Japanese Journal of Clinical Oncology Advance Access originally published online on June 23, 2005
Japanese Journal of Clinical Oncology 2005 35(7):395-399; doi:10.1093/jjco/hyi111
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© 2005 Foundation for Promotion of Cancer Research
Long-term Outcome of a Low-dose Intravesical Bacillus Calmette–Guerin Therapy for Carcinoma In Situ of the Bladder: Results After Six Successive Instillations of 40 mg BCG
1 Department of Urology, Hamamatsu University School of Medicine and 2 Department of Urology, Seirei Mikatahara General Hospital, Hamamatsu, Shizuoka, Japan
For reprints and all correspondence: Soichi Mugiya, Department of Urology, Hamamatsu University School of Medicine, 1-20-1, Handayama, Hamamatsu, 431-3192 Japan. E-mail: mugiya{at}hama-med.ac.jp
Received March 20, 2005; accepted May 15, 2005
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Abstract |
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 TOP Abstract INTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONReferences |
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Background: In Japan, bacillus Calmette–Guerin (BCG: Tokyo 172 strain) instillation is generally performed at a dose of 80 mg once weekly for eight consecutive weeks; however, many adverse effects including severe ones have been reported. We employed a dose of 40 mg once a week for six consecutive weeks in principle for carcinoma in situ (CIS) of the bladder, and retrospectively evaluated its effectiveness and safety.
Methods: A total of 43 patients with CIS of the bladder were treated by this method and followed-up for a subsequent 12–79 months (median, 54 months). The patients consisted of 35 males and eight females aged 45–87 years (mean, 67.5 years). Intravesical BCG instillation at a dose of 40 mg was conducted once a week for six consecutive weeks.
Results: A complete response (CR) was achieved in 84% of the patients, in whom the recurrence-free rate was 72.4% after 3 years and 61.9% after 5 years. The median CR duration was 37.5 months. Two patients underwent total cystectomy, but none died of bladder cancer. As adverse effects, bladder irritation symptoms were observed in 48.8%, pyuria in 46.5%, macroscopic hematuria in 18.6% and fever (>37.5°C) in 9.3%. There were no severe adverse effects requiring discontinuation of drug administration.
Conclusion: Our present study corroborated both the effectiveness and safety of low-dose BCG therapy for CIS of the bladder. This therapy warrants further study by prospective randomized trials in the future.
Key Words: BCG • CIS • Tokyo 172 strain • low-dose • adverse effect
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INTRODUCTION |
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TOPAbstractINTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONReferences |
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Many studies have shown the usefulness of intravesical bacillus Calmette–Guerin (BCG) instillation for superficial bladder cancer since the first report by Morales et al. (1) in 1976. It has also been suggested by recent studies that intravesical BCG instillation is effective against carcinoma in situ (CIS) of the urinary bladder (2–4).
In Japan, BCG (Tokyo 172 strain) instillation at a dose of 80 mg once weekly for eight consecutive weeks is generally performed (5), but adverse effects related to BCG are major obstacles (6). Many investigations have been conducted using various doses and durations of BCG instillation for improving efficacy and reducing adverse effects (7,8).
Recently, Irie et al. (8) reported that a decreased dose BCG (Tokyo 172 strain) regimen notably reduced the associated toxicity, while maintaining the therapeutic efficacy. In the present study, we retrospectively reviewed 43 patients with CIS of the bladder treated by intravesical BCG therapy in order to ascertain our hypothesis that a low dose (40 mg) of BCG might be associated with equipotent efficacy and less adverse reactions compared with those by the standard regimen (80 mg dose) usually employed in Japan.
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PATIENTS AND METHODS |
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The subjects were 43 patients who were histopathologically diagnosed as having CIS by cold cup random biopsy or transurethral resection of the bladder mucosa between April 1998 and November 2004, treated by BCG instillation, and followed-up for 1 year or more. CIS tumor was classified into primary or secondary groups for assessment (9). In brief, primary CIS was defined as a tumor that was initially diagnosed as bladder neoplasm with no other bladder neoplasm present at the same time. Secondary CIS was defined as a tumor that was associated with occurrence of other bladder neoplasms, such as concurrent or subsequent (following previous diagnosis of bladder neoplasms after tumor-free interval) ones.
