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T2a Transitional Cell Carcinoma of the Bladder: Long-term Experience With Intravesical Immunoprophylaxis With Bacillus Calmette-guerin
0022-5347/03/1693-0931/0 THE JOURNAL OF UROLOGY® Copyright © 2003 by AMERICAN UROLOGICAL ASSOCIATION
Vol. 169, 931–935, March 2003 Printed in U.S.A.
DOI: 10.1097/01.ju.0000049002.75782.39
T2A TRANSITIONAL CELL CARCINOMA OF THE BLADDER: LONGTERM EXPERIENCE WITH INTRAVESICAL IMMUNOPROPHYLAXIS WITH BACILLUS CALMETTE-GUERIN ¨ RGEN E. GSCHWEND, SIMONE H. MAIER, BJOERN G. VOLKMER, JU EVELYN M. SEIDL-SCHLICK, DIETMAR BACH AND IMRE ROMICS From the Departments of Urology, University of Ulm, Ulm, St. Agnes Hospital, Bocholt, Germany, and Semmelweis University, Budapest, Hungary
ABSTRACT
Purpose: In this prospective study we evaluate the effect of combined transurethral resection of early muscle invasive bladder cancer and immunotherapy with bacillus Calmette-Guerin (BCG) in patients unfit for radical cystectomy or refusing more aggressive therapies. Materials and Methods: A total of 22 patients with a mean age 73.6 years were included in the study. Inclusion criteria were histologically proven muscle invasive transitional cell carcinoma of the bladder with a tumor-free second resection and negative staging examinations in patients unfit for radical cystectomy or refusing more aggressive therapies. All patients received 6 weekly instillations of 120 mg. BCG starting 14 to 21 days after the last transurethral resection of the tumor. Followup at 3 months included cystoscopy, urinary cytology, ultrasound of the abdomen and chest x-ray. Every 6 months computerized tomography of the abdomen and bone scans were performed. Results: The overall 5-year survival rate was 69.1%, while the disease specific 5-year survival rate was 94%. One muscle invasive recurrence was noted at 69 months, which was again treated with the same regimen but ultimately led to radical cystectomy 21 months later. One patient died of progressive recurrence in the upper urinary tract. The 5-year recurrence-free survival rate was 46.5%. The only severe complication was BCG pneumonitis. Conclusions: The data show encouraging results for transurethral resection of bladder tumor with intravesical BCG therapy in select patients with T2a bladder cancer who are not candidates for radical cystectomy. KEY WORDS: carcinoma, transitional cell; neoplasm invasiveness, immunotherapy, bladder
Patients with T2a muscle invasive transitional cell carcinoma of the bladder are at risk for local recurrence, tumor progression and metastatic spread. The rate of under staging by transurethral resection of bladder tumors and the lack of efficient therapeutic options have led to the recommendation of radical cystectomy as first-line treatment. Optimized operative techniques, growing experience treating geriatric patients and advanced intensive care modalities have extended the cystectomy population within the last 20 years. However there remains a small group of patients with early muscle invasive (T2a) bladder cancer who are neither eligible for radical cystectomy nor chemoradiotherapy. Since the first report in 1976 by Morales et al of a beneficial effect of intravesical instillations of bacillus Calmette-Guerin (BCG) on the recurrence and course of bladder cancer,1 BCG has become an established therapeutic option for patients with completely resected superficial bladder carcinoma, especially those with high grade transitional cell carcinoma.2 We report the results of a prospective study in patients with T2a bladder cancer not eligible for cystectomy or chemoradiotherapy who were treated with transurethral resection combined with intravesical BCG immunoprophylaxis. PATIENTS AND METHODS
Between July 1986 and June 1997 all patients with muscle invasive transitional cell carcinoma of the bladder not eligible for radical cystectomy or chemoradiotherapy, or refusing these options underwent a second transurethral resection of Accepted for publication September 13, 2002.
