Adjuvant Intravesical Instillation For Primary T1G3 Bladder Cancer

Skip to main content Research ArticleClinical Studies Adjuvant Intravesical Instillation for Primary T1G3 Bladder Cancer: BCG versus MMC in Korea IN-CHANG CHO, EUN KYOUNG KIM, JAE YOUNG JOUNG, HO KYUNG SEO, JINSOO CHUNG, WEON SEO PARK and KANG HYUN LEE Anticancer Research April 2012, 32 (4) 1493-1498; IN-CHANG CHO

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EUN KYOUNG KIM

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JAE YOUNG JOUNG

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HO KYUNG SEO

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JINSOO CHUNG

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WEON SEO PARK

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KANG HYUN LEE

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• For correspondence: uroonco@ncc.re.kr

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Abstract

Aim: To compare the efficacy of bacillus Calmette-Guerin (BCG) and mitomycin-C (MMC) intravesical instillation for primary T1G3 bladder cancer (BC). Patients and Methods: This retrospective study included 107 patients with newly diagnosed primary T1G3 BC who were treated by transurethral resection (TUR) plus intravesical instillation. The BCG group was administered BCG-RIVM (2×108 colony forming unit) instilled once weekly for 6 weeks, or the same regimen as induction therapy followed by three once-weekly instillations at 3, 6, 12 and 18 months after initiation of the induction therapy. The MMC group was administered MMC (30 mg) in six weekly instillations, or the same regimen with subsequent monthly instillations for one year. We evaluated differences between these agents in disease recurrence-free survival and disease progression rate at the time of recurrence. Results: The mean observation period was 24.3±28.6 months. The BCG and MMC groups comprised 53 patients (49.5%) and 54 patients (50.5%), respectively. During the observation period, recurrences developed in 61 patients (57.0%). The median time to recurrence for the BCG and MMC arm were 24.0 and 26.0 months, respectively. There were no significant differences for recurrence-free survival between the two groups (log-rank p=0.616). At the time of recurrence, 9.4% (5 out of 53) of patients in the BCG arm and 7.4% (4 out of 54) patients in the MMC arm also experienced by disease progression (p=1.000). Conclusion: There were no statistically significant differences regarding recurrence and disease progression rate at the time of recurrence between the two adjuvant treatments in primary T1G3 BC. Thus, large prospective studies in Asian population are required.

• Bladder carcinoma
• instillation therapy
• bacillus Calmette-Guerin
• mitomycin-C

Bladder cancer (BC) presenting as T1 grade 3 (T1G3) non-muscle invasive lesion carries a high risk due to the possibility of recurrence and invasive or metastatic progression to muscle (1-3). Transurethral resection (TUR) followed by adjuvant intravesical chemotherapy or immunotherapy is the treatment of choice of T1 high-grade BC. T1G3 BC is classified as a high-risk tumor and some authors support immediate radical cystectomy due to the high tendency of this tumor to progress (4, 5). However, although cystectomy may provide the best opportunity for cancer eradication and cure, the procedure is associated with non-negligible intraoperative mortality, significant postoperative-related morbidity, and impairment of patients' quality of life (6).

There are a number of immunological agents and several chemotherapeutics that have been administered intravesically for the management of nonmuscle-invasive BC. Intravesical adjuvant therapy with mitomycin C (MMC) or bacillus Calmette-Guerin (BCG) after TUR is a standard therapy for patients with intermediate- or high-risk nonmuscle-invasive BC (7, 8). The choice between chemotherapy and immunotherapy largely depends on the main concern: recurrence or progression. BCG has demonstrated proven efficacy in preventing disease recurrence. Chemotherapeutic agents such as mitomycin and doxorubicin are also effective in this setting, although equivalence to BCG has not been demonstrated (9). However, in some studies, maintenance therapy with BCG is required to clearly demonstrate the superiority of BCG (10, 11) and long-term MMC appears to be superior to short-term BCG (12). Randomized trials reported no significant difference in disease progression or survival between BCG and MMC, although one meta-analysis reported that BCG was more active than MMC in the prevention of disease progression (13). However, a recent meta-analysis of individual patient data, which had a longer follow-up than previously published meta-analyses, indicated that there was no significant difference in terms of disease progression (10). All studies that have reported toxicity indicated that it is more severe with BCG, and intravesical BCG has been linked with very serious side-effects in a small number of patients. Therefore, there is a clear need to establish the most appropriate agent in the treatment of individualized BC subgroups.