Excluded were patients who met the following exclusion criteria: previous BCG instillation; active tuberculosis lesions; on anti-tuberculosis drugs; active double cancer; intolerability for drug instillation due to severe bladder irritation symptoms; or severe impairment in cardiopulmonary, renal, hepatic or bone marrow function.
BCG (40 mg: Tokyo 172 strain) was suspended in 40 ml of physiological saline and transurethrally instilled into the bladder, and the suspension was retained for 
2 h after instillation. BCG instillation was performed once a week for six consecutive weeks in principle. Maintenance BCG therapy was not performed. When adverse effects were found, the administration intervals were prolonged to 1–2 weeks. BCG therapy was withdrawn at the discretion of either the patient or the attending physician depending on the adverse effects. In patients with secondary CIS, BCG instillation was initiated 2 weeks after transurethral resection of the bladder tumor (TURBT) for superficial bladder cancer.
One month after the final instillation, cystoscopy, three urine cytological examinations and random biopsy were performed, and response to therapy was then evaluated according to the criteria for the assessment of the treatment effects for CIS of the bladder (10). In brief, complete response (CR) was defined as no evidence of viable tumor cells on random biopsy specimens, with negative urine cytology on three consecutive studies. Patients who did not achieve CR were classified as no change (NC) or progressive disease (PD). PD was defined as the cystoscopically evidenced occurrence of a new lesion or development of muscle invasion on biopsy specimens.
Patients were examined every 3 months after the therapy by cystoscopy and urinary cytology. Biopsy or TURBT were performed when needed. The present investigation was approved by the institutional review board of our hospitals. Informed consent was obtained from all patients.
The incidence of adverse effects related to BCG was analyzed in all patients. The recurrence-free rate was calculated by the Kaplan–Meier method, and statistically analyzed by the log rank method. Differences between two groups were analyzed by Mann–Whitney U-test and 
2 test.
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RESULTS |
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Table 1 shows the characteristics of the patients. There were 35 males and eight females, and their ages ranged from 45 to 87 years (mean, 67.5 years). Primary CIS was observed in 13 patients and secondary CIS in 30. The follow-up period was 12–79 months (median, 54 months).
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Of the 13 patients with primary CIS, 11 (85%) showed CR, and two showed NC. Of the 30 patients with secondary CIS, 25 (83%) showed CR, and five showed NC (Table 2). The overall CR rate was 84%, and there was no significant difference between these two groups (P = 0.917). As the results of investigation of therapeutic effects according to the classification of CIS location into either focal or diffuse groups, CR was achieved in eight out of 12 patients in the focal group, with CR in 28 out of 31 in the diffuse group. There was no significant difference in therapeutic effects between these two groups (P = 0.059). In a similar manner, the number of concurrent tumors did not have any influence on the therapeutic effects.
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Of the 36 patients with CR, 12 showed intravesical recurrence while one developed ureteral cancer. The median CR duration of all patients was 37.5 months, while that of the primary and secondary CIS groups was 39 and 36 months, respectively. There was also no significant difference between these two groups (P = 0.718) (Table 2). Therefore, 3- and 5-year recurrence-free rates were 72.4 and 61.9%, respectively, for all CR patients (Fig. 1). Taken together, there was no significant difference between the patients with primary and secondary CIS (P = 0.326). In the 12 patients with intravesical recurrence, the recurrent lesion was characterized as CIS of the bladder in six patients and superficial bladder cancer in the remaining six (pT1 in four and pTa in two patients). These six patients with recurrent CIS underwent the second cycle of BCG instillation (40 mg, six times) and showed CR, but one of them subsequently had repeated recurrence and finally underwent total cystectomy. Histopathological examination of a surgical specimen revealed pT4a as the depth of tumor invasion. The remaining six patients with superficial bladder cancer were treated by TURBT, and in none of these patients was either recurrence or metastasis subsequently observed (no evidence of disease: NED). The patient with ureteral cancer (pT1) underwent total nephroureterectomy on the affected side; thereafter, however, this patient showed recurrent CIS of the contralateral upper urinary tract and is now on BCG instillation.
