Optimal Timing of Radical Cystectomy for Patients with Invasive Transitional Cell Carcinoma of the Bladder

Jpn J Clin Oncol 2002;32(1)14 18 Optimal Timing of Radical Cystectomy for Patients with Invasive Transitional Cell Carcinoma of the Bladder Isao Hara, Hideaki Miyake, Shoji Hara, Akinobu Gotoh, Hiroshi Okada, Soichi Arakawa and Sadao Kamidono Department of Urology, Kobe University School of Medicine, Kobe, Japan Received August 8, 2001; accepted October 4, 2001 Objective: To determine whether the timing of radical cystectomy affects the survival of patients with invasive transitional cell carcinoma (TCC) of the bladder. Methods: Between January 1985 and June 2000, 167 patients underwent radical cystectomy in our institution. Among them, 50 patients who did not receive any perioperative therapies, including chemotherapy and radiotherapy, were divided into two groups, viz. 28 patients who underwent radical cystectomy within 3 months after the primary diagnosis of invasive bladder cancer (group A) and 22 who underwent radical cystectomy more than 3 months after the primary diagnosis (group B), and we then compared several clinicopathological factors and the survival between these two groups. Results: No significant difference was observed in the patients clinicopathological characteristics except for age between these two groups. The median follow-up periods for groups A and B were 53 and 48 months, respectively. In groups A and B, an average of 1.2 (range 1 2) and 1.4 (range 1 3) transurethral resections (TURs) of bladder cancer were performed, respectively (p = 0.83). Twenty of 28 patients in group A underwent orthotopic neobladder replacement, whereas only four of 22 underwent neobladder creation (p = 0.001). The recurrence-free, cause-specific and overall survival rates in group A were significantly higher than those in group B (p < 0.05, p <0.05andp < 0.05, respectively). Final pathological analysis revealed that the distributions of pathological stage, tumor grade and lymph node metastasis were similar between groups A and B; however, the incidence of vascular involvement in group B was significantly higher than that in group A (p < 0.05), despite the lack of a significant difference in the incidence of vascular involvement in TUR specimens between these two groups. Conclusions: These findings suggest that radical cystectomy in the early disease process, especially before the occurrence of vascular involvement, may result in the improvement of survival of patients with invasive TCC of the bladder. Key words: invasive bladder cancer timing of radical cystectomy survival INTRODUCTION Radical cystectomy has evolved to be the gold standard treatment for muscle invasive bladder cancer with an overall 5-year disease-free survival rate of 50 70% (1 3). However, muscleinvasive TCC has an aggressive malignant phenotype that has been shown to have a high propensity for disease-recurrence (1 4). In fact, several studies have reported that recurrence develops in up to 50% of patients who are considered as undergoing curative surgery based on the findings of pathological examinations (1 4). Furthermore, to date, there have been no supportive perioperative therapies that significantly improve For reprints and all correspondence: Isao Hara, Department of Urology, Kobe University School of Medicine, 7 5 1 Kusunoki-cho, Chuo-ku, Kobe, 650-0017, Japan the survival of patients with invasive TCC (5 7). These findings suggest that the currently accepted therapeutic strategy for muscle-invasive TCC should be re-evaluated. Recently, several options, which affect the timing of radical cystectomy for invasive TCC, have been reported. For example, continent urinary diversions have been developed and offered to patients undergoing radical cystectomy (8), among which orthotopic neobladder has become the most favored form of urinary diversion, especially since the risk of surgical complications associated with these procedures has decreased with improved operative techniques and additional surgical experience (8,9). However, various problems caused by urinary diversion remain to be elucidated (8,9) and, therefore, the correct timing of cystectomy and the optimal kind of urinary diversion are still difficult challenges for both the urologist and patient. In 2002 Foundation for Promotion of Cancer Research

