease-free survival, disease recurrence, and progression rate in patients with NMI bladder cancer. In addition, side effects were also similar in patients who received MMC with BCG and BCG alone, thereby suggesting that the combination therapy (MMC followed by BCG infusion) holds no advantage over BCG alone.
Ethics
Ethics Committee Approval: The institutional ethical committee approved the study (IEC/SNMC/1210/2010).
Informed Consent: Informed written consent was obtained from all patients before enrolling them into the study.
Peer-review: Externally peer-reviewed.
Authorship Contributions
Concept: N.K., S.J., D.A., Design: N.K., Data Collection or Processing: N.K., S.J., D.A., Analysis or Interpretation: N.K., S.J., D.A., Literature Search: S.J., D.A., Writing: N.K., S.J.
Conflict of Interest: No conflict of interest was declared by the authors.
Financial Disclosure: The authors declared that this study received no financial support.