We retrospectively compared the efficacy of BCG and MMC intravesical instillations for primary T1G3 BC in a cohort of single-racial Korean patients. To our knowledge, this is the first study comparing intravesical BCG and MMC in terms of tumor recurrence and disease progression in T1G3 BC in Asian with such a large number of patients and such a long follow-up period.

Patients and Methods

Study population. The study protocol was approved by the Institutional Review Board of the Korean National Cancer Center. From March 2001 to December 2011, 138 selected patients affected by T1G3 BC were treated by TUR and were followed-up through April 2011. The definition of primary T1G3 BC was those BC diagnosed with pT1G3 disease at the first presentation of bladder cancer. After review of our BC database, patients with non primary T1G3 BC and/or with carcinoma in situ (Cis) were excluded. Patients who underwent immediate cystectomy due to concern regarding progression to muscle-invasive BC were also excluded. Other exclusion criteria were previous pelvic radiotherapy or chemotherapy, chronic urinary tract infection, and the presence of another type of cancer. After thorough pathology review, the diagnosis of T1G3 BC was confirmed when the proper muscle layer was clearly visible and free of tumor. All hematoxylin-eosin-stained sections were examined by a single pathologist (W.S.P), who was blind to the clinical outcome, to determine the grade and stage according to the 1997 TNM staging system and the 1998 WHO/ISUP classification. Double reading of grade and stage showed complete concordance. A total of 107 patients with primary T1G3 BC were enrolled in this study, of whom 86 (80.4%) were male. The median patient age was 65 years (range 37-90 years) and the mean observation period was 24.3±28.6 months.

Treatment and data collection. All patients were examined by cytology, cystoscopy, intravenous urography or computed tomography of the abdomen-pelvis, and complete TUR of the tumor and underlying muscular layer. TUR was performed with curative intent by multiple surgeons. As a rule, surgeons resected bladder tumors completely divided into three layers to the deep muscle with safe surrounding margin. A repeat TUR was performed in 25 patients (23.4%) at 2-6 weeks after initial surgery. Repeat TUR was performed in limited circumstances on a consistent basis. Indications for repeat TUR were lack of muscularis propria in initial TUR specimens, suspicion of residual tumor and referral after initial TUR had been carried out elsewhere.

In 36 patients, p53 and Ki-67 immunohistochemical staining of TUR specimen was performed. Our detailed method of staining was described in a prior study (14). All slides for p53 and Ki-67 were evaluated by the same pathologist (W.S.P). Only the nuclear staining result was used to interpret positivity for p53 and Ki-67. All reactive nuclei were considered positive, irrespective of their intensity (15-16).

We presented BCG and MMC instillation to the patients as an adjuvant treatment option. After the description of advantages and disadvantages of these two agents, patients who preferred efficacy of treatment underwent BCG instillation and patients who expressed concern at treatment complications underwent MMC instillation. The BCG group were administered BCG-RIVM [2×108 colony-forming units (CFU)] that was intravesically instilled once weekly for six weeks, or the same regimen as induction therapy followed by three once-weekly instillations at 3, 6, 12 and 18 months after initiation of the induction therapy. The MMC group was administered MMC (30 mg) in six weekly instillations or the same regimen with subsequent monthly instillations for one year. During surveillance, cystoscopy and urinary cytology were performed at three-month intervals in the first two years, at six-month intervals in the next three years and annually thereafter. Intravenous urography or computed tomography was performed at bladder tumor diagnosis and repeated every year.

Statistical analysis. We evaluated differences between these agents in disease recurrence-free survival (RFS) and disease progression rate at the time of recurrence. Recurrence was defined as the reappearance of a biopsy-proven lesion, and progression as the development of muscle-invasive disease or metastasis. The interval to recurrence was calculated from the performance of TUR to the first pathologically confirmed recurrence or the last follow-up visit. Patients who had died while free of disease or who were lost to follow-up before recurrence were censored at the point of death or the last follow-up date.

For statistical analysis, Fisher's exact test and chi-square test were used to evaluate the association between categorical variables. The Kaplan-Meier method was used to calculate RFS, and differences were evaluated with the log-rank test. For the analyses of disease progression rate at the time of recurrence, the chi-square test using 2×2 table was used. The result was considered significant if the two-sided p-value was <0.05. SPSS® for Windows®, version 12.0 (SPSS Inc. Chicago, IL, USA) was used for statistical analysis with two-sided p<0.05 considered significant.

