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Keywords:

  • bladder neoplasms;
  • carcinoma in situ;
  • histology;
  • intravesical therapy

Abstract

  1. Top of page
  2. Abstract
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. Conclusion
  8. References

Abstract Background: To elucidate the most efficient topical therapy for carcinoma in situ of the bladder, the efficacy of intravesical mitomycin C plus doxorubicin therapy was compared with bacillus Calmette-Guerin (BCG) therapy. The clinical behavior of the tumor was analysed according to the histological grade.

Methods: Forty-two patients with carcinoma in situ of the bladder were randomized to intravesical BCG (21 patients) or mitomycin C plus doxorubicin sequential therapy (21 patients) as first line treatment. The non-responders underwent the subsequent instillation of the other intravesical therapy alternately. Of the patients, 27 had grade 2 and 15 had grade 3 cancer.

Results: Both topical therapies were equally effective with initial response rates of 86% (18/21) for BCG and 81% (17/21) for mitomycin C plus doxorubicin, irrespective of the tumor grade. Of seven initial non-responders, five patients achieved a complete response by subsequent instillation, resulting in a total response rate of 95%. After a mean follow-up of 47 months, five patients (12%) developed disease progression. The progression rates were not different between the topical therapies, but were significantly higher in grade 3 than in grade 2 cases.

Conclusion: It appears likely that mitomycin C plus doxorubicin instillation has an equivalent efficacy to BCG as the initial therapy of carcinoma in situ and the combination of them would be the most efficient tr eatment for the disease. Moreover, histological grading would be clinically useful in defining the tumor characteristics and behavior of carcinoma in situ of the bladder.


Introduction

  1. Top of page
  2. Abstract
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. Conclusion
  8. References

Bacillus Calmette-Guerin (BCG) is considered to be the most effective agent for the initial topical therapy of carcinoma in situ of the urinary bladder. It provides long-term protection from tumor recurrence and progression. However, the management of patients with refractory carcinoma in situ to BCG or those with recurrent disease after BCG therapy is still controversial.

We have previously reported the results of mitomycin C plus doxorubicin sequential instillation as first line therapy for patients with carcinoma in situ.1,2 In the current study we compared the efficacy of mitomycin C plus doxorubicin therapy with BCG therapy for carcinoma in situ. We also analysed the clinical behavior of carcinoma in situ according to the histological grade of the tumor to discover the most efficient and optimal topical therapy.

Methods

  1. Top of page
  2. Abstract
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. Conclusion
  8. References

Patients and histological grading

The subjects were 42 consecutive patients with transitional cell carcinoma in situ of the bladder. The therapy was randomized to the patients according to the histological grade of carcinoma in situ. Patients were recruited between January 1988 and December 1999. Of the patients 19 had primary carcinoma in situ with no history of bladder cancer and 23 had secondary carcinoma in situ with concomitant gross superficial (pT1 or less) bladder cancer.

The criteria used to define carcinoma in situ and the histological grades 2 and 3 disease were previously reported.2 Briefly, grade 2 carcinoma in situ was defined as a lesion with moderate compared to marked (grade 3) nuclear abnormalities. In grade 2 carcinoma in situ the nuclear size is rather uniform and smaller (10–15 μm) than that in grade 3 disease (15–20 μm or greater). Of the patients, 27 had grade 2 and 15 had grade 3 carcinoma in situ (Table 1).

Table 1.  Patient background and clinical outcomes according to the initial therapy
 Mitomycin C plus doxorubicin (n = 21)BCG (n = 21)P-value
  1. CR, complete response.

Patient background
Tumor type
Primary/ secondary12/97/14NS
Sex
Men/women17/417/4NS
Histological grade
Grade 2/grade 313/814/7NS
Median age (range)70 (48–87)72 (45–86)NS
Clinical outcomes
Initial CR (%)17 (81)18 (86)NS
CR by total topical therapies (%)21 (100)19 (90)NS
Recurrence after CR (%)11 (52)2 (11)0.003
Progression (%)2 (10)3 (14)NS
Cancer deaths (%)1 (5)2 (10)NS

Treatment protocol and follow up

Of the patients, 21 received intravesical BCG and 21 received intravesical mitomycin C plus doxorubicin sequential therapy as the first line treatment after transurethral resection of the tumor. The details of intravesical BCG and mitomycin C plus doxorubicin sequential therapy have been reported previously.1,2 The response was assessed within 2 months after topical instillation therapies. A complete response was defined as no evidence of residual carcinoma in situ on multiple mucosal biopsies and negative urine cytology for at least 4 weeks. Patients who did not achieve a complete response received a subsequent course of the other intravesical therapy. Total cystectomy was recommended to those patients who did not respond to the topical instillation therapies.