the tumor site at our hospital. When the second resection revealed a tumor-free deep muscle layer and further staging examinations, including chest x-ray, ultrasound of the abdomen, excretory urography, computerized tomography of the abdomen and bone scan, did not reveal any pathological findings, the patients were included in this study. Exclusion criteria were secondary malignancies within the last 5 years, age younger than 18 years, squamous cell carcinoma or adenocarcinoma of the bladder, or suspicion of immunodeficiency. The patients received 6 weekly intravesical instillations of 120 mg. BCG (Pasteur or Connaught) in 50 cc saline starting 14 to 21 days after the last resection of the bladder tumor. No maintenance therapy was given. Followup in all patients at 3 months included cystoscopy, urinary cytology, ultrasound of the abdomen and chest x-ray. Computerized tomography of the abdomen and bone scans were performed every 6 months. Further examinations depended on symptoms. All local recurrences were confirmed by transurethral resection. After informed consent was obtained 15 men and 7 women of 820 patients treated with transitional cell carcinoma of the bladder were included in this study (see table). Mean patient age was 73.6 years (range 43 to 89). Of these patients 9 refused (2 because of age) and 13 were not eligible for more aggressive therapies because of severe concomitant diseases. Mean followup was 45 months (range 11 to 119), and 16 patients were followed for more than 24 months. No patient was lost to followup until death. All patients had primary muscle invasive tumors, and none had received prior intravesical therapies. All 9 patients with T2a GIII tumors had
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BLADDER CARCINOMA AND BACILLUS CALMETTE-GUERIN IMMUNOPROPHYLAXIS Patient data
Pt.—Age Reason Against Primary No. Chemoradiotherapy Stage 1—81 2—71 3—68 4—81 5—77 6—77 7—80 8—81 9—89 10—82 11—75 12—73 13—63 14—56 15—76 16—74 17—43 18—65 19—75 20—76 21—89 22—68
Lung Heart Heart Heart/refusal Kidney Cerebrum Heart Lung Refusal (age) Heart Heart/refusal Heart Refusal Refusal Refusal Heart Refusal Heart Lung Refusal Refusal (age) Heart
T2a T2a T2a T2a T2a T2a T2a T2a T2a T2a T2a T2a T2a T2a T2a T2a T2a T2a T2a T2a T2a T2a
Ca In Situ
GII GIII GIII GIII GIII GII GII GII GII GII GIII GIII GII GII GII GIII GIII GII GII GII GII GIII
— Yes Yes Yes Yes — — — — — Yes Yes — — — Yes Yes — — — — Yes
Solitary/ Mos. Multifocal Followup Solitary Multifocal Multifocal Solitary Multifocal Solitary Multifocal Multifocal Multifocal Solitary Solitary Solitary Multifocal Multifocal Solitary Multifocal Solitary Multifocal Multifocal Multifocal Solitary Solitary
11 12 12 13 20 23 25 29 30 31 34 42 45 46 48 49 53 68 80 92 104 119
Mos. Survival (outcome)
Mos. Recurrence-Free Survival (tumor stage)
Mos. Progression-Free Survival (tumor stage)
11⫹ 11⫹ 11⫹ 12 (no evidence of disease) 12⫹ 12⫹ 12 (no evidence of disease) 12⫹ 12⫹ 13⫹ 13⫹ 13⫹ 20 (dead from disease) 17 (T3 GIII, renal pelvis) 17 (T3 GIII, renal pelvis) 23⫹ 23⫹ 23⫹ 25 (no evidence of disease) 25⫹ 25⫹ 29 (no evidence of disease) 29⫹ 29⫹ 30⫹ 6 (Ta GII) 30⫹ 31 (no evidence of disease) 31⫹ 31⫹ 34⫹ 34⫹ 34⫹ 42⫹ 42⫹ 42⫹ 45⫹ 35 (Ta GII) 45⫹ 46⫹ 46⫹ 46⫹ 48⫹ 7 (T1 GII) 48⫹ 49⫹ 21 (T3a GIII) 21 (T3a GIII) 53⫹ 53⫹ 53⫹ 68 (no evidence of disease) 60 (Ta GI) 68⫹ 80⫹ 80⫹ 80⫹ 92⫹ 41 (Ta GII) 92⫹ 104⫹ 104⫹ 104⫹ 119⫹ 69 (T2a GIII) 90 (T3a GIII)
peritumoral carcinoma in situ, including 4 with concomitant multifocal carcinoma in situ. Data were analyzed using the Kaplan-Meier-Method including overall survival disease specific, recurrence-free and progression-free survival rates. RESULTS
All 22 patients underwent a second transurethral resection of bladder tumor. The histological results were tumor-free in 16 cases, residual superficial transitional cell carcinoma with a tumor-free muscle layer in 5 and minimal residual muscle invasive disease with a tumor-free deep muscle layer in 1. All patients had negative urine cytologies 3 and 6 months after resection. During followup 6 of 22 patients died of concomitant diseases without clinical evidence of tumor recurrence or progression. In 1 patient an invasive infiltrating transitional cell carcinoma of the renal pelvis developed at 17 months. The patient refused any therapy and died 3 months later. The calculated overall 5-year survival rate was 69.1%, while the disease specific 5-year survival rate was 94.1% (fig. 1). In 1 patient