Results

Instillation agents and other clinicopathological factors. Fifty-three patients (49.5%) belonged to the BCG group, and 54 (50.5%) belonged to the MMC group. The BCG group was consisted of 26 patients (49.0% of BCG group) with induction therapy only and 27 patients (51.0% of the BCG group) with maintenance therapy. The MMC group consisted of 29 patients (53.7% of the MMC group) with six week therapy only and 25 patients (46.3% of the MMC group) with one year therapy. The two groups did not differ in the percentage on each treatment protocol (chi-square test, p=0.700). Twenty-three patients (25.8%) had a pathology of lymphovascular invasion. Altered expressions were noted for p53 (77.8%) and for Ki-67 (83.3%) (out of 36 cases studied). No significant difference was found between the two intravesical agents in relation to clinicopathological factors (Table I).

BCG vs. MMC on recurrence. Disease recurrence developed in 61 patients (57.0%). During follow-up, none of the patients had a discontinuation of therapy due to adverse events. The median time to recurrence was 24.0 months for the BCG group and 26.0 months for the MMC group. The overall two-year RFS rates were 45.7% for the BCG group and 52.1% for the MMC group. The log-rank test showed no significant differences between the two groups (log-rank test, p=0.616). The Kaplan-Meier estimates are graphically presented in Figure 1.

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Table I.

Patients' characteristics.

Progression at the time of recurrence. Fifty four percent (29 out of 53) of patients in the BCG group and 59% (32 out of 54) of patients in the MMC group had disease recurrence. Of these, in 17.2% (5 out of 29) of patients in the BCG arm and 12.5% (4 out of 32) of patients in the MMC arm, recurrence was accompanied by disease progression (p=0.731). Considering these cases in regard to cases overall, 9.4% (5 out of 53) of patients in the BCG arm and 7.4% (4 out of 54) of patients in the MMC arm experienced recurrence with disease progression (p=1.000). No difference was noted in the progression rate at the time of recurrence between the BCG and MMC groups (Figure 2).

Discussion

Although a tumor of T1G3 is a nonmuscle-invasive bladder tumor, it harbors the potential for high recurrence and progression. It was estimated that the 3-year recurrence rate is 80% and progression to muscle-invasive disease is 35%-48% (17). Cystectomy has been advocated for years as the treatment option for this category of tumors (18). However, the patient's quality of life is important. Prior to cystectomy, we have tried to be meticulous in our use of TUR and adjuvant intravesical instillation. In particular, the selection of effective bladder instillation agents is very important. Although the effect of adjuvant intravesical MMC in preventing recurrence after TUR is well established, its efficacy in preventing progression has not been demonstrated. Moreover, the role of BCG in preventing progression and death from high risk nonmuscle-invasive BC has not been conclusively proven due to the conflicting results obtained by different studies (17, 19, 20).

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Figure 1.

Recurrence-free survival curves according to the instillation agent used.

In the current study, we compared the efficacy of BCG and MMC treatments in a Korean population with primary T1G3 BC. None of the patients had received previous intravesical therapy. In both group, similar recurrence rates were found. The 2-year recurrence-free rates were 45.7% for the BCG group and 52.1% for the MMC group. No difference was found in the progression rate at the time of recurrence between the two groups. This is an interesting finding because it suggests an equal efficacy of BCG and MMC for high-risk BC. In patients with high-risk BC, the superiority of BCG compared with intravesical chemotherapy is well accepted. Several authors favor BCG over MMC in high-risk nonmuscle-invasive BC. One study reported a significant advantage for BCG regarding tumor recurrence in patients with high-risk bladder, including Cis, pT1G3, and recurrent tumors (21). These results were confirmed in another study that reported a significantly better recurrence-free survival in patients with recurrent BC (22). On the basis of these data, BCG has become the treatment of choice for grade 3 and high-risk BC. It should be pointed out, however, that these data were not homogeneous for high-risk nonmuscle-invasive tumors. BCG adjuvant therapy is more efficacious only when it is applied with a scheme that includes induction followed by three years of maintenance, as demonstrated in a trial (23) in which a significant difference was evident in terms of RFS and progression-free survival. A meta-analysis revealed that prior chemotherapy treatment in patients enrolled in a chemotherapy treatment biased results in favour of BCG (24). Once the data were stratified according to the presence or absence of prior drug treatment, intravesical chemotherapy showed a 21%-82% greater reduction in tumor recurrence at 1, 2, and 3 years than did BCG. In addition, bearing in mind that MMC and alternative adjuvant treatments have fewer systemic and local side-effects than BCG, this would mean that MMC should be considered an alternative choice for high-risk BC (11). Optimal therapy of T1G3 BC still remains a matter of controversy.

