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Journal of Clinical Oncology, Vol 24, No 15 (May 20), 2006: pp. 2318-2324 © 2006 American Society of Clinical Oncology. DOI: 10.1200/JCO.2006.05.8149 Radiochemotherapy After Transurethral Resection for High-Risk T1 Bladder Cancer: An Alternative to Intravesical Therapy or Early Cystectomy?
From the Department of Radiation Therapy, Department of Urology, University of Erlangen, Erlangen; and Department of Radiation Therapy, University of Lübeck, Lübeck, Germany Address reprint requests to Claus Rödel, MD, Department of Radiation Therapy, Universitätsstr 27, D-91054 Erlangen, Germany; e-mail: claus.roedel{at}strahlen.med.uni-erlangen.de
Purpose For high-risk T1 bladder cancer, the most important issue is how to restrict radical cystectomy to selective patients with a high likelihood of tumor progression and to choose an initial bladder-sparing approach in others without affecting survival. Radiotherapy or radiochemotherapy (RT/RCT) may help to strike a balance between intravesical treatment and early cystectomy. Patients and Methods Between 1982 and 2004, 141 patients with high-risk T1 bladder cancer (84 patients with T1 grade 3 [T1G3]; others with T1G1/2 and associated carcinoma-in-situ, multifocality, tumor diameter > 5 cm, or multiple recurrences) were treated with RT (n = 28) or platinum-based RCT (n = 113) after transurethral resection of bladder tumor (TURBT). Six weeks after RT/RCT, response was evaluated by restaging TURBT. Salvage cystectomy was recommended for patients with persistent disease and for tumor progression after initial complete response (CR). Median follow-up was 62 months; 65 patients have been observed for 5 years or more. Results CR was achieved in 121 of 137 patients (88%; four patients without restaging TURBT). Tumor progression for the entire group of 141 patients was 19% and 30% at 5 and 10 years, respectively (for 121 patients with CR, 15% and 29%; for 84 patients with T1G3, 13% and 29%, respectively). Disease-specific survival rates were 82% and 73% at 5 and 10 years (CR, 89% and 79%; T1G3, 80% and 71%, respectively). More than 80% of survivors preserved their bladder; 70.4% were "delighted" or "pleased" with their urinary function. Conclusion RT/RCT after TURBT with selective bladder preservation is a reasonable alternative to intravesical treatment or early cystectomy for high-risk T1 bladder cancer.
Management of high-grade transitional cell carcinoma involving the lamina propria (stage T1) but not penetrating into the muscularis propria represents a challenge for the treating physician. With transurethral resection of the bladder tumor (TURBT) alone, the risk of recurrence for this group of patients approaches 80% and the risk of progression to muscle-invasive disease is 50% to 65%.1 Adjuvant intravesical therapy with Bacille Calmette-Guérin (BCG) or chemotherapeutic agents, such as mitomycin, may decrease the overall recurrence rate by approximately 30% compared with TURBT alone. However, tumor progression still occurs in 15% to 40% within the first 5 years, and these patients are at risk of dying from urothelial cancer.2 Thus, several groups have recommended immediate cystectomy without a trial of intravesical treatment to prevent any risk of progression.3-6 Five-year disease-specific survival (DSS) rates in the range of 70% to 90% have been achieved with this radical approach; however, the morbidity and mortality associated with cystectomy are still in the range of 20% and 1% to 4%, respectively, and quality of life is altered despite techniques of orthotopic bladder reconstruction. It is evident that undertreatment and overtreatment are critical and controversial issues for this group of patients.7 It is our hypothesis that radiotherapy (RT) with or without chemotherapy may be more effective in preventing tumor progression than standard intravesical treatment, and that this approach may also help to select nonresponding patients at high risk for tumor progression for salvage cystectomy at an early time point. It has been the ongoing policy at the University of Erlangen (Erlangen, Germany) to use RT or radiochemotherapy (RT/RCT) after TURBT with selective bladder preservation for high-risk T1 bladder cancer since 1982.8-10 We now present the long-term result of this approach in a group of 141 patients with a median follow-up of 62 months.