Follow-up examinations consisted of cystoscopy and urine cytology every 3 months and excretory urography every 12 months. Follow up ranged from 3 to 143 months (mean 47 months) at the last follow up in March 2000. The end-points of the study were progression of the disease, defined as occurrence of an invasive tumor (pT2 or more) or metastasis.

Statistical analysis

Statistical differences between the two groups were computed using the Mann–Whitney U-test with P < 0.05 considered significant.

Results

  1. Top of page
  2. Abstract
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. Conclusion
  8. References

After the initial instillation therapy, 17 of 21 patients (81%) achieved a complete response with mitomycin C plus doxorubicin compared to 18 of 21 (86%) receiving BCG (P = 0.68). All four non-responders to initial mitomycin C plus doxorubicin therapy achieved a complete response to subsequent BCG therapy. One of the three non-responders to initial BCG therapy achieved a complete response to subsequent mitomycin C plus doxorubicin. The other two patients developed a papillary tumor 2 months later and a lung metastasis 3 months later, respectively. Consequently, 40 of 42 patients (95%) achieved a complete response with total topical instillation therapies (Table 1). The response rates were not significantly different between grade 2 and 3 tumors (Table 2).

Table 2.  Clinical outcomes according to the histological grade of carcinoma in situ
 Grade 2 (n = 27)Grade 3 (n = 15)P-value
  1. CR, complete response; MA, mitomycin C plus doxorubicin sequential therapy.

Patient background
Tumor type
Primary/ secondary<8/1911/40.007
Sex
Men/women21/613/2NS
Median age (range)68 (45–87)73 (58–87)NS
Initial therapy
MA/BCG13/148/7NS
Clinical outcomes
Initial CR (%)
MA11 (85)6 (75)NS
BCG13 (93)5 (71)NS
Total24 (89)11 (73)NS
CR by total topical therapies (%)26 (96)14 (93)NS
Recurrence after CR (%)8 (31)5 (36)NS
Progression (%)1 (4)4 (27)0.029
Cancer deaths (%)03 (20)0.008

After a mean follow up of 47 months, local recurrence occurred in 13 patients (31%) and disease progression occurred in five (12%). Although the recurrence rates were significantly higher in those receiving mitomycin C plus doxorubicin therapy, the progression rates were not different between the two arms. However, the progression rates were significantly higher in grade 3 than in grade 2 cases (Tables 1,2). Of the patients with progression, four had grade 3 disease. Two of these patients achieved a complete response to initial BCG but developed invasive disease at 57 and 120 months, respectively and the former died of cancer. One patient did not respond to initial BCG therapy and developed a lung metastasis and died. The remaining one achieved a complete response to initial mitomycin C plus doxorubicin but developed pT3N1 disease 45 months later and died. One of the patients with grade 2 carcinoma in situ achieved a complete response to initial mitomycin C plus doxorubicin but developed pT4a disease 41 months later. Consequently, three patients (7%) died of cancer.

Discussion

  1. Top of page
  2. Abstract
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. Conclusion
  8. References

In the current study, mitomycin C plus doxorubicin sequential therapy showed an equivalent efficacy to BCG therapy for carcinoma in situ. These results agree with those of previous studies suggesting an overall complete response rate of 70–80% in patients with carcinoma in situ treated by BCG.3 Furthermore, all four patients who did not respond to initial mitomycin C plus doxorubicin achieved a complete response to subsequent BCG therapy and one patient who had failed initial BCG therapy achieved a complete response to subsequent mitomycin C plus doxorubicin. The total response rate was 95%. Although the recurrence rate was significantly higher in patients treated with mitomycin C plus doxorubicin than in the BCG arm, both therapies achieved favorable results with a rather low progression rate (overall 12%). Previous studies have suggested progression rates of 10–20% for carcinoma in situ patients with an initial complete response to BCG therapy.4,5

These findings are of great interest because the mechanism of action of these therapies differs. Bacillus Calmette-Guerin causes an immunological reaction, which is then strongly associated with cell apoptosis. Mitomycin C plus doxorubicin is a DNA damaging process that induces cell necrosis. So the combination of these two effective therapies with a different mechanism of action would be the most efficient and optimal treatment for carcinoma in situ of the bladder.