Jpn J Clin Oncol 2002;32(1) 15 Table 1. Patients characteristics Characteristic Group A (n =28) Group B (n =22) p-value Mean age (range) (years) 64.2 (54 76) 72.5 (59 84) <0.01 Gender (male/female) 23/5 19/3 NS Mean follow-up period (range) (months) 53.3 (8 79) 48.8 (8 66) NS Mean interval from diagnosis of invasive disease to cystectomy (range) (months) 1.9 (1.2 2.8) 3.6 (3.1 5.3) <0.05 Numbers of TUR (range) 1.2 (1 2) 1.4 (1 3) NS Clinical T stage (%) T2 27 (96) 21 (95) NS T3 1(4) 1(5) T4 0(0) 0(0) Clinical N stage (%) N0 28 (100) 21 (95) NS N1 or more 0(0) 1(5) Grade* (%) G1 0(0) 0(0) NS G2 4(14) 3 (14) G3 24 (86) 19 (86) Multiplicity (%) Single 9(32) 8 (36) NS Multiple 19 (68) 14 (64) Tumor size (%) <2 cm 13 (46) 11 (50) NS 2 cm 15 (54) 11 (50) Vascular involvement* (%) Negative 14 (50) 13 (59) NS Positive 14 (50) 9 (41) Type of urinary diversion Neobladder 20 (71) 4 (18) <0.001 Incontinent urinary diversion 8(29) 18 (82) *Determined based on the findings of initial transurethral resection (TUR). Not significant. addition, several studies have reported the strategies (10 13), including radical transurethral resection (TUR) plus systemic chemotherapy and intra-arterial chemotherapy plus radiation, for invasive disease in an attempt to preserve the bladder, but it is still unclear whether these options result in improved survival. In the present study, we analyzed the relationship between the interval from the diagnosis of invasive bladder cancer to radical cystectomy and survival in a homogeneous contemporary series of patients with adequate follow-up after treatment with radical cystectomy for invasive TCC of the bladder. PATIENTS AND METHODS Between January 1985 and June 2000, 167 patients with invasive TCC of the bladder underwent radical cystectomy, pelvic lymphadenectomy (bilateral iliac and obturator nodes dissection) and urinary diversion for invasive bladder cancer in our institution. Among them, 50 patients who did not receive any perioperative therapies, including chemotherapy and radiotherapy, were divided into two groups, viz. 28 patients who underwent radical cystectomy within 3 months after the primary diagnosis of invasive bladder cancer (group A) and 22 who underwent radical cystectomy more than 3 months after the primary diagnosis (group B). Bladder cancer was diagnosed by transurethral resection. Physical examination, laboratory studies, chest radiography and intravenous pyelogram (IVP) were performed in all patients. Computed tomography (CT), magnetic resonance imaging and/or abdominal ultrasonography were used for clinical staging. All pathological examinations were performed by a single pathologist. The tumor stage and grade were examined

16 Timing of radical cystectomy Table 2. Comparison of survival rates according to the 1997 TNM system and the World Health Organization system, respectively. Vascular involvement was defined only when cancer cells were detected in a thin-walled, endothelium-lined space consisting of blood and/or lymph vessels. We directed particular attention toward artefacts due to peritumoral edema and tissue shrinkage for the detection of vascular involvement. In our institution, concomitant urethrectomy was performed in patients with preoperative histologically confirmed bladder cancer of the urethra and/or prostate. When the patient was physiologically able to tolerate a major operation and perform the normal activities of daily life without compromise, it basically depended on the patient s decision whether orthotopic neobladder replacement or incontinent urinary diversion (ureterocutaneostomy or ileal conduit) was selected, except for one case, that is, neobladder was contraindicated only in patients with urethral involvement. The patients were initially seen 2 months after surgery and then every 3 months for 2 years and every 6 months until disease progression or death. Laboratory studies and urinary cytology were performed every 3 months and chest radiography, abdominal and/or pelvic CT and IVP were carried out every 6 months. For those patients who underwent neobladder replacement, neocystoscopy was performed every 12 months. All survival data were analyzed as the cause-specific survival by the Kaplan Meier technique using a log-rank test. The prognostic value for some parameters was determined by multivariate Cox regression models. The level of significance was set at p < 0.05. RESULTS Group A (year) Survival rate (%) Group B (year) 1 3 5 1 3 5 p-value Recurrence-free survival 86.9 86.9 86.9 72.2 52.5 52.5 <0.05 Cause-specific survival 91.4 86.9 86.9 85.2 58.6 52.5 <0.05 Overall survival 91.4 80.3 80.3 81.2 52.5 47.3 <0.05 In this series, 50 patients underwent radical cystectomy and pelvic lymphadenectomy, including simultaneous orthotopic neobladder replacement in 24 patients (ileal neobladder in one patient, ascending colon neobladder in six patients and sigmoid colon neobladder in 17 patients) and incontinent urinary diversionin26patients(ureterocutaneostomyinfourpatients and ileal conduit in 22 patients). We then divided them into two groups according to the timing of radical cystectomy as described above and the comparison between the patients characteristics of these two groups is summarized in Table 1. No significant difference was observed in the gender, the follow-up period, the number of previous TURs of bladder tumors, tumor size, multiplicity, the distribution of clinical T Table 3. Comparison of final pathological examination Pathological T stage (%) Group A (n =28) Group B (n =22) p-value T2 20 (75) 14 (64) NS T3 6(21) 6 (27) T4 1(4) 2(9) Pathological N stage (%) N0 27 (96) 19 (86) NS N1 or more 1(4) 3 (14) Grade* (%) G1 0(0) 0(0) NS G2 5(18) 4 (18) G3 23 (82) 18 (82) Vascular involvement* (%) Negative 15 (54) 6 (27) <0.05 Positive 