Patient Characteristics Between September 1982 and December 2004, a total of 141 patients with primary or recurrent high-risk T1 bladder cancer were treated with either RT alone (n = 28) or concomitant RCT (n = 113) after initial TURBT. Risk factors for T1 tumors were defined as high grade (grade 3), associated carcinoma in situ (Tis), multifocal lesions, tumor diameter more than 5 cm, or tumors refractory to repeated TURBT with or without intravesical therapy. Patient and tumor characteristics are listed in Table 1. Patients were informed both by the treating urologists and the radiotherapists about treatment alternatives (ie, intravesical treatment or early cystectomy), and gave informed consent to undergo RCT. This series included patients unfit for cystectomy because of advanced age or comorbidities, as well as patients refusing radical surgery.
Treatment Protocol Treatment was commenced by TURBT aimed at maximal, complete resection (if feasible) of the tumor mass. Residual tumor was assessed histologically by biopsies from all resection margins: R0 indicated a visibly and microscopically complete TURBT, R1 indicated microscopic residual tumor, and R2 indicated macroscopic residual tumor. Additional evaluation included chest radiography and computed tomography of the abdomen and pelvis. RT was initiated 4 to 6 weeks after initial TURBT using 6- to 10-MV photons and a four-field box technique with individually shaped portals and daily fractions of 1.8 to 2 Gy on 5 consecutive days. A median dose of 55.8 Gy (range, 45.0 to 61.4 Gy) was applied to the bladder. Pelvic nodes were irradiated with a median dose of 50.4 Gy (range, 36.0 to 54.1 Gy). Since October 1985, chemotherapy has been given simultaneously for 5 consecutive days during the first and fifth week of RT. Forty-three patients received cisplatin 25 mg/m2/d; in 16 patients with decreased creatinine clearance (< 50 mL/min), carboplatin 65 mg/m2/d was administered. Since 1993, 54 patients were treated with a combination of cisplatin or carboplatin and fluorouracil 600 mg/m2/d. A total of eight patients also received deep regional hyperthermia within an ongoing phase II study.
Assessment of Response, Local Control, Late Toxicity, and Quality of Life
Statistics
Response to RT/RCT at Restaging TURBT A CR at restaging TURBT was achieved in 121 of 137 patients (88%; Fig 1). Four patients did not undergo restaging TURBT due to noncompliance2 or advanced age/comorbidity,2 but additional follow-up for these patients was available (two were free of tumor, one experienced disease progression, one died as a result of unrelated disease). Fifteen patients had persistent tumor (Ta, five patients; Tis, three patients; T1, seven patients), and in one patient tumor progression (distant metastases) was detected at the time of restaging TURBT. If analysis is restricted to patients with T1 grade 3 (T1G3; n = 84), the CR rate was 89% (Table 1). The only significant predictive factor for CR was the completeness (R status) of the initial TURBT (P < .001; Table 1).
Salvage Treatment for Persistent and Recurrent Disease For nonresponders, salvage cystectomy was performed in four patients with persistent Ta (two patients) or T1 (two patients) tumor, three of whom remained tumor free for 121, 150, and 187 months, respectively, and one of whom died as a result of urothelial cancer 43 months after cystectomy (Fig 1). For the remaining 11 patients with residual tumor, TURBT with or without intravesical therapy resulted in long-term local control in four patients (Tis, three patients; T1, one patient); in seven patients (Ta, three patients; T1, four patients), disease progression occurred at further follow-up. Thus, for nonresponders, salvage treatment was successfully applied in seven of 16 patients (44%), tumor progression occurred in 56%, and eight patients died as a result of urothelial cancer (in one patient, the cause of death was unknown).
Among the 121 patients with CR at restaging TURBT, 72 (60%) have been continuously free of tumor, 36 patients (30%) experienced a
Overall Failure Rates and Tumor Progression
Tumor progression for the entire group of 141 patients was 19% and 30% at 5 and 10 years, respectively. In 84 patients with T1G3, the figures were 13% and 29% at 5 and 10 years, respectively. For 121 patients with CR, tumor progression occurred in 15% and 28% at 5 and 10 years, respectively (Fig 2). None of the factors analyzed significantly predicted tumor progression (Table 1).