The clinical significance of histological grading of bladder carcinoma in situ has yet to be defined. We have already reported the grading criteria and their clinical significance: grade 2 carcinoma in situ appears to be a precursor of papillary high grade cancer, while grade 3 disease is a precursor of nodular cancer.2 As to a prognostic factor, the current results suggest that the histological grade is very important in defining disease progression in carcinoma in situ of the bladder. Several studies have shown that p53 accumulation is an important prognostic indicator of bladder cancer progression.6–8 However, others have reported that, in superficial gross bladder tumors, p53 accumulation is not associated with tumor progression and the grade is more substantial as a prognostic factor than the molecular markers in assessing the risk of progression.9–11 A larger scale study is needed to define whether histological grade or p53 accumulation are the only independent predictors of progression in carcinoma in situ. However, until a more significant indicator is detected and available in the routine clinical setting, the histological grade would be the most simple and clinically useful predictor of tumor development and progression in carcinoma in situ of the bladder.

Conclusion

  1. Top of page
  2. Abstract
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. Conclusion
  8. References

In conclusion, our results suggest that mitomycin C plus doxorubicin instillation is as effective as BCG as initial therapy for carcinoma in situ of the bladder. A combination of these therapies would be the most efficient and optimal treatment for the disease. Moreover, histological grading would be clinically useful in defining the tumor characteristics and behavior of carcinoma in situ of the bladder.

References

  1. Top of page
  2. Abstract
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. Conclusion
  8. References
  • 1
    Fukui I, Sekine H, Kihara K et al. Intravesical combination chemotherapy with mitomycin C and doxorubicin for carcinoma in situ of the bladder. J. Urol. 1989; 141: 5314.
  • 2
    Sekine H, Fukui I, Yamada T, Yamada T, Kojima S, Ohshima H. Histological grading of carcinoma in situ of the bladder: Its clinical significance in patients who underwent intravesical mitomycin C and doxorubicin sequential therapy. J. Urol. 1996; 155: 949.
  • 3
    Hudson MA & Herr HW. Carcinoma in situ of the bladder. J. Urol. 1995; 153: 56472.
  • 4
    Herr HW, Badalament RA, Amato DA et al. Superficial bladder cancer treated with bacillus Calmette-Guerin: a multivariate analysis of factors affecting tumor progression. J. Urol. 1989; 141: 229.
  • 5
    Harland SJ, Charig CR, Highman W, Parkinson MC, Riddle PR. Outcome in carcinoma in situ of bladder treated with intravesical bacille Calmette-Guerin. Br. J. Urol. 1992; 70: 2715.
  • 6
    Sarkis AS, Dalbagni G, Cordon-Cardo C et al. Nuclear overexpression of p53 protein in transitional cell bladder carcinoma: A marker for disease progression. J. Natl Cancer Inst. 1993; 85: 539.
  • 7
    Sarkis AS, Dalbagni G, Cordon-Cardo C et al. Association of p53 nuclear overexpression and tumor progression in carcinoma in situ of the bladder. J. Urol. 1994; 152: 38892.
  • 8
    Cordon-Cardo C, Dalbagni G, Saez GT et al. p53 mutations in human bladder cancer: Genotypic versus phenotypic patterns. Int. J. Cancer 1994; 56: 34753.
  • 9
    Underwood MA, Reeves J, Smith G et al. Over-expression of p53 and its significance for recurrent progressive bladder tumors. Br. J. Urol. 1996; 77: 65966.
  • 10
    Vollmer RT, Humphrey PA, Swanson PE, Wick MR, Hudson ML. Invasion of the bladder by transitional cell carcinoma: Its relation to histologic grade and expression of p53, MIB-1, c-erb B-2, epidermal growth factor, and bcl-2. Cancer 1998; 82: 71523.
  • 11
    Lipponen PK. Over-expression of the p53 nuclear oncoprotein in transitional cell carcinoma of the bladder and its prognostic value. Int. J. Cancer 1993; 53: 36570.