muscle invasive local recurrence developed 69 months after BCG immunoprophylaxis. Pathological evaluation revealed T2a transitional cell carcinoma and a subsequent tumor-free second resection. The patient still refused radical cystectomy and BCG immunoprophylaxis was repeated. T2 GIII bladder carcinoma with multifocal carcinoma in situ was present 21 months later, which was treated with radical cystectomy and urinary diversion with an ileal conduit. Overall only 2 of 22 patients presented with tumor progression for a 5-year progression-free survival rate of 88.8% (fig. 2). In 6 patients superficial transitional cell carcinoma of the bladder developed during followup (Ta GI 1, Ta GII 2, T1 GII 3). These tumors were completely resected with a tumor-free deep layer on second transurethral resection. All patients received a second cycle of BCG immunoprophylaxis. Overall superficial tumor recurrence developed in 8 of 22 patients for a 5-year recurrence-free survival rate of 46.5% (fig. 2). Only 1 severe treatment associated complication was observed. After the last intravesical instillation of BCG 1 patient suf-
FIG. 1. Overall and disease specific survival rates in 22 patients with T2a bladder cancer treated with transurethral resection and BCG immunoprophylaxis.
BLADDER CARCINOMA AND BACILLUS CALMETTE-GUERIN IMMUNOPROPHYLAXIS
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FIG. 2. Recurrence-free and progression-free survival rates in 22 patients with T2a bladder cancer treated with transurethral resection and BCG immunoprophylaxis.
fered from BCG pneumonitis with acute respiratory distress syndrome. He completely recovered after steroid therapy and disease is now in complete remission. DISCUSSION
In 1976 Morales et al reported the first encouraging results of intravesical BCG for patients with transitional cell carcinoma of the bladder.1 While the first published studies used mixed populations with superficial and early muscle invasive tumors,3 the majority of later studies focused on the effect of BCG immunoprophylaxis on the recurrence and progression of superficial bladder cancer. Today intravesical BCG instillation can be regarded as the first choice prophylaxis for recurrent superficial transitional cell carcinoma, at least for high risk tumors such as carcinoma in situ. Radical cystectomy is considered the gold standard for muscle invasive transitional cell carcinoma of the bladder. The disease specific survival rate for pT2a bladder cancer ranges between 63% and 82% at 5 years according to larger series.4 –7 Data on the tumor specific survival rate for T2a bladder cancer treated with transurethral resection alone are limited. The 5-year disease specific survival rates in this group range between 45% and 70%.8 –12 These results are 10% to 20% worse compared to those of cystectomy cases. Reasons for this difference are clinical under staging by transurethral resection of bladder tumor alone and lack of information regarding lymph node status. Large cystectomy series have shown that lymph node metastases can be expected in 10% of early muscle infiltrating tumors.13 The staging error in the depth of tumor invasion from T2a to more invasive tumors is estimated to be at least 25%.7, 14 In regard of disease specific survival our results are close to the survival outcome of patients treated with cystectomy. Reasons for this correlation may be a reduced rate of under staging due to an aggressive transurethral resection until the tumor was completely resected and a tumor-free deep muscle layer was confirmed; a reduced rate of recurrent high grade superficial transitional cell carcinoma, and a potential systemic effect of BCG on the disease. Such a systemic effect of BCG was discussed 60 years ago.15 Our data are in accordance with those of Netto and Lemos who reported a partial response rate of 70% following oral BCG in 20 patients with muscle invasive bladder cancer.16 In addition to the risk of systemic disease patients with early