DSS, Overall Survival, and Bladder Preservation
Toxicity and Quality of Life Due to Urinary Symptoms Grade 3 and 4 acute toxicity due to RT/RCT were restricted to 23% of patients with diarrhea, 4% with nausea/vomiting, and 20% with leucopenia. No treatment-related death occurred. The percentages of patients with chronic sequelae are listed in Table 2. Two patients underwent cystectomy because of a shrinking bladder and another two patients required surgical intervention due to intestinal obstruction. Seventy-one of 72 patients alive with their bladder preserved completed the quality-of-life questionnaire due to urinary symptoms of the International Prostate Symptom Score (Table 3): 50 patients (70.4%) were "delighted" or "pleased" with their urinary condition. Forty-four of these 50 patients (88%) have been free of tumor continuously. In the group of patients less content with their urinary condition (n = 21), 12 patients (57%) had experienced a superficial tumor relapse and had received additional TURBT with (n = 6) or without (n = 6) intravesical BCG.
Urothelial cancers are sensitive to radiation. The rationale to use RT/RCT as a treatment component in high-risk T1 bladder cancer arises from the proven efficacy of this approach in more advanced disease. Several groups have reported excellent results of combined-modality treatment, including TURBT, RT, and concomitant chemotherapy in muscle-invasive bladder cancer.13,14 With these programs, cystectomy has been reserved for patients with incomplete response or local relapse after trimodality treatment. In patients with high-risk T1 disease, the most important issue is how to restrict radical cystectomy to selective patients with a high risk of tumor progression, and to choose an initial bladder-sparing approach in others without affecting survival. For most patients, initial management involves TURBT, and intravesical immunotherapy or chemotherapy.
The initial diagnosis of T1 disease is associated with significant understaging errors of as much as 25% to 40%.1 Moreover, in approximately 5% of correctly staged pT1 lesions and in up to 36% of nonmuscle-invasive bladder cancer upstaged to In our series of 141 high-risk T1 bladder cancer patients, tumor progression occurred in 19% at 5 years and 30% at 10 years. If this analysis was restricted to T1G3 patients, the progression rate was 13% at 5 years and 29% at 10 years, which compares favorably to most contemporary series of T1G3 patients treated with standard BCG (Table 4). The DSS rate for the entire group of 141 patients was 82% at 5 years and 70% at 10 years. These figures are in the same range as a primary cystectomy series in T1 bladder cancer (62% to 90% at 5 years).3-6 However, in our series, more than 80% of the surviving patients preserved their bladder, and more than 70% were "delighted" or "pleased" with their urinary function.
A total of 18 patients (13%) died as a result of distant metastases in our series (and an additional nine patients [6%] died as a result of urothelial cancer, but the exact tumor location was not documented). These figures are in the same range as those reported in primary cystectomy series for superficial bladder cancer. Madersbacher et al26 reported that 27% of patients with histopathologically confirmed pTa/pTis/pT1 bladder cancer developed distant metastases in their series of radical cystectomy within a median follow-up time of 31 months. The largest cystectomy series, studied by Stein et al,27 comprising 1,054 patients included 208 patients with stage pT1 tumors. The recurrence-free survival rates at 5 and 10 years were 80% and 75%, respectively. Although the progression rate was low in our series, it also became evident that about half of all patients either did not achieve a CR (12%) or experienced recurrence during follow-up. This was true well beyond 5 years. In a series studied by Herr,28 tumor progression in patients with T1G3 bladder cancer treated with or without BSG occurred in 35% within the first 5 years, in 16% after 5 to 10 years, and in 12% of those observed for 10 to 15 years. Thus, close and lifelong surveillance and adequate treatment for these patients is of utmost importance. For patients with residual tumor at restaging TURBT, we generally recommend immediate salvage cystectomy regardless of (residual) tumor stage. Given that restaging is scheduled 6 weeks after completion of RT/RCT, patients with persistent, nonresponding cancer may thus be selected for radical surgery at an early point of time. This approach was successful in three of four patients. If, for different reasons (such as patient age, comorbidity, or refusal), salvage cystectomy was not performed, progression and death from urothelial cancer occurred in eight of 12 patients (67%), reflecting the aggressive nature of these RT/RCT-refractory tumors.