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Figure 2.

Progression rate at the time of recurrence.

Articles about T1G3 BC in Asians are rare. Moreover, data focused on the pure primary high risk non-muscle-invasive BC are more lacking. As far as we know, this is first study to compare intravesical treatments in primary T1G3 BC in Asians. In the present study, the recurrence rate of T1G3 BC during the 2-year follow-up was about 50% when only patients with a histologically confirmed muscle layer in the TUR specimens were analyzed. At the time of recurrence, about 8% of all patients also experienced disease progression. Previous studies reported similar results (20, 21). However, in this study, BCG was not superior to MMC. This could have been due to a variety of reasons; the small number of participants may be one.

However, another possibility is worth mentioning. In 2005, South Korea ranked the highest in tuberculosis (TB) incidence among members of the Organization for Economic Cooperation and Development (OECD). The active-TB incidence rate per 100,000 individuals in South Korea was 87, which was well above the average incidence rate of 17.7 in OECD member countries (25, 26). TB bacteria are typically controlled by the immune system after infection, and the infection becomes active when the bacteria spread out of control. Approximately 30% of individuals who come into contact with an active-TB patient become infected, and about 10% of these infected individuals develop active-TB. Thus, a large number of patients will carry deactivated tuberculosis bacteria (25, 26). Intravesical BCG is arguably the most effective immunotherapy for BC. Based on its well-defined activity as an immune adjuvant, BCG has long been hypothesized to exert antitumor activity by helping to generate a tumor-specific immune response, which in turn eliminates tumor (27). However, the relevance of any direct effect on tumor cells with molecular changes that may affect drug sensitivity and the relevance to sensitivity of immune modulation is still unknown. Korea's high incidence of TB could be have implications for the results of this study. Furthermore, this study targeted patients in a homogenous country. The study populations were native Korean. Racial, ethnic, and environmental differences may also have affected the efficacy of the two agents.

Certain limitations must be considered when conclusions are drawn from our results. Firstly, this study has relatively even number of patients in each subgroup but is not a randomized trial. In counseling with patients, after a description of advantages and disadvantages of these two agents, patients who preferred the efficacy of treatment underwent BCG instillation and patients who were concerned with the complication of treatment underwent MMC instillation. This consultation could have lead to selection bias. Secondly, we did not analyze progression-free survival. All the patients that experienced BCG or MMC treatment failure underwent a second-line intravesical instillation or a cystectomy. This was an unavoidable limitation. From a different perspective, it could be an advantage of this study due to the sincerity of data that avoid the crossover. A third limitation was that a repeat TUR was performed selectively, introducing a risk of understaging. However, our standard procedure required that initial TUR be performed aggressively to obtain enough of muscle tissue. The goal of repeat TUR was to provide a wide resection margin and deep tumor removal to achieve complete resection of suspected residual tumor. Repeat TUR was only carried out in cases without muscularis propria in initial TUR specimens with a suspicion of residual tumor and in cases referred after initial TUR was done elsewhere. Thus, we believe that the risk of understaging was minimized.

In conclusion, the present study showed that there were no statistically significant differences regarding recurrence and disease progression rate at the time of recurrence between the BCG and MMC treatments in primary T1G3 BC of a Korean population.

Acknowledgements

This study was supported by a Korean National Cancer Center Grant, No. 1010850.

Footnotes

• Competing Interests

  The Authors declare they have no competing interests.

• Author's Contribution

  ICC, JYJ, and, KHL conceived the study, managed data, carried out statistical analysis, and coordinated the study; EKK and WSP collected and managed required data; HKS and JC collected required data and participated in writing the paper. All Authors read and approved the manuscript.

• Received February 16, 2012.
• Revision received March 12, 2012.
• Accepted March 13, 2012.

• Copyright© 2012 International Institute of Anticancer Research (Dr. John G. Delinassios), All rights reserved

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Anticancer Research Vol. 32, Issue 4 April 2012

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