muscle invasive bladder cancer have an increased risk of local recurrence. This finding is supported by the relatively high rate of concomitant carcinoma in situ and multifocal tumors. Therefore, the local recurrence rate can be estimated as high as that of high grade papillary tumors or carcinoma in situ of the bladder. Herr reported a 35% local recurrence rate of muscle invasive tumors in 45 patients with initial T2-4 tumors treated with transurethral resection.11 Our recurrence-free 5-year survival rate was 46.5%. These rates are comparable to those (range 41% to 60%) of aggressive superficial transitional cell carcinoma of the bladder (T1 GIII and carcinoma in situ) treated with transurethral resection of bladder tumor and BCG immunoprophylaxis.17, 18 Similar to patients with high grade superficial transitional cell carcinoma BCG maintenance therapy might have an additional beneficial effect in our cases, since superficial transitional cell carcinoma recurred within 7 to 41 months in at least 5 patients. Until today a significant reduction in the progression rate of superficial transitional cell carcinoma by BCG immunoprophylaxis has not been proven. However, another muscle invasive tumor developed in only 2 of our patients at 17 and 69 months, respectively. This rate does not differ from the progression rates reported for high grade papillary tumors treated with transurethral resection of bladder tumor and BCG immunoprophylaxis. Our overall 5-year survival rate of 69% reflects high comorbidity since only 1 patient died of tumor. The rate of severe complications from BCG immunoprophylaxis was low compared to the reported complication rates of radical cystectomy. Therefore, we assume, that this treatment option might be indicated even for patients with bladder cancer and severe concomitant diseases.
CONCLUSIONS
Our data show encouraging results with transurethral resection and BCG immunoprophylaxis in patients with T2a transitional cell carcinoma of the bladder who were unfit for or refused more aggressive therapies. Our data may theoretically support a beneficial systemic effect of BCG for muscle invasive transitional cell carcinoma. However, the real value of this study protocol compared to transurethral resection of bladder tumor alone and radical cystectomy can only be determined by a randomized prospective study. Since radical cystectomy has been accepted as standard therapy for T2a
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BLADDER CARCINOMA AND BACILLUS CALMETTE-GUERIN IMMUNOPROPHYLAXIS
transitional cell carcinoma of the bladder, it is unlikely that such a study will be conducted. REFERENCES
1. Morales, A., Eidinger, D. and Bruce, A. W.: Intracavitary bacillus Calmette-Guerin in the treatment of superficial bladder tumors. J Urol, 116: 180, 1976 2. Lamm, D. L., Blumenstein, B. A., Crawford, E. D., Crissmann, J. D., Lowe, B. A., Smith, J. A. et al: Randomized intergroup comparison of bacillus Calmette-Guerin immunotherapy and Mitomycin C chemotherapy prophylaxis in superficial transitional cell carcinoma of the bladder: a Southwest Oncology Group study. Urol Oncol, 1: 119, 1995 3. Lamm, D. L.: Bacillus Calmette-Guerin immunotherapy for bladder cancer. J Urol, 134: 40, 1985 4. Bassi, P., Ferrante, G. D., 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. J Urol, 161: 1494, 1999 5. Gschwend, J. E., Fair, W. R. and Vieweg, J.: Radical cystectomy for invasive bladder cancer: contemporary results and remaining controversies. Eur Urol, 38: 121, 2000 6. Malkowicz, S. B., Nichols, P., Lieskovsky, G., Boyd, S. D., Huffman, J. and Skinner, D. G.: The role of radical cystectomy in the management of high grade superficial bladder cancer (PA, P1, PIS, P2). J Urol, 144: 641, 1990 7. Dutta, S. C., Smith, J. A., Jr., Shappell, S. B., Coffey, C. S., Chang, S. S. and Cookson, M. S.: Clinical understaging of high risk nonmuscle invasive urothelial carcinoma treated with radical cystectomy. J Urol, 166: 490, 2001 8. RUTT (Registry of Urinary Tract Tumors). Harnwegstumorregister, Jahresbericht. Verh Dtsch Ges Urol, 37: 685, 1985 9. Henry, K., Miller, J., Mori, M., Loening, S. and Fallon, B.: Comparison of transurethral resection to radical therapies for stage B bladder tumors. J Urol, 140: 964, 1988 10. O’Flynn, J. D., Smith, J. D. and Hanson, J. S.: Transurethral resection for the assessment and treatment of vesical neoplasms. A review of 800 consecutive cases. Eur Urol, 1: 38, 1975 11. Herr, H. W.: Conservative management of muscle-infiltrating