INTRODUCTION: The purposes of the present prospective study were: (1) to investigate the role of a fluoroquinolone (ofloxacin) in reducing the side effects of bacillus Calmette-Guerin (BCG) therapy in patients with nonmuscle invasive bladder cancer; (2) to determine if ofloxacin had any influence on the antitumor efficacy of the BCG therapy.
METHODS: From December 2006 to December 2007, 100 consecutive patients were enrolled in the study. Patients were randomly assigned to group 1 (n = 50) to receive ofloxacin or group 2 (n = 50) to receive a placebo. The groups were similar in patient age, sex, tumor stage, and tumor grade. Patients were followed for 12 months. The efficiency of the BCG therapy was determined clinically using an adverse event scale index. The patients were also evaluated endoscopically.
RESULTS: During the study period, there were 267 adverse events occurring after more than 850 BCG instillations. A significant decrease of burning with micturition was noted in group 1 (n = 41) when compared with group 2 (n = 19) (P = .03). Ofloxacin did not significantly reduce the occurrence of any other mild, moderate, or severe adverse events. After a follow-up of 12 months, results showed that ofloxacin did not affect the efficacy of BCG therapy. There were no significant differences between the 2 groups in disease recurrence or progression rates.
CONCLUSION: Instituting antibiotic prophylaxis with ofloxacin after each BCG instillation appears to be an efficient and safe method of improving treatment tolerability for burning with micturition. Ofloxacin reduced this adverse event without serious consequences. By decreasing the burning symptoms, patients may be more inclined to continue the BCG treatment.
KEYWORDS: Bladder; Transitional cell carcinoma; BCG therapy; Adverse events;
CORRESPONDENCE: Yassine Nouira, 5 Rue Ibn Messaoud El Menzah 6 – 2091, Ariana, Tunisia ().
CITATION: Urotoday Int J. 2009 Oct;2(5). doi:10.3834/uij.1944-5784.2009.10.13
INTRODUCTION
Bacillus Calmette-Guerin (BCG) was first reported to be efficacious in the treatment of superficial bladder cancer by Morales et al in 1976 [1]. Subsequent investigations have demonstrated the efficacy of BCG in the prophylaxis and treatment of high-risk superficial bladder tumors. Thus, BCG is now recommended as an adjunctive treatment for superficial bladder tumors.
There is no current consensus on the optimal instillation protocol for BCG, but all investigators agree that it is essential to use maintenance therapy. Unfortunately, the use of maintenance therapy is hindered by troublesome adverse reactions. For example, during a course of 6 weekly BCG instillations, Vegt et al [2] found that approximately 5% of patients experienced severe adverse reactions and 30% to 80% had minor local or systemic reactions.
Several drugs have been proposed to prevent adverse BCG reactions, but none have proven efficiency. Moreover, some have a specific toxicity, such as the liver toxicity caused by isoniazid [3].
The fluoroquinolone ofloxacin has been proven effective in treating systemic BCG infection without interfering in antitumor efficacy, but only in an animal model [4]. The purposes of the present prospective study were: (1) to investigate the role of ofloxacin in reducing the side effects of BCG therapy in patients with nonmuscle invasive bladder cancer; (2) to determine if ofloxacin had any influence on the antitumor efficacy of the BCG therapy.
METHODS
Participants
From December 2006 to December 2007, 100 consecutive patients were enrolled in the study. All patients presented a history of papillary, nonrecurrent, superficial (pTa or pT1) transitional cell carcinoma of the bladder.
The patients were randomly placed into 2 groups, according to a numerical table of randomization (Epitable®). Group 1 (n = 50) received fluoroquinolone (ofloxacin); group 2 (n = 50) received a placebo. The groups were similar in patient age, sex, tumor stage, and tumor grade. The mean age was 59.5 years (SD = 7.89; range, 42 to 76 years) in group 1 and 58.1 years (SD = 6.32; range, 45 to 75 years) in group 2. Group 1 had 49 males and 1 female; group 2 had 48 males and 2 females. Figure 1 shows the patient distribution according to tumor stage and grade for each group. The exposure time to the BCG therapy was the same for the 2 groups.
