Jpn J Clin Oncol 2002;32(11)461 465 Clinical Study of G3 Superficial Bladder Cancer without Concomitant CIS Treated with Conservative Therapy Takashi Saika, Tomoyasu Tsushima, Yasutomo Nasu, Ryoji Arata, Haruki Kaku, Nobuyuki Kusaka and Hiromi Kumon Department of Urology, Okayama University Medical School, Okayama, Japan Received May 20, 2002; accepted August 21, 2002 INTRODUCTION 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. Key words: transitional cell carcinoma bladder superficial bladder cancer 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 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 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. 2002 Foundation for Promotion of Cancer Research
462 G3 superficial bladder cancer Table 1. Patients characteristics Age (years) 49 85 (median, 68.0) Gender Male 34 Female 5 Stage Ta 1 T1 38 Tumor number Solitary 16 Multiple 23 Tumor size <1 cm 5 1 3 cm 24 >3 cm 10 Tumor morphology Papillary pedunculated 14 Papillary sessile 14 Non-papillary pedunculated 2 Non-papillary sessile 9 PATIENTS AND METHODS 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 intraarterial 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. 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. RESULTS 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,
Jpn J Clin Oncol 2002;32(11) 463 Fig. 1. (a) Recurrence-free rate according to tumor grade. (b) Progression-free rate according to tumor grade. (c) Survival rate according to tumor grade. Progression-free and survival rates of patients with G3 did not show a statistically significant difference from those of patients with G1 or patients with G2 superficial bladder cancer. Only the rate of recurrence showed a statistically significant difference according to tumor grade (P = 0.006). multivariate analysis showed that tumor morphology has the strongest impact on progression (Table 2). DISCUSSION 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
464 G3 superficial bladder cancer Fig. 2. Recurrence-free rate according to adjuvant therapy. A statistically significant difference was recognized. IVC = intravesical chemotherapy. Fig. 3. Progression-free rate according to tumor morphology in G3 superficial cases. Patients with papillary tumor showed a higher progression-free rate than those with non-papillary tumor. Fig. 4. Survival according to tumor morphology in G3 superficial cases. Patients with non-papillary sessile tumor showed a lower survival rate than those with other tumor types. 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
Jpn J Clin Oncol 2002;32(11) 465 Table 2. Factors of recurrence, progression and prognosis in G3 superficial bladder cancer (P values) 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. References Recurrence Progression Prognosis Univariate analysis Age* 0.945 0.093 0.349 Tumor No. (multiple/solitary) 0.295 0.730 0.543 Tumor size (3 cm ) 0.544 0.667 0.877 Tumor size (5 cm ) 0.094 0.199 0.453 Tumor morphology (papillary/non-papillary) 0.181 0.0002 0.062 Tumor morphology (non-papillary sessile) 0.131 0.003 0.033 Adjuvant therapy 0.031 0.578 0.300 Multivariate analysis Tumor No. (multiple/solitary) 0.5094 0.1230 0.3164 Tumor size (5 cm ) 0.0999 0.1733 0.1082 Tumor morphology (non-papillary sessile) 0.9860 0.0447 0.1391 Adjuvant therapy 0.1180 0.8465 0.7818 Values in bold show statistical significance (P < 0.05). *Comparison was made between 65 years old or more and less than 65 years old. Comparison was made between 3 cm in diameter or more and less than 3 cm. Comparison was made between 5 cm in diameter or more and less than 5 cm. 1. Jakse G, Loidl W, Seeber G. Stage T1, grade 3 transitional cell carcinoma of the bladder: an unfavorable tumor? J Urol 1987;137:39 43. 2. Stockle M, Alken P, Engelmann U, Jacobi GH, Riedmiller H, Hohenfellner R. Radical cystectomy often too late? Eur Urol 1987;13:361 7. 3. Anderstrom C, Johansson S, Nilsson S. The significance of lamina propria invasion on the prognosis of patients with bladder tumours. J Urol 1980;124:23 36. 4. Malstrom P, Busch C, Norlen BJ. Recurrence, progression and survival in bladder cancer. Scand J Urol Nephrol 1987;21:185 95. 5. Bracken RB, McDonald MW, Johnson DE. Cystectomy for superficial bladder cancer. Urology 1981;18:459 63. 6. Cookson MS, Sarosdy MF. Management of stage T1 superficial bladder cancer with intravesical Bacillus Calmette-Guérin therapy. J Urol 1992;148:797 801. 7. Prout GR Jr, Griffin PP, Shipley WU. Bladder carcinoma as a systemic disease. Cancer 1979;43:2532 9. 8. Vincente J, Laguna LP, Duarte D, Algaba F, Chechile G. Carcinoma in situ as a prognostic factor for G3, pt1 bladder tumours. Br J Urol 1991;68:380 2. 9. Serretta V, Piazza S, Pavone C, Piazza B, Pavone-Macaluso M. Results of conservative treatment (transurethral resection plus adjuvant intravesical chemotherapy) in patients with primary T1, G3 transitional cell carcinoma of the bladder. Urology 1996;47:647 51. 10. Obama T, Matsumura Y, Ohmori H. Intravesical chemotherapy. Can Chem Pharm 1987;20(Suppl):60 2. 11. Tsushima T, Matsumura Y, Ozaki Y, Yoshimoto J, Ohmori H. Prophylatic intravesical instillation therapy with adriamycin and mitomycin C in patients with superficial bladder cancer. Can Chem Pharm 1987; 20(Suppl):72 6. 12. Matsumura Y, Tsuahima T, Ozaki Y, Yoshimoto J, Akagi T, Obama T, et al. Intravesical chemotherapy with 4 -epi-adriamycin in patients with superficial bladder tumors. Can Chem Pharm 1986;16:176 7. 13. Esring D, Treeman JA, Stein JP, Skinner DG. Early cystectomy for clinical stage T1 transitional cell carcinoma of the bladder. Semin Urol Oncol 1997;15:154 60. 14. Kakizoe T, Tobisu M, Mizutani T. An analysis by step sectioning of early invasive bladder cancer with superficial reference to G3, pt1 disease. Jpn J Cancer Res 1992;83:1354 8. 15. Van Brussel JP, Mickisch GH. Prognostic factors in renal cell and bladder cancer. Br J Urol 1999;83:902 8. 16. Llopis J, Alcaraz A, Ribal MJ, Sole M, Ventura PJ, Barranco MA, et al. p53 expression predicts progression and poor survival in T1 bladder tumours. Eur Urol 2000;37:644 53. 17. Steiner G, Bierhoff E, Schmidt D, Leissner J, Wolf HK, Albers P. p53 immunoreactivity in biopsy specimens of T1G3 transitional cell carcinoma of the bladder a helpful parameter in guiding the decision for or against cystectomy? Eur J Cancer 2000;36:610 4. 18. Ghoji K, Nomi M, Okamoto M, Takenaka A, Hara I, Okada H, et al. Conservative therapy for stage T1b, grade 3 transitional cell carcinoma of the bladder. Urology 1999;53:308 13.