bladder cancer: prospective experience. J Urol, 138: 1162, 1987 12. Herr, H. W.: Transurethral resection of muscle-invasive bladder cancer: 10-year outcome. J Clin Oncol, 19: 89, 2001 13. Vieweg, J., Gschwend, J. E., Herr, H. W. and Fair, W. R.: The impact of primary stage on survival in patients with lymph node positive bladder cancer. J Urol, 161: 72, 1999 14. Lee, R. and Droller, M. J.: The natural history of bladder cancer. Implications for therapy. Urol Clin North Am, 27: 1, 2000 15. Holmgren, I.: La tuberculine et le BCG chez les chance´ reux. Schweiz Med Wochenschr, 65: 1203, 1935 16. Netto, N. R., Jr. and Lemos, G. C.: Bacillus Calmette-Guerin immunotherapy of infiltrating bladder cancer. J Urol, 132: 675, 1984 17. Lamm, D. L., Blumenstein, B. A., Crissman, J. D., Montie, J. E., Gottesman, J. E., Lowe, B. A. et al: Maintenance bacillus Calmette-Guerin immunotherapy for recurrent TA, T1 and carcinoma in situ transitional cell carcinoma of the bladder: a randomized Southwest Oncology Group study. J Urol, 163: 1124, 2000 18. Brake, M., Loertzer, H., Horsch, R. and Keller, H.: Recurrence and progression of stage T1, grade 3 transitional cell carcinoma of the bladder following intravesical immunotherapy with bacillus Calmette-Guerin. J Urol, 163: 1697, 2000 EDITORIAL COMMENT Radical cystectomy is a formidable procedure. The cardiac, vascular and respiratory systems of most patients with bladder cancer have been adversely impacted by years of cigarette smoking. Many are overweight and older than 65 years, representing additional risk factors for major pelvic surgery. The reconstruction must be precise. There are suture and staple anastomoses that must heal without leaking and yet remain patent. Due to dramatic improvements in perioperative care, operative mortality has declined to less than 5%. However, perioperative morbidity hovers around 20% to 25%. Thus, it is no surprise that most of these procedures are performed at large hospital centers with state-of-the-art intensive care units and fellows and residents to help with the intraoperative and postoperative care. A reason that bladder preservation is an attractive option for muscle invasive bladder cancer is the desire on the part of the
patient and the urologist to avoid this major procedure. Although an orthotopic bladder substitute has made radical cystectomy more palatable, approximately 20% to 30% of patients are not candidates because of cancer related factors, age, co-morbidity or altered renal function. Bladder preservation provides the advantages of less surgery, no diversion and the potential to retain a more normal sex life. Volkmer et al provide us with an alternative for a select group of patients with transitional cell carcinoma which has invaded the superficial muscularis propria of the bladder. They performed a thorough transurethral resection followed by intravesical BCG instillation. They suggest that since this approach is reasonable for initial treatment of patients with high grade T1 transitional cell carcinoma, why not for limited T2? The authors were obviously selective, treating 22 patients in 11 years. They excluded patients with prior transitional cell carcinoma, which eliminates patients more likely to have recurrence. Mean patient age was almost 74. In the abstract the authors state that there was “a tumor-free second resection,” however, 1 patient had “minimal residual muscle invasion” (negative deep muscle) and 5 had superficial transitional cell carcinoma (no tumor in the muscularis propria). Thus, only 16 of the 22 patients had no tumor on the re-staging transurethral resection. Thus, assuming the patients did not already have metastasis (in which case cystectomy will not be curative), this approach is not unlike the management of high grade T1 transitional cell carcinoma with a second transurethral resection (to confirm less than T2 and resect residual tumor) followed by intravesical BCG. With careful monitoring and proceeding to radical cystectomy if there is a subsequent high grade tumor, the results for T1 transitional cell carcinoma are comparable to initial cystectomy.1 Is this similar approach comparable for “limited T2” transitional cell carcinoma? According to the table, after completing BCG 5 patients had high grade Ta-T1 transitional cell carcinoma, 1 had a T2a