Procedure
Three weeks after complete transurethral resection, all patients received induction treatment with Pasteur’s BCG strain at the dose of 75 mg. The BCG therapy protocol consisted of 6 weekly instillations as an induction treatment, followed by 6 monthly instillations as maintenance therapy. Patients were advised not to urinate for 2 hours after BCG instillation.
Patients in group 1 received ofloxacin at the dose of 400 mg per day. The first dose (200 mg) was given 6 hours after the instillation and the second equal dose was given 12 hours after the first capsule. Patients in group 2 received 2 capsules of placebo at the same times. These procedures were similar to those used in a previous study [5]. Patients were blind to the treatment type, and the placebo pills were similar in appearance to the ofloxacin pills.
Follow-up Evaluation
Patients were followed for 12 months to determine tolerability and efficacy of the BCG therapy. Adverse events were recorded at day 1, day 3, and day 7 after the first instillation. Follow-up then occurred weekly during the induction treatment and monthly during maintenance therapy.
Adverse events in the 2 groups were classified according to the BCG adverse event scale index of the World Health Organization. When an adverse event was noted, it was categorized according to degrees of severity: class 1 (mild), class 2 (moderate) and class 3 (severe). This scale has been used previously to assess the effectiveness of BCG therapy [6]. The variables listed on the scale as mild adverse events were urgency, hematuria, burning with micturition, urinary incontinence, dysuria, pelvic pain, renal pain, prostatitis, epididymitis, orchitis, renal abscess, and urethral stenosis. Moderate adverse events were fever, muscle pain, asthenia, arthralgia, skin rash, arthritis, and uveitis. Severe adverse events were life-threatening complications such as circulatory collapse, respiratory distress, disseminated intravascular coagulopathy, miliary, vascular sepsis, and hepatitis.
When an adverse event was detected, the urologist decided whether instillation should be continued based on the severity of the event. If the adverse event was serious, BCG therapy was stopped and local chemotherapy was substituted.
The efficacy of BCG therapy was assessed endoscopically after the induction treatment, at the end of the maintenance treatment, and every 6 months thereafter. Only suspect lesions were biopsied.
Data Analysis
Based on data of previous publications [5] and using the statistics program Epitable®, the authors calculated that 50 patients in each group were sufficient to obtain valid and reliable statistical results for the number of variables analyzed. The chi-square or Fisher exact test was used to compare the variables, depending on the frequency within the cells; statistical significance was set at P < .05.
RESULTS
During the study period, patients in both group 1 (receiving ofloxacin) and group 2 (receiving a placebo) had a total of 267 adverse events after more than 850 BCG instillations. Twenty three cases of mild fever were reported by patients (11 in group 1; 12 in group 2); these cases were not confirmed by measurement and not included in the final analysis.
Table 1 contains the type and location of side effects observed in both groups and the probability of significant between-group differences. Adverse reactions observed in only 1 patient were not tabled. The majority of adverse events were local; 67.7% and 71.8% of the patients in group 1 and group 2, respectively, had at least 1 local adverse event. The only statistically significant between-group difference in local side effects was for burning with micturition, which occurred less often in the group receiving ofloxacin (P = .03). There were a few regional side effects such as prostatitis and orchitis that were well managed by appropriate antibiotics. There were systemic adverse events in both groups, but only 1 case of BCGitis in group 2. The BCGitis was managed aggressively by four antituberculous drugs with a good outcome. None of the group differences in regional or systemic adverse effects were statistically significant. In summary, the data did not show any influence of ofloxacin in the occurrence of adverse events with the exception of burning with micturition, which occurred less frequently in the group taking ofloxacin Figure 2.
The withdrawal rate of BCG therapy due to product toxicity was the same for patients in the 2 groups (14 patients in group 1; 17 patients in group 2) and the differences were not statistically significant (P = .68).
Ofloxacin did not affect the efficacy of BCG therapy after 12 months of follow-up. There were no significant differences between the 2 groups in recurrence rate or the progression of the disease Table 2.