For patients with a To date, no randomized studies have been published addressing our hypothesis that RT with or without chemotherapy may be as effective as or even superior to standard BCG for high-risk T1 bladder cancer. Our long-term results in this large group of patients suggest that TURBT plus RT/RCT with selective bladder preservation may help to strike a balance between intravesical treatment and immediate cystectomy. A randomized trial comparing the efficacy of BCG versus RCT in preventing tumor recurrence and progression in this group of patients with high-risk T1 bladder cancer would be a major step forward.
The authors indicated no potential conflicts of interest.
Conception and design: Karl-Michael Schrott, Rolf Sauer, Claus Rödel Administrative support: Karl-Michael Schrott, Rolf Sauer Provision of study materials or patients: Christian Weiss, Carolin Wolze, Dirk Gerhard Engehausen, Oliver J. Ott, Frens S. Krause, Karl-Michael Schrott, Jürgen Dunst, Rolf Sauer, Claus Rödel Collection and assembly of data: Christian Weiss, Carolin Wolze, Dirk G. Engehausen, Oliver J. Ott, Frens S. Krause, Karl-Michael Schrott, Jürgen Dunst, Rolf Sauer, Claus Rödel Data analysis and interpretation: Christian Weiss, Carolin Wolze, Dirk Gerhard Engehausen, Oliver J. Ott, Frens S. Krause, Karl-Michael Schrott, Jürgen Dunst, Rolf Sauer, Claus Rödel Manuscript writing: Christian Weiss, Carolin Wolze, Dirk Gerhard Engehausen, Oliver J. Ott, Frens S. Krause, Karl-Michael Schrott, Jürgen Dunst, Rolf Sauer, Claus Rödel Final approval of manuscript: Christian Weiss, Carolin Wolze, Dirk G. Engehausen, Oliver J. Ott, Frens S. Krause, Karl-Michael Schrott, Jürgen Dunst, Rolf Sauer, Claus Rödel
Presented in part at the 47th Annual Meeting of the American Society of Therapeutic Radiology and Oncology, October 16-20, 2005, Denver, CO. Authors' disclosures of potential conflicts of interest and author contributions are found at the end of this article.
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Wiesner C, Pfitzenmaier J, Faldum A, et al: Lymph node metastases in non-muscle invasive bladder cancer are correlated with the number of transurethral resections and tumour upstaging at radical cystectomy. BJU Int 95:301-305, 2005[Medline] 17. Kulkarni JN, Gupta R: Recurrence and progression in stage T1G3 bladder tumour with intravesical bacille Calmette-Guerin (Danish 1331 strain). BJU Int 90:554-557, 2002[CrossRef][Medline] 18. Pansadoro V, Emiliozzi P, de Paula F, et al: Long-term follow-up of G3T1 transitional cell carcinoma of the bladder treated with intravesical bacille Calmette-Guerin: 18-year experience. Urology 59:227-231, 2002[Medline] 19. Brake M, Loertzer H, Horsch R, et al: Long-term results of intravesical bacillus Calmette-Guerin therapy for stage T1 superficial bladder cancer. Urology 55:673-678, 2000[Medline] 20. Bogdanovic J, Marusic G, Djozic J, et al: The management of T1G3 bladder cancer. Urol Int 69:263-265, 2002[Medline] 21. 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Copyright © 2006 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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ABSTRACT
INTRODUCTION
T2) in the bladder, or any evidence of pelvic lymph node involvement or distant metastases. Actuarial rates of overall failures, tumor progression, and survival were calculated from the time of initial TURBT to the time of the respective end point, the last follow-up visit, or death using the method of Kaplan and Meier. Differences were analyzed using the log-rank test. The 
2 test (two tailed) was used to determine statistical significance between proportions for the end point CR after RT/RCT. Level of significance was .05 (two sided) in all of the statistical testing. 
T1 tumor relapse, and 13 patients (10%) had tumor progression (
