Are there Time-period-related Differences in the Prophylactic Effects of Bacille Calmette-Guérin Intravesical Instillation Therapy in Japan ?

BCG intravesical instillation therapy has been the gold standard option for NMIBC in the two decades (Smith et al., 1999; Oosterlinck et al., 2001; http://www. nccn.org; http://www.uroweb.org; http://www.auanet. org; Schwaibold et al., 2006). Initially, no generally accepted guidelines were available, and there was no risk classification. However, a first guideline for BCG indication was published by the American Urological Association (AUA) (Smith et al., 1999), and subsequently many similar guidelines were issued by the European Association of Urology (EAU) (Oosterlinck et al., 2001) and the National Comprehensive Cancer Network (NCCN), with change year by year (http://www.nccn. org; http://www.uroweb.org; http://www.auanet.org). In particular, options for prophylactic use of BCG against NMIBC have been revised, because of modification in pathological diagnostic classification, introduction and building a consensus regarding retrans urethral resection (TUR) procedures (Sivalingam et al., 2005; Schwaibold


Introduction
BCG intravesical instillation therapy has been the gold standard option for NMIBC in the two decades (Smith et al., 1999;Oosterlinck et al., 2001; http://www.nccn.org;http://www.uroweb.org;http://www.auanet.org; Schwaibold et al., 2006).Initially, no generally accepted guidelines were available, and there was no risk classification.However, a first guideline for BCG indication was published by the American Urological Association (AUA) (Smith et al., 1999), and subsequently many similar guidelines were issued by the European Association of Urology (EAU) (Oosterlinck et al., 2001) and the National Comprehensive Cancer Network (NCCN), with change year by year (http://www.nccn.org; http://www.uroweb.org;http://www.auanet.org).In particular, options for prophylactic use of BCG against NMIBC have been revised, because of modification in pathological diagnostic classification, introduction and building a consensus regarding re-trans urethral resection (TUR) procedures (Sivalingam et al., 2005;Schwaibold
BCG treatment was terminated before the course of 6-8 instillations could be performed in a number of cases, but a minimum of 4 applications was performed in all.The patients were asked to refrain where possible from urination within two hours of the instillation and were monitored for bladder irritation, temperature change and other clinical symptoms.A tuberculin test, blood examinations, chest X-rays, cystoscopy and urinary cytology were conducted in all cases prior to BCG instillation and also at other times when considered appropriate.
Follow up was performed once a week during the weekly treatment periods, and then every 1-3 months after cessation of treatment, depending on the patients' situation.Recurrence with progression was defined with reference to muscle invasive disease (Schwaibold et al., 2006).Recurrence free survival was defined as the period elapsed between the last BCG induction instillation.
Surgically resected materials were routinely fixed in 10% buffered formalin and embedded in paraffin for sectioning and histopathological assessment of hematoxylin and eosin stained sections.Tumor grading and staging were performed with reference to the 3 rd edition of the "General Rules for Clinical and Pathological Studies on Bladder Cancer of the Japanese Urological Association and the Japanese Society of Pathology ".
Univariate statistical analyses were accomplished using Fisher's exact test, and multivariate analyses were conducted with Cox's hazard model.Cumulative nonrecurrence rates were estimated using the Kaplan-Meier method, and the significance of differences between curves was tested by the Log-rank test.A value of p<0.05 was considered statistically significant.Simple linear regression analysis was used to determine the correlation coefficient between the period of BCG treatment and clinical variables.All the statistical analyses were performed using SPSS Version 17.

Results
In total, recurrence was seen in 55 of the 146 cases (37.7%).Three and 5 year recurrence free rates were 69.9% and 64.7%.This result was similar to those outlined in previous and recent reports (Okamura et al., 1996;Smith et al., 1999;Oosterlinck et al., 2001;Martínez-Piňeiro et al., 2005;Margel et al., 2007;Ojea et al., 2007;Sylvester et al., 2011;Maurizio et al., 2012;Cho et al., 2012;Librenjak et al., 2012;Meijer et al., 2012;Segal et al., 2012).Patient characteristics of each group are summarized in Table 1.Instillation time was decreased from the 1990's, dose was reduced, T1 stage was decreased, and multiple tumor cases increased over the three time periods, all demonstrating significant alteration.Figure 1     Progression with recurrence was seen in 14 cases (9.6%), and 1 patient died of cancer.Seven of the cases of progression (i.e., half of all such cases) were among the 46 Group C patients (15.2%).Excluding these progressive cases, there were no significant differences among the remaining 132 patients in the three groups.

Discussion
In our study, the results indicated a tendency for a lower non-recurrence rate since 2000, which might be related to differences in the background characteristics, like greater average numbers of tumors per case, increased low dose cases in the 2000's.We believe that this finding is the first such report in the literature concerning BCG intravesical instillation therapy.
Change of histopathological bladder cancer grading and staging criteria could clearly exert an influence and the distinction between high malignant potential and noninvasive low malignant potential tumors has received more emphasis.Consequently, the name of superficial bladder cancer has been changed to NMIBC and in Japan the pathological classification modified from T1a and T1b to T1 only in the 1990's.However, in our series the more recent cases were more likely to be Ta rather than T1, contrary to expectation from the lower non-recurrence rate.
To increase the efficacy of BCG maximally, BCG treatment recommendation or guideline could be more soften for the patients with multiple recurrent low grade tumors, who refused surgery, or who cannot perform surgery for severe complications, because many urologists have been used to adverse effects of BCG these days.On the other hand, long-term outcome of efficacy treated with high-risk NIBC has been reported as poor prognosis, and the author suggested that rethinking the paradigm shift of this disease very recently (Thomas et al., 2012).
In conclusion, This study results revealed a trend showing a low non-recurrence rate since 2000 in Japan.This is thought to stem from a number of factors, including changes in BCG indication criteria and the evolution of histopathological diagnostic criteria.

Figure 2 .
Figure 1.Recurrence Free Survival Curves After BCG Treatment by Decade.

Fig 3 .
Fig 3. Median age distribution of Japanese patients' literatures by age

Table 1 . Patients' Characteristics of BCG Treatment in Three Different Age Groups
illustrates recurrence free