DISCUSSION
Frequent recurrence and progression of superficial bladder cancer after transurethral resection is a major problem during treatment. BCG is among the most powerful and least expensive immunotherapeutic agents to date [6]. It prevents recurrent superficial bladder cancer in more than 60% of cases and has an obvious influence on progression [7].
It has been established that the efficacy of BCG therapy is related to maintenance. The results reported by Lamm et al [8] suggest that an initial induction cycle of 6 weekly intravesical BCG instillations is suboptimal unless maintenance therapy is given at 3, 6, 12, 18, 24, 30, and 36 months. The authors reported that BCG therapy has long-term benefit, with an 83% 5-year survival rate [8]. Nevertheless, the rising number of BCG instillations unavoidably increases the incidence of adverse events. The urologist is faced with balancing an efficient maintenance therapy against numerous debilitating side effects.
Several methods and drugs have been tried to improve the tolerability of BCG therapy. Some authors reduced the BCG dosage levels, while others limited the number of maintenance therapy sessions [9]. Additional drugs have been used to decrease the incidence of adverse events. Van der Meijden et al [3] tried isoniazid with success in a randomized trial conducted for the European Organization for Research and Treatment of Cancer (EORTC). The previous studies have not definitively proven the efficacy of the medications or their lack of deleterious influence on the antitumor action of BCG therapy [5].
In the present study, the authors used a fluoroquinolone (ofloxacin), which avoided major antituberculous agents and the risk of developing new treatment resistances. The efficacy and safety of ofloxacin were tested by Dureck et al [4] in a recent prospective study using animals. The authors proved the efficacy of fluoroquinolones in reducing the side effects of BCG therapy, especially systemic infections. The authors also proved, with an orthotopic murine bladder tumor model, that quinolones do not impair the antitumor efficacy of BCG therapy [4].
When the groups receiving ofloxacin and a placebo in the present study were compared, the number and types of adverse events were not significantly different with the exception of burning with micturition. This side effect occurs frequently and causes discomfort for patients receiving BCG therapy.
The present data showed no fluoroquinolone action on systemic adverse events. This phenomenon can be explained by the BCG therapy mechanism, in that there is no direct toxic effect of BCG on tumor cells. Instead, BCG produces a cascade of immune reactions that result in tumor destruction. BCG induces local inflammatory reactions which are responsible for local side effects [10].
Unfortunately, local inflammation of the bladder urothelium leads to the release of cytokines such as interleukin-1, interleukin-8, interferon-gamma, and others. Cytokines activate unspecific inflammatory cells such as macrophages and NK-lymphocytes. These immune cells and cytokines are responsible for the systemic adverse events [11]. Quinolone has an antibiotic action in reducing BCG adverse events, by destroying the BCG microorganisms. These drugs have absolutely no effect on immune reactions and, as such, no effect on systemic expressions [5].
Results of the present study indicated that ofloxacin did not affect BCG therapy efficacy during the 12-month follow-up period. There was no significant difference between the 2 groups in recurrence or progression of disease. These results are explained by the pharmacokinetics of the drug, in that the optimum concentration level is obtained 6 hours after oral administration. In the study protocol, the first capsule was taken 6 hours after the BCG instillation. Regarding this delay, the authors allowed enough time for the attachment of live bacilli to the urothelium which represents the initial step of the immune reaction. Therefore, ofloxacin did not interfere with the immune reaction but destroyed the exceeding bacilli in the bladder and reduced the contact time of BCG with bladder mucosa. These actions decrease the adverse events without jeopardizing the antitumor processes [5].
CONCLUSIONS
Instituting antibiotic prophylaxis with ofloxacin after each BCG instillation appears to be an efficient and safe method of improving treatment tolerability for the adverse effect of burning with micturition. The present study showed that ofloxacin significantly reduced this local adverse event without serious consequences. This result is motivating given the current medical environment, although other adverse events were not significantly altered by this drug. By decreasing the burning symptoms, patients may be more inclined to continue the BCG treatment. Studies with larger samples and longer follow-up time are needed to confirm the results.
Conflict of Interest: None declared.
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