13 (46) 16 (73) *Determined based on findings of radical cystectomy specimens. Not significant. stage, N stage and tumor grade and the incidence of vascular involvement between these groups, whereas the mean age in group B was significantly higher than that in group A (p < 0.01) and the ratio of patients who underwent neobladder creation in group A was significantly higher than that in group B (p < 0.001). The median follow-up periods for groups A and B were 53 and 48 months, respectively. As shown in Table 2, the recurrence-free, cause-specific and overall survival rates in group A were significantly higher than those in group B (p < 0.05, p < 0.05 and p < 0.05, respectively). During the observation period in the present study, three and 10 patients in groups A and B, respectively, died of cancer metastases, which were initially diagnosed as retroperitoneal lymph node metastasis in six patients, lung metastasis in five and bone metastasis in two. Final pathological examinations revealed that no significant difference was observed in the distribution of the T stage, N stage and tumor grade, whereas the incidence of vascular involvement in group B was significantly higher than that in group A (p < 0.05) (Table 3). In addition, the mean interval and range from the diagnosis of invasive disease to radical cystectomy inpatients with and without subsequent vascular involvement were 1.7 (1.2 3.3) and 3.9 (1.3 5.3) months, respectively (p < 0.01). However, a Cox multivariate regression analysis revealed that only the pathological stage and nodal involvement were independent prognostic predictors, irrespective of gender, age, tumor grade, vascular involvement, tumor size, multiplicity, type of urinary diversion and the interval from the diagnosis of invasive bladder cancer to radical cystectomy (data not shown).

Jpn J Clin Oncol 2002;32(1) 17 DISCUSSION The finding that cancer cells have broken through the basement membrane and into the muscular propria reflects a different malignant potential with a propensity for metastases; therefore, muscle-invasive bladder cancer is the usual indication for radical cystectomy and pelvic lymphadenectomy. Despite recent therapeutic advances, such as surgical techniques and perioperative cytotoxic chemotherapy, the survival of invasive bladder cancer patients with pathological risk factors, including advanced stage, lymph node metastasis and vascular involvement, after radical cystectomy remains unsatisfactory (1 5). Furthermore, several therapeutic options for invasive diseases, which affect the timing of radical cystectomy, have become available (10 13). Recently, Sanchez- Ortiz et al. reported that a delay of radical cystectomy of longer than 3 months is associated with advanced pathological stage and decreased survival (14). These findings prompted us to re-evaluate the current therapeutic strategy for invasive TCC of the bladder and here we performed a retrospective analysis in a homogeneous contemporary series of patients who underwent radical cystectomy but not any perioperative therapies for invasive bladder cancer, focusing on the significance of the interval from the diagnosis of invasive disease to radical cystectomy. In this series, the patients characteristics between groups A and B were similar except for age and the ratio of patients with orthotopic neobladder. There were some reasons for these differences in age and the type of urinary diversions between these groups. For example, as part of the informed consent, although age alone was not a contraindication, older patients must be made aware that they may have a more frequent postoperative incidence of postoperative complications, such as nocturnal incontinence, than younger men. The reluctance of elderly patients to undergo radical surgery may also be reflected in this difference. However, because of the similar characters in the remaining factors, this difference may not interfere with the objectives of the present study. The timing of the treatment of bladder cancer is extremely important, since ~20% of new cases are invasive disease and an additional 10% of superficial diseases subsequently progress (15). In this series, no significant difference was observed in the average number of previous TURs between groups A and B, while the prognosis of patients with group A was significantly better than that in group B, suggesting that a delay in performing radical cystectomy could be closely associated with the poorer survival in patients with invasive bladder cancer. In fact, a final pathological examination revealed a higher incidence of vascular involvement in group B than group A, despite the lack of a significant difference in the incidence of vascular involvement in the specimens obtained by TUR. These findings may suggest that vascular involvement frequently occurred during the longer interval from the diagnosis to radical surgery in group B compared with group A, resulting in the poorer survival. Various types of urinary diversion have recently been developed and recent advances in this area provide