lesion and 2 had T3 lesions. Mean followup is only 45 months and only 16 patients have been followed longer than 2 years, which is to short for me to be confident of this treatment approach based on this limited series. However, Herr retrospectively analyzed the outcome of 99 patients with muscle invasive transitional cell carcinoma who had either no tumor, carcinoma in situ or T1 tumor on a second transurethral resection (reference 12 in article). The bladder was initially preserved, that is no cystectomy, and minimum followup was 10 years or death. Of the patients 24% died of transitional cell carcinoma and 57% retained the bladder. The series of Herr dates from 1979 to 1989. All patients did not receive BCG and some may not have had a cystectomy at the first sign of a new high grade transitional cell carcinoma. Herr suggests that despite close followup, patients who meet the criteria for this transurethral resection based bladder preservation approach must assume an 8% to 16% risk that a recurrent or new invasive tumor will cause death from transitional cell carcinoma. This figure is reasonable in my view and must be weighed against the operative mortality and morbidity of cystectomy. However, it all begins with the decision to perform a second transurethral resection. A review of the initial transurethral resection specimen with the pathologist along with information garnered from the initial endoscopy will help select patients for bladder preservation. Bladder cancer covers a wide spectrum. The reason that radical transurethral resection followed by chemotherapy and radiationchemotherapy protocols falls is because the entire urothelium has been exposed to the carcinogen and new tumors develop in many patients. Thus, the patient is contemplating bladder removal again if these new or recurrent tumors are high grade or invasive. If he has had radiation as part of a bladder preservation program the morbidity of the salvage cystectomy is higher. My initial impression of this small series was that the risk of under staging is too high and BCG should not be effective if there is residual muscle invasive transitional cell carcinoma. On further reflection, however, the approach is not unreasonable for a well selected population. The separation of T2 classification into superficial and deep muscle invasion is controversial and not terribly accurate. Cheng et al concluded that the size of a muscle invasive tumor was more predictive than the depth.2 Smaller tumors would seem more amenable to complete excision by transurethral resection. There may be another lesson from this article. The authors were prepared to use this bladder preservation approach for patients with limited muscle invasive transitional cell carcinoma, and they only found 2 appropriate candidates a year while treating more than 800 patients with bladder cancer. Most of these 800 patients probably had Ta and T1 transitional cell carcinoma. However, they obviously saw many with T2–T4 and metastatic transitional cell carcinoma. In the broad picture patients with muscle invasive bladder cancer are
BLADDER CARCINOMA AND BACILLUS CALMETTE-GUERIN IMMUNOPROPHYLAXIS being diagnosed too late.3 These tumors either grow rapidly or there is a delay in diagnosis because the patient has no symptoms or the physician does not recognize the need to investigate hematuria promptly and, thus, the tumors are too extensive for a transurethral resection based protocol. In my view this situation requires a public health initiative aimed at patients at high risk of bladder cancer, for example cigarette smokers and industrial exposure. Mark S. Soloway Department of Urology University of Miami School of Medicine Miami, Florida
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1. Soloway, M. S., Sofer, M. and Vaidya, A.: Contemporary management of stage T1 transitional cell carcinoma of the bladder. J Urol, 167: 1573, 2002 2. Cheng, L., Neumann, R. M., Scherer, B. G., Weaver, A. L., Leibovich, B. C., Nehra, A. et al: Tumor size predicts the survival of patients with pathologic stage T2 bladder carcinoma. Cancer, 85: 2638, 1999 3. Vaidya, A., Soloway, M. S., Hawke, C., Tiguert, R. and Civantos, F.: De novo muscle invasive bladder cancer: is there a change in trend? J Urol, 165: 47, 2001
Vol. 169, 931–935, March 2003 Printed in U.S.A.
