Japanese Journal of Clinical Oncology 34:202-205 (2004)
© 2004 Foundation for Promotion of Cancer Research
15-Year Experience on Intravesical Therapy of T1G3 Urinary Bladder Cancer: a Conservative Approach
1 Department of Surgery and 2 Department of Anatomical and Cellular Pathology, Chinese University of Hong Kong, Prince of Wales Hospital, Hong Kong, China
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ABSTRACT |
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 TOP ABSTRACT INTRODUCTIONSUBJECTS AND METHODSRESULTSDISCUSSIONAcknowledgmentREFERENCES |
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Objective: To report the recurrence, progression and survival in patients with T1G3 transitional cell carcinoma (TCC) of the urinary bladder treated with sequential intravesical bacillus Calmette–Guérin (BCG) and chemotherapeutic agents (doxorubicin or epirubicin) on long-term follow up.
Methods: Between July 1988 and September 1999, all patients in a single center with T1G3 bladder TCC, after complete transurethral resection (TURBT), received either 81 mg of Connaught strain BCG or 50 mg of doxorubicin or epirubicin as adjuvant therapy. A conservative approach was adopted whereby those with superficial recurrences were eligible to crossover, even repeatedly, until progression to muscle invasion. Recurrence, progression and disease-specific survival were analyzed.
Results: There were 36 patients included, with 26 males and 10 females. The mean age was 71.6 years (range 53–85 years). Final analysis was made at a median follow-up of 23.5 months (range 0–125 months) for recurrence, 33 months (range 0–125 months) for progression and 45.5 months (range 3–125 months) for survival. Sixteen (44.4%) patients showed recurrence. Nine (25%) of these 16 patients progressed. Five (13.9%) of those who progressed died of TCC. The 10 year Kaplan–Meier estimates for recurrence-free survival, progression-free survival and disease-specific survival were 48, 68 and 81%, respectively. Figures with this conservative approach were comparable to those with more aggressive approaches reported in the literature.
Conclusions: Adjuvant intravesical therapy with either BCG or a chemotherapeutic agent (doxorubicin or epirubicin) and crossover on recurrence was an effective conservative treatment for T1G3 bladder TCC.
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INTRODUCTION |
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TOPABSTRACTINTRODUCTIONSUBJECTS AND METHODSRESULTSDISCUSSIONAcknowledgmentREFERENCES |
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T1G3 tumors, although classified as superficial bladder cancer, behave aggressively. These tumors, if treated by transurethral resection (TURBT) alone, frequently progress. Early cystectomy is recommended by some urologists and adjuvant bacillus Calmette–Guérin (BCG) by others. When recurrence occurs after the first course of BCG, some urologists will choose to give a second course, although others will suggest that more than two courses may risk disease progression.
In our institute, we adopted a conservative approach for T1G3 bladder transitional cell carcinoma (TCC). After complete TURBT, BCG or a chemotherapeutic agent was given as adjuvant therapy. Superficial recurrences were eligible to crossover, even repeatedly, until progression to muscle invasion occurred. We report our experience on recurrence, progression and survival with this group of patients.
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SUBJECTS AND METHODS |
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TOPABSTRACTINTRODUCTIONSUBJECTS AND METHODSRESULTSDISCUSSIONAcknowledgmentREFERENCES |
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All patients with T1G3 bladder TCC newly diagnosed between July 1988 and September 1999 in the Prince of Wales Hospital were reviewed retrospectively. All patients gave informed consent for TURBT and adjuvant therapy. After complete resection of all visible tumors, the patients received either 81 mg of Connaught strain BCG or a chemotherapeutic agent as adjuvant therapy. There was no specific protocol for allocation of BCG or chemotherapeutic agent in this group of patients. Doxorubicin was used as the chemotherapeutic agent before September 1991 and epirubicin afterwards. The first instillation was administered 2 weeks after the TURBT.
An 81 mg dose of Connaught strain BCG, corresponding to (6.6–19.2) x 108 colony-forming units, diluted with 50 ml of saline, was administered intravesically and retained for 2 h. Percutaneous BCG was not given. The treatment was given as an induction course weekly for 6 weeks and then a maintenance course monthly for 10 months. For doxorubicin or epirubicin, 50 mg of either agent diluted with 50 ml of saline was administered intravesically and retained for 2 h. The treatment was given weekly for 4 weeks, monthly for 5 months and then 3-monthly for 6 months.