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Table 3 summarizes the instillation times of BCG to achieve the initial negativity of urinary cytology in 36 patients with CR and the number of cases classified according to the instillation times. There was no case of reversal from negativity to positivity during treatment. The number of recurrent cases is also presented according to the instillation times. A significant difference was not observed in the recurrence ratio between the early responders receiving 1–3 instillations and the late responders given 4–6 instillations (P = 0.078). We could not find any specific factors which could predict either early or late responders prior to commencement of treatment.
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Patients who did not achieve CR from the first cycle of BCG therapy underwent an additional 6 week cycle under the same conditions as stated above. Of the seven patients, five achieved CR, and no subsequent recurrence was observed in four of the five patients. One of the five patients showed recurrence of CIS twice and was lost to follow-up. One patient with NC underwent the second cycle of BCG instillation (40 mg, 12 times) and showed CR once, but subsequently revealed recurrence. Finally this patient underwent total cystectomy, and histopathological examination of a surgical specimen showed pT3a as the depth of tumor invasion. The remaining patient with NC was subjected to the second cycle of BCG instillation (40 mg, six times). Though biopsy showed no carcinoma, negative conversion was not observed by urine cytological examination. This patient did not give consent for subsequent close examination/treatment and was lost to follow-up.
In this series, although none of the 43 patients died of bladder cancer, two died of unrelated causes. Therefore, 36 patients are currently alive with no evidence of bladder cancer, and one is now being treated by BCG instillation.
Adverse effects developed in 30 patients (69.8%) (Table 4). Bladder irritation symptoms such as urinary frequency and pain on urination were observed in 21 patients (48.8%), with pyuria [>50/high power field (HPF)] in 20 (46.5%), macroscopic hematuria in eight (18.6%) and fever (>37.5°C) in four (9.3%). There were no severe adverse effects including contracted bladder requiring discontinuation of drug administration nor complications requiring medication with anti-tuberculosis drugs or surgery. The planned BCG treatment course was completed in all cases.
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DISCUSSION |
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TOPAbstractINTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONReferences |
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Since the first report of intravesical BCG instillation by Morales et al. (1) in 1976, this therapy has spread to various countries. In Japan, a clinical test of the Tokyo 172 strain was initiated in 1982, and subsequently this drug began to be covered by the national health insurance system in 1996; it became commercially available in 1997. Although anti-tumor effects and adverse effects may vary depending on the types of BCG strains (11), instillation at a dose of 80 mg once weekly for 8 weeks has been established as the standard administration method of BCG (Tokyo 172 strain) in Japan (5).
Akaza et al. (12) reported that after the treatment of CIS of the bladder with BCG (Tokyo 172 strain) instillation at a dose of 80 mg once weekly for eight consecutive weeks, 27 of the 32 patients (84%) achieved CR. Although the optimal dose of the Tokyo 172 strain had been determined by previous clinical studies (5), we anticipated that it would be possible to reduce the instillation dose, given that the BCG Tokyo 172 strain is more potent [269.91 ± 28.64 x 106 c.f.u. (colony-forming units)/mg] than other strains (13), indicating that equipotent efficacy can be attained even at half of its standard dose (8). On the other hand, we should pay attention to the frequent occurrence of harmful events related to BCG (6), which urges us to reduce the possible complications. By referring to the previous clinical data obtained by BCG instillation at a standard dose (80 mg), we investigated the treatment outcomes in our patients given a lower dose (40 mg) of BCG, attempting to pursue the optimal method of medication with the BCG Tokyo 172 strain for CIS of the bladder.