DOI: 10.1097/01.ju.0000049002.75782.39
T2A TRANSITIONAL CELL CARCINOMA OF THE BLADDER: LONGTERM EXPERIENCE WITH INTRAVESICAL IMMUNOPROPHYLAXIS WITH BACILLUS CALMETTE-GUERIN ¨ RGEN E. GSCHWEND, SIMONE H. MAIER, BJOERN G. VOLKMER, JU EVELYN M. SEIDL-SCHLICK, DIETMAR BACH AND IMRE ROMICS From the Departments of Urology, University of Ulm, Ulm, St. Agnes Hospital, Bocholt, Germany, and Semmelweis University, Budapest, Hungary
ABSTRACT
Purpose: In this prospective study we evaluate the effect of combined transurethral resection of early muscle invasive bladder cancer and immunotherapy with bacillus Calmette-Guerin (BCG) in patients unfit for radical cystectomy or refusing more aggressive therapies. Materials and Methods: A total of 22 patients with a mean age 73.6 years were included in the study. Inclusion criteria were histologically proven muscle invasive transitional cell carcinoma of the bladder with a tumor-free second resection and negative staging examinations in patients unfit for radical cystectomy or refusing more aggressive therapies. All patients received 6 weekly instillations of 120 mg. BCG starting 14 to 21 days after the last transurethral resection of the tumor. Followup at 3 months included cystoscopy, urinary cytology, ultrasound of the abdomen and chest x-ray. Every 6 months computerized tomography of the abdomen and bone scans were performed. Results: The overall 5-year survival rate was 69.1%, while the disease specific 5-year survival rate was 94%. One muscle invasive recurrence was noted at 69 months, which was again treated with the same regimen but ultimately led to radical cystectomy 21 months later. One patient died of progressive recurrence in the upper urinary tract. The 5-year recurrence-free survival rate was 46.5%. The only severe complication was BCG pneumonitis. Conclusions: The data show encouraging results for transurethral resection of bladder tumor with intravesical BCG therapy in select patients with T2a bladder cancer who are not candidates for radical cystectomy. KEY WORDS: carcinoma, transitional cell; neoplasm invasiveness, immunotherapy, bladder
Patients with T2a muscle invasive transitional cell carcinoma of the bladder are at risk for local recurrence, tumor progression and metastatic spread. The rate of under staging by transurethral resection of bladder tumors and the lack of efficient therapeutic options have led to the recommendation of radical cystectomy as first-line treatment. Optimized operative techniques, growing experience treating geriatric patients and advanced intensive care modalities have extended the cystectomy population within the last 20 years. However there remains a small group of patients with early muscle invasive (T2a) bladder cancer who are neither eligible for radical cystectomy nor chemoradiotherapy. Since the first report in 1976 by Morales et al of a beneficial effect of intravesical instillations of bacillus Calmette-Guerin (BCG) on the recurrence and course of bladder cancer,1 BCG has become an established therapeutic option for patients with completely resected superficial bladder carcinoma, especially those with high grade transitional cell carcinoma.2 We report the results of a prospective study in patients with T2a bladder cancer not eligible for cystectomy or chemoradiotherapy who were treated with transurethral resection combined with intravesical BCG immunoprophylaxis. PATIENTS AND METHODS
Between July 1986 and June 1997 all patients with muscle invasive transitional cell carcinoma of the bladder not eligible for radical cystectomy or chemoradiotherapy, or refusing these options underwent a second transurethral resection of Accepted for publication September 13, 2002.