patients with an improved quality of life (16,17). However, various problems caused by urinary diversion remain to be elucidated, such as metabolic acidosis, urolithiasis, enuresis and impaired body image (8,16), and, therefore, the correct timing of cystectomy and the optimal kind of urinary diversion have been common dilemmas for both the urologist and patient. Recently, some studies have indicated that the option of orthotopic neobladder may influence the decision in favor of earlier cystectomy (9,18,19). In the current series, patients who selected orthotopic neobladder replacement as their urinary diversion tended to receive radical cystectomy earlier than those who selected incontinent urinary diversion. These findings suggest that the orthotopic bladder replacement may decrease the reluctance to perform radical cystectomy early in the disease process. In conclusion, the present findings suggest that radical cystectomy in the early disease process, especially before the occurrence of vascular involvement, may result in the improvement of the survival of patients with invasive TCC of the bladder. We therefore recommend performing radical cystectomy as early as possible after the primary diagnosis of invasive bladder cancer. References 1. Bassi P, Ferrante GD, Piazza N, Spinadin R, Carando R, Pappagallo G, et al. Prognostic factors of outcome after radical cystectomy for bladder cancer: a retrospective study of a homogeneous patient cohort. JUrol 1999;161:1494 7. 2. Slaton JW, Swanson DA, Grossman HB, Dinney, CP. A stage specific approach to tumor surveillance after radical cystectomy for transitional cell carcinoma of the bladder. JUrol1999;162:710 4. 3. Hara S, Miyake H, Fujisawa M, Okada H, Arakawa S, Kamidono S, et al. Prognostic variables in patients who have undergone radical cystectomy for transitional cell carcinoma of the bladder. Jpn J Clin Oncol 2001;31:399 402. 4. Ennis RD, Petrylak DP, Singh P, Bagiella E, O Toole KM, Benson MC, et al. The effect of cystectomy and perioperative methotrexate, vinblastine, doxorubicin and cisplatin chemotherapy on the risk and pattern of relapse in patients with muscle invasive bladder cancer. JUrol2000;163:1413 8. 5. Lerner SP, Skinner E, Skinner DG. Radical cystectomy in regionally advanced bladder cancer. Urol Clin N Am 1992;19:713 23. 6. Gohji K, Sugino M, Arakawa S, Matsumoto O, Kamidono S, Fujii A, et al. Preoperative adjuvant therapy for urinary bladder cancer. Nippon Hinyoukika Gakkai Zasshi 1990;81:1404 11 (in Japanese). 7. Miyake H, Gohji K, Hara I, Eto H, Yamanaka K, Arakawa S, et al. Long-term results of neoadjuvant M-VAC (methotrexate, vinblastine, doxorubicin and cisplatin) for locally invasive transitional cell carcinoma of the urothelium. Int J Clin Oncol 1999;4:32 5. 8. Turner WH, Bitton A, Studer UE. Reconstruction of the urinary tract after radical cystectomy: the case for continent urinary diversion. Urology 1997;49:663 7. 9. Hautmann RE, Paiss T. Does the option of the ileal neobladder stimulate patient and physician decision toward earlier cystectomy? J Urol 1998;159:1845 50. 10. Thomas DJ, Roberts JT, Hall RR, Reading J. Radical transurethral resection and chemotherapy in the treatment of muscle-invasive bladder cancer: a long-term follow-up. BJU Int 1999;83:432 7. 11. Feneley MR, Mellon JK. Management dilemmas in bladder cancer: radical TUR +/ systemic chemotherapy in the treatment of muscle-invasive bladder cancer. Semin Urol Oncol 2000;18:300 7. 12. Miyanaga N, Akaza H, Okumura T, Sekido N, Kawai K, Shimazui T, et al. A bladder preservation regimen using intra-arterial chemotherapy and

18 Timing of radical cystectomy radiotherapy for invasive bladder cancer: a prospective study. Int J Urol 2000;7:41 8. 13.KageyamaY,OkadaY,AraiG,HyochiN,SuzukiM,MasudaH,etal. Preoperative concurrent chemoradiotherapy against muscle-invasive bladder cancer: results of partial cystectomy in elderly or high-risk patients. Jpn J Clin Oncol 2000;30:553 6. 14. Sanchez-Ortiz F, van Aradalen KN, Wein AJ, Markowicz SB, Huang, WC. A prolonged interval between the diagnosis of muscle invasion and cystectomy is associated with worse outcome in bladder cancer. JUrol 2000;165(Suppl):259. 15. Newling D. Preventing recurrence and progression in superficial bladder cancer. Curr Opin Urol 1996; 6:272 5. 16. Frazier HA, Robertson JE, Paulson DF. Complications of radical cystectomy and urinary diversion: a retrospective review of 675 cases in 2 decades. JUrol1992;148:1401 5. 17. Bjerre BD, Johansen C, Steven K. Health-related quality of life after cystectomy: bladder substitution compared with ileal conduit diversion. A questionnaire survey. Br J Urol 1995;158:400 5. 18. Skinner DG, Boyd SD, Lieskovsky G, Bennet C, Hopwood B. Lower urinary tract reconstruction following cystectomy: experience and results in 126 patients using the Kock ileal reservoir with bilateral ureteroileal urethrostomy. JUrol1991;146:756 60. 19. Hautmann RE, Miller K, Steiner U, Wenderoth U. The ileal neobladder: 6 years of experience with more than 200 patients. JUrol1993;150:40 5.