Patients were evaluated with cystoscopy every 3 months for 2 years and then urine cytology every 6 months. Cystoscopy, biopsy and TURBT were carried out if necessary. A conservative approach was adopted whereby those with superficial recurrences, after complete TURBT, were eligible to crossover to the other intravesical agent, even repeatedly, until progression to muscle invasion occurred.
At the time of final evaluation, follow-up information was obtained from patient records, patient or family contact and through information available at the tumor registry of our hospital. Moreover, patients were called back for cystoscopy if none had been done in the past year.
The time to first recurrence, time to progression and disease-specific survival were analyzed. Recurrence was defined as histologically proven recurrence. Progression was considered as stage T2 disease or above, positive lymph node or distant metastasis. Disease-specific death was defined as death due to bladder TCC. Recurrence-free interval, progression-free interval and patient survival were defined as the time from TURBT to the end point (recurrence, progression, death or censored). Toxicity was not recorded in this study.
The Kaplan–Meier method was used to calculate the survival curves. The Cox proportional hazards model was used for multivariate analysis to assess the influence of several variables (initial adjuvant treatment, patient and tumor characteristics) on the survival curves.
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RESULTS |
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TOPABSTRACTINTRODUCTIONSUBJECTS AND METHODSRESULTSDISCUSSIONAcknowledgmentREFERENCES |
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There were 36 patients included, with 26 males and 10 females. The mean age was 71.6 years (range 53–85 years). Six patients harbored tumors up to 1 cm, 16 had tumors ranging from 1.1 to 3 cm, 10 had tumors larger than 3 cm and four had the sizes of their tumors unspecified. Twenty patients had solitary tumors and 16 had multiple tumors. BCG was used as the initial adjuvant therapy in 18, doxorubicin in five and epirubicin in 13 patients.
Final analysis of treatment results was made at a median follow-up of 23.5 months (range 0–125 months) for time to first recurrence, 33 months (range 0–125 months) for time to progression and 45.5 months (range 3–125 months) for duration of survival. Of the eight patients called back for cystoscopy, none was found to be harboring asymptomatic tumor.
Sixteen (44.4% of a total of 36) patients showed recurrence. The median time to the first recurrence was 6.5 months (range 3–40 months). The 10 year Kaplan–Meier estimate for recurrence-free survival was 48% (Fig. 1). Of these 16 patients, six did not receive any additional course of intravesical therapy, nine received one more course of intravesical therapy and one patient received two additional courses.
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Progression occurred in nine (25% of a total of 36) of those 16 patients who showed recurrence. The median time to progression was 17 months (range 4–38 months). The 10 year Kaplan–Meier estimate for progression-free survival was 68% (Fig. 2). The first sites of progression were the bladder muscle in six, lymph nodes in one and distant metastases in two patients. Three (8.3% of a total of 36) and one (2.8% of a total of 36) of those showing progression received cystectomy and radiotherapy, respectively.
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For these nine patients with progression, three progressed without prior superficial recurrence, five progressed after one local recurrence (one recurred as T1G2, two recurred as T1G3 and two had their stage and grade of recurrences unspecified) and one progressed after two recurrences (first as T1G3 then as TaG3).
Five (13.9% of a total of 36) and three (8.3% of a total of 36) of those who progressed died of bladder TCC and other unrelated causes, respectively. One patient who progressed was still alive 44 months after the initial TURBT and 34 months after cystectomy for muscle invasion. Ten (27.8% of a total of 36) patients with no evidence of progression of disease died of causes unrelated to bladder TCC. The 10 year Kaplan–Meier estimates for disease-specific survival (Fig. 3) and overall survival were 81 and 46%, respectively.
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With the Cox proportional hazards model, the initial adjuvant treatment (BCG versus chemotherapeutic agent), gender, age, tumor size and tumor number did not correlate with time to first recurrence, time to progression and disease-specific survival. Only age correlated with overall survival.
