Japanese Journal of Clinical Oncology 32:461-465 (2002)
© 2002 Foundation for Promotion of Cancer Research
Clinical Study of G3 Superficial Bladder Cancer without Concomitant CIS Treated with Conservative Therapy
Department of Urology, Okayama University Medical School, Okayama, Japan
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ABSTRACT |
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 TOP ABSTRACT INTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONREFERENCES |
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Objective: The treatment for superficial G3 transitional cell carcinoma (TCC) of the urinary bladder remains controversial. It is important to reveal the clinical features of superficial G3 bladder cancer that can be treated conservatively.
Patients and Methods: A total of 39 patients with primary superficial bladder cancer (Ta, T1) with G3 components but without concomitant carcinoma in situ (CIS), who had been treated initially with transurethral resection (TUR), were retrospectively analyzed for factors related to tumor recurrence, progression and survival. The patients were 34 males and five females whose age ranged from 49 to 85 years (average, 68 years). Initial tumor stages were Ta in one patient and T1 in 38. Initial treatments were TUR alone in 18 patients and TUR with adjuvant therapy (intravesical chemotherapy or BCG therapy) in 21. Factors examined included age, gender, morphology, size and number of tumors and adjuvant therapies.
Results: Follow-up periods were 3–138 months (median, 37 months). Tumor recurrence, progression and cancer death were observed in 23, seven and four cases, respectively. The 5-year progression-free rate (75%) and survival rate (83%) in 39 patients with G3 did not show a statistically significant difference from those of the 109 patients with G1 or the 187 patients with G2 superficial bladder cancer who were treated with TUR initially. Only the rate of recurrence of patients with G3 was significantly higher than that of patients with G2 or G1. Adjuvant therapies reduced the recurrence rate of the patients with G3. Only tumor morphology, papillary or non-papillary, affected both the progression-free rate and the survival rate of patients with G3. There were no statistically significant differences associated with other factors.
Conclusion: The results suggest that superficial G3 bladder cancer could be treated with TUR initially, especially for papillary tumors.
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INTRODUCTION |
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TOPABSTRACTINTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONREFERENCES |
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The treatment for superficial G3 transitional cell carcinoma (TCC) of the urinary bladder remains controversial. Jakse et al. (1) reported that ~50% of patients with T1 G3 TCC developed invasive cancer within 1 year after initial diagnosis. Stockle et al. (2) reported a 5-year survival rate of 90% for patients who had undergone radical cystectomy at diagnosis and 62% for patients who had undergone cystectomy after one or more recurrences. Anderstrom et al. (3) and Malmstrom et al. (4) also reported a survival advantage with early cystectomy. Although early cystectomy for superficial bladder cancer gives the patient a significant survival advantage, more than half of patients show no progression after the initial TUR. Bracken et al. (5) reported a 5-year survival rate of 88% in 29 patients who received a radical cystectomy after a median of two TURs. Since cystectomy at diagnosis may be an over-treatment for more than half of patients with superficial G3 cancers, several investigators have recommended conservative therapy (6,7). It has also been reported that the prognosis of patients treated by conservative therapy depends on the presence or absence of concomitant CIS (8,9). The value of revealing the clinical features of conservatively treated superficial G3 bladder cancer without concomitant CIS is clear. In this retrospective study, we evaluated clinical features, such as recurrence rate, progression rate, survival and clinical factors, of superficial G3 patients treated in our department.
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PATIENTS AND METHODS |
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TOPABSTRACTINTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONREFERENCES |
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Patients’ Characteristics
Between January 1961 and December 1998, 354 patients with superficial TCC of the bladder without concomitant carcinoma in situ (CIS) were initially treated by TUR. The staging accuracy, including confirmation of without concomitant CIS, was confirmed by histopathological findings on random biopsy of microscopically normal bladder mucosa (standard 7 lesion and around the tumor) and TUR specimens of tumor; repeat TURs were performed for patients who were suspected to have residual tumors. Fifty-eight of those patients had G3 components histopathologically; 109 bladder cancer patients with G1 component only [median age, 61years; 92 males and 17 females; stage, Ta 96 and T1 13; adjuvant intravesical chemotherapy (IVC) in 57] and 187 bladder cancer patients with G2 but no G3 components (median age, 65 years; 165 males and 22 females; stage, Ta 115 and T1 72; adjuvant IVC in 116) were treated by TUR in this period. These patients with G1/G2 superficial bladder cancer had not had any remarkable adjuvant therapies except IVC at the time of initial treatment. Partial cystectomies were performed in eight patients with superficial G3 bladder cancer during this period since they were diagnosed as having muscle-infiltrating disease. No total cystectomies were performed for superficial bladder cancer as initial therapy. Eleven patients with G3 bladder cancer were excluded from the analysis since they were treated by intra-arterial infusion chemotherapy or systemic chemotherapy as a neo-adjuvant therapy. Finally, 39 patients with superficial G3 bladder cancer but no concomitant CIS who had been treated by TUR initially were analyzed in this study. Details of the patients’ characteristics are shown in Table 1.