To evaluate the effectiveness and safety of BCG instillation for CIS of the bladder, Ozono et al. (14) performed a prospective randomized study. They compared anti-tumor effects, the recurrence-free rate in patients with CR and adverse effects between groups treated by BCG (Tokyo 172 strain) instillation at a dose of 80 mg eight times or at a dose of 40 mg 10 times, but observed no differences (14). Similarly, Okaneya et al. (15) also reported that BCG therapy with a 40 mg dose 10 times showed overall therapeutic efficacy almost comparable with that obtained with an 80 mg dose eight times in patients with CIS of the bladder. They subsequently evaluated the treatment results of BCG instillation at 40 mg but observed no difference in the CR rate or the recurrence-free rate between instillation eight or 10 times (16). They suggested, therefore, that 40 mg would be an adequate dose, and a comparative study should be performed to determine the appropriate frequency of instillations (16). Recently, Takashi et al. (17) reported that the dose (40 versus 80 mg) of BCG was not a significant determinant for CR in patients with CIS of the bladder.
In previous studies, the CR rate after BCG (Tokyo 172 strain) instillation for CIS of the bladder was reported to be 78–84% at a dose of 80 mg (12,18). At a dose of 40 mg, the CR rate was documented to be 78–85% in the group treated by instillation 10 times (15,19) and 69–70% in the group treated by instillation eight times (16,17), respectively.
In the present study, the anti-tumor effects of BCG instillation at a dose of 40 mg six times were similar to those in previous studies, as described above. Interestingly, repeated instillation was found to be effective in five patients with recurrent CIS, and five of seven patients with NC underwent BCG instillation again (40 mg, six times) and attained CR. These findings indicate that a second cycle of BCG instillation after the initial BCG failure attained sufficient efficacy, as previously reported. (20)
Despite good clinical efficacy, intravesical BCG instillation raises some serious problems such as frequent occurrence of various adverse effects. Akaza et al. (5) observed bladder irritation symptoms in 69%, fever in 43.7% and macroscopic hematuria in 31%. Infrequent but severe adverse effects have also been reported (6), making it necessary to define the optimal BCG instillation method to improve safety while maintaining its efficacy. Although assessment criteria for adverse effects vary among reports, the incidence of local symptoms in the bladder (bladder irritation symptoms, hematuria and pyuria) in this study turned out to be similar to those in previous studies. In contrast, however, the incidence of systemic symptoms (fever) and that of severe complications was lower in this study than in the previous studies reporting fever in 31% in the group treated by instillation at 80 mg eight times (12) or general malaise in 2% (12).
Takashi et al. (7) reported that the degree of toxicity due to BCG therapy was significantly lower in patients treated by instillation at a dose of 40 mg than in the group treated at a dose of 80 mg. Irie et al. (8) also reported a significantly lower incidence of severe adverse effects requiring discontinuation of instillation in the group receiving the 40 mg dose than in those receiving 80 mg. More recently, Koga et al. (21) investigated the relationship between adverse drug reactions and patient background to clarify risk factors for the development of adverse drug reactions. They concluded that the dose of 80 mg was a significant risk factor compared with 40 mg. Therefore, we postulate that the lower dose employed in their studies and ours may be associated with the lower incidence of adverse effects.
The present study indicates that it is possible to obtain equal efficacy while decreasing the instillation times in some cases. Takashi et al. (17) also reported that the instillation times (4–7 versus 8–10) of BCG was not a significant determinant for CR in patients with CIS of the bladder. Although these findings might provide potential for a decrease in the instillation times of BCG, further studies are warranted to address this interesting issue after careful investigation in more cases.
In conclusion, we re-evaluated in this study the instillation method including the frequency (7,14,15,22). As a result, it is shown that we could improve the safety of BCG (Tokyo 172 strain) without reducing its efficacy. These results suggest that 40 mg six times would be an adequate BCG instillation regimen for CIS of the bladder, but we need prospective randomized studies on lower doses and instillation frequency to establish the optimal treatment regimen further.
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References |
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TOPAbstractINTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONReferences |
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