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DISCUSSION |
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TOPABSTRACTINTRODUCTIONSUBJECTS AND METHODSRESULTSDISCUSSIONAcknowledgmentREFERENCES |
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T1G3 tumors if treated with TURBT alone would progress in 40% of cases (1). Early cystectomy was employed by some urologists (2–5) and adjuvant BCG by others (6–9). Even if adjuvant BCG was used, most would recommend cystectomy for recurrent disease (8). Some would still choose to give a second course of BCG (9), although others suggested that more than two courses might risk disease progression (10). Moreover, prospective randomized trials had showed the superiority of BCG over intravesical chemotherapy for recurrence and progression in superficial bladder TCC (11–13). Regarding T1G3 tumors, van der Meijden et al. (14) showed that BCG prolonged time to recurrence but not time to progression when compared with epirubicin.
In our institute, we adopted an even more conservative approach for T1G3 bladder TCC and employed adjuvant BCG or chemotherapeutic agents. Moreover, crossover was also allowed for recurrent disease until progression occurred. The conservative approach saves the patients with T1G3 tumors from radical therapies and their possible associated complications, but renders them a life-long risk of progression of and death from bladder cancer and confers on them the need of life-long surveillance of the lower urinary tract. The purpose of this review was to compare our results with those from more aggressive approaches reported in the literature.
Patard et al. (15) reviewed recent studies up to 2000 regarding T1G3 tumors treated with adjuvant BCG and found recurrence, progression and disease-specific survival rates of 25–74%, 7.7–52% and 69–100%, respectively. A review of the literature up to 2003 found five more studies involving T1G3 tumors treated with adjuvant BCG (14, 16–19). The corresponding figures were 28–70%, 3–33% and 77–98%, respectively. Our figures for recurrence, progression and disease-specific survival rates are 44.4, 25 and 86.1%, respectively, and are hence comparable to those for T1G3 tumors treated with adjuvant BCG reported in the literature, although we were using an even more conservative approach of adjuvant intravesical therapy. Our 10 year Kaplan–Meier estimates for recurrence-free survival, progression-free survival and disease-specific survival were 48, 68 and 81%, respectively.
Our small sample size and the large number of deaths due to causes other than bladder cancer will affect the disease-specific survival and may contribute to the failure to identify a statistically significant independent variable for that. However, here lies the message that many patients with T1G3 tumors will die with or without bladder cancer rather than die of bladder cancer and will save unnecessary radical cystectomy or radiotherapy and the possible associated complications if a conservative policy such as ours is adopted.
Our figures are also comparable to those for T1G3 tumors treated with cystectomy reported in the literature. In the same review, Patard et al. (15) found that disease-specific survival after cystectomy oscillated between 61.5 and 90%. As mentioned above, our disease-specific survival rate and 10 year Kaplan–Meier estimate for disease-specific survival were 86.1 and 81%, respectively.
Sequential epirubicin and BCG were also employed by Bono et al. (20), but for primary T1G3 tumors, rather than crossover on recurrence as in our series. With a mean follow-up of 48 months, they reported a recurrence rate of 23.4%, a progression rate of 7.4% and a disease-specific survival rate of 95%, which were superior to our corresponding figures.
We conclude from our data that adjuvant intravesical therapy with either BCG or a chemotherapeutic agent (doxorubicin or epirubicin) and crossover on recurrence is an effective conservative treatment for T1G3 bladder TCC.
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Acknowledgment |
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TOPABSTRACTINTRODUCTIONSUBJECTS AND METHODSRESULTSDISCUSSIONAcknowledgmentREFERENCES |
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We are indebted to the Lithotripsy and Urodynamics Center of the Prince of Wales Hospital for their invaluable assistance with patient contact and arrangement of cystoscopic surveillance.
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FOOTNOTES |
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+ For reprints and all correspondence: Chi Wai Cheng, Department of Surgery, Chinese University of Hong Kong, Prince of Wales Hospital, Hong Kong, China. E-mail: drmcheng{at}hotmail.com
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TOPABSTRACTINTRODUCTIONSUBJECTS AND METHODSRESULTSDISCUSSIONAcknowledgmentREFERENCES |
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Received November 21, 2003; accepted January 27, 2004
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