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Adjuvant Therapy
Doxorubicin-based IVC was performed in 17 patients as adjuvant therapy, according to our IVC protocols (10–12). Bacillus Calmette-Guérin (BCG) therapy was given to four patients postoperatively. No adjuvant therapy was given in 18 cases.
Follow-up
Cystoscopy was performed every 3 months for 2 years after TUR, then every 4 months from 2 to 3 years, every 6 months from 3 to 5 years and annually after 5 years. Urine cytology was examined at the time of cystoscopy. Intravenous pyelography, pelvic computed tomography and chest radiography were performed annually. The median follow-up period was 37 months (range, 3–138 months) after the initial TUR.
Statistical Analysis
Recurrence-free rate, progression-free rate and survival rate were determined using the Kaplan–Meier method and differences were evaluated by the log-rank test. As a statistical analysis of the factors at the time of initial treatment, multivariate analyses by Cox’s proportional hazards model were performed. P < 0.05 was considered statistically significant.
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RESULTS |
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TOPABSTRACTINTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONREFERENCES |
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Tumor recurrence was observed in 23 patients (58.9%). The mean interval between TUR and the first recurrence was 6.9 months (range, 2–40 months). During a median time of 15 months (range, 2–52 months) after the initial TUR, seven patients (17.9%) were recognized as having disease progression (muscle invasive recurrence or distant metastases) and five patients (12.8%) underwent radical cystectomy. Disease progression was recognized in four patients at first recurrence and one patient had distant metastasis without local recurrence. The average recurrence frequency to disease progression was 1.6 times. In summary, 74.3% of the patients have survived and are tumor free. Six patients died of other causes. Four patients (10.3%) died of bladder cancer at a median time of 50.6 months (range, 3–139 months); the 5-year survival rate was 83.3%. The progression-free and survival rates of the 39 patients with G3 did not show a statistically significant difference from those of the 109 patients with G1 or of the 187 patients with G2 superficial bladder cancer who were treated with TUR initially. Only the rate of recurrence of patients with G3 bladder cancer was significantly higher than that of patients with G2 or G1 bladder cancer (Fig. 1). Adjuvant therapy significantly reduced the recurrence rate (Fig. 2). There was a significant correlation between tumor morphology and both the progression-free and survival rates (Figs 3 and 4). In addition, multivariate analysis showed that tumor morphology has the strongest impact on progression (Table 2).
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DISCUSSION |
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TOPABSTRACTINTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONREFERENCES |
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Early radical cystectomy for superficial G3 cancer is indicated for several reasons (3–5,13,14). A significant proportion of these tumors will progress to muscle invasion and metastatic disease. Moreover, there are no established methods for detecting patients with highly malignant potential, although there are a number of reports demonstrating risk factors for progression, including tumor size, growth pattern, number of tumors, lymphovascular invasion, alteration of p53 and Rb, e-cadherin and epidermal growth factor (15–17). There also exists the possibility of staging error. Finally, in an era of nerve-sparing cystectomy combined with orthotopic bladder substitution, cystectomy has less of an impact on quality of life.
A conservative approach, however, is not unacceptable as a first-line treatment, since cystectomy is an over-treatment for a considerable number of patients with G3 cancer. Even with neobladder construction, radical cystectomy still creates a considerable burden for the patient. Our results showed that the disease progression rate 5 years from the first TUR was ~25%. If all patients receive early radical cystectomy, it may be unnecessary for 75% of them. There has been no randomized study demonstrating a clear difference in survival rate between those receiving immediate and those receiving delayed cystectomy, especially among patients with relatively favorable prognostic factors, such as absence of concomitant CIS. Therefore, we believe that immediate radical cystectomy should not be performed routinely for all patients with superficial G3 bladder cancer.
It is necessary to determine which patients with G3 cancer should be treated conservatively. In this study, we excluded patients with concomitant CIS, because this factor may have a significant influence on the disease outcome (8,9). Vincente et al. (8) reported that the 5-year cause-specific survival rate was 83% in patients without concomitant CIS, which is similar to our results; in patients with concomitant CIS, however, the survival rate was only 30%. It seems clear that G3 superficial cancer with concomitant CIS should be regarded differently from ‘superficial.’ Our study showed that among patients with superficial G3 bladder cancer but no concomitant CIS, the factor associated with tumor progression is tumor morphology, and conservative treatment is reasonable for G3 superficial cancer if the tumor morphology is papillary. Although several workers (6,7,18) have emphasized the effectiveness of BCG instillation therapy in patients with superficial G3 bladder cancer, the usefulness of the therapy could not be clarified since only four of our patients were treated with BCG as adjuvant therapy. Our analysis also revealed that intravesical chemotherapy provided effective recurrence control.
Next, the problem of staging error remains; however, we seldom suspected staging error in our patients with a careful staging procedure as described previously. Therefore, staging error did not become a problem in our study.
In conclusion, TUR was a successful initial treatment for primary superficial G3 bladder cancer without concomitant CIS, especially papillary tumors.
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FOOTNOTES |
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+ For reprints and all correspondence: Takashi Saika, Department of Urology, Okayama University Medical School, 2–5–1 Shikatacho, 700-8558 Okayama, Japan. E-mail: saika@iwa.att.ne.jp
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Received May 20, 2002; accepted August 21, 2002
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