the tumor site at our hospital. When the second resection revealed a tumor-free deep muscle layer and further staging examinations, including chest x-ray, ultrasound of the abdomen, excretory urography, computerized tomography of the abdomen and bone scan, did not reveal any pathological findings, the patients were included in this study. Exclusion criteria were secondary malignancies within the last 5 years, age younger than 18 years, squamous cell carcinoma or adenocarcinoma of the bladder, or suspicion of immunodeficiency. The patients received 6 weekly intravesical instillations of 120 mg. BCG (Pasteur or Connaught) in 50 cc saline starting 14 to 21 days after the last resection of the bladder tumor. No maintenance therapy was given. Followup in all patients at 3 months included cystoscopy, urinary cytology, ultrasound of the abdomen and chest x-ray. Computerized tomography of the abdomen and bone scans were performed every 6 months. Further examinations depended on symptoms. All local recurrences were confirmed by transurethral resection. After informed consent was obtained 15 men and 7 women of 820 patients treated with transitional cell carcinoma of the bladder were included in this study (see table). Mean patient age was 73.6 years (range 43 to 89). Of these patients 9 refused (2 because of age) and 13 were not eligible for more aggressive therapies because of severe concomitant diseases. Mean followup was 45 months (range 11 to 119), and 16 patients were followed for more than 24 months. No patient was lost to followup until death. All patients had primary muscle invasive tumors, and none had received prior intravesical therapies. All 9 patients with T2a GIII tumors had
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BLADDER CARCINOMA AND BACILLUS CALMETTE-GUERIN IMMUNOPROPHYLAXIS Patient data
Pt.—Age Reason Against Primary No. Chemoradiotherapy Stage 1—81 2—71 3—68 4—81 5—77 6—77 7—80 8—81 9—89 10—82 11—75 12—73 13—63 14—56 15—76 16—74 17—43 18—65 19—75 20—76 21—89 22—68
Lung Heart Heart Heart/refusal Kidney Cerebrum Heart Lung Refusal (age) Heart Heart/refusal Heart Refusal Refusal Refusal Heart Refusal Heart Lung Refusal Refusal (age) Heart
T2a T2a T2a T2a T2a T2a T2a T2a T2a T2a T2a T2a T2a T2a T2a T2a T2a T2a T2a T2a T2a T2a
Ca In Situ
GII GIII GIII GIII GIII GII GII GII GII GII GIII GIII GII GII GII GIII GIII GII GII GII GII GIII
— Yes Yes Yes Yes — — — — — Yes Yes — — — Yes Yes — — — — Yes
Solitary/ Mos. Multifocal Followup Solitary Multifocal Multifocal Solitary Multifocal Solitary Multifocal Multifocal Multifocal Solitary Solitary Solitary Multifocal Multifocal Solitary Multifocal Solitary Multifocal Multifocal Multifocal Solitary Solitary
11 12 12 13 20 23 25 29 30 31 34 42 45 46 48 49 53 68 80 92 104 119
Mos. Survival (outcome)
Mos. Recurrence-Free Survival (tumor stage)
Mos. Progression-Free Survival (tumor stage)
11⫹ 11⫹ 11⫹ 12 (no evidence of disease) 12⫹ 12⫹ 12 (no evidence of disease) 12⫹ 12⫹ 13⫹ 13⫹ 13⫹ 20 (dead from disease) 17 (T3 GIII, renal pelvis) 17 (T3 GIII, renal pelvis) 23⫹ 23⫹ 23⫹ 25 (no evidence of disease) 25⫹ 25⫹ 29 (no evidence of disease) 29⫹ 29⫹ 30⫹ 6 (Ta GII) 30⫹ 31 (no evidence of disease) 31⫹ 31⫹ 34⫹ 34⫹ 34⫹ 42⫹ 42⫹ 42⫹ 45⫹ 35 (Ta GII) 45⫹ 46⫹ 46⫹ 46⫹ 48⫹ 7 (T1 GII) 48⫹ 49⫹ 21 (T3a GIII) 21 (T3a GIII) 53⫹ 53⫹ 53⫹ 68 (no evidence of disease) 60 (Ta GI) 68⫹ 80⫹ 80⫹ 80⫹ 92⫹ 41 (Ta GII) 92⫹ 104⫹ 104⫹ 104⫹ 119⫹ 69 (T2a GIII) 90 (T3a GIII)
peritumoral carcinoma in situ, including 4 with concomitant multifocal carcinoma in situ. Data were analyzed using the Kaplan-Meier-Method including overall survival disease specific, recurrence-free and progression-free survival rates. RESULTS
All 22 patients underwent a second transurethral resection of bladder tumor. The histological results were tumor-free in 16 cases, residual superficial transitional cell carcinoma with a tumor-free muscle layer in 5 and minimal residual muscle invasive disease with a tumor-free deep muscle layer in 1. All patients had negative urine cytologies 3 and 6 months after resection. During followup 6 of 22 patients died of concomitant diseases without clinical evidence of tumor recurrence or progression. In 1 patient an invasive infiltrating transitional cell carcinoma of the renal pelvis developed at 17 months. The patient refused any therapy and died 3 months later. The calculated overall 5-year survival rate was 69.1%, while the disease specific 5-year survival rate was 94.1% (fig. 1). In 1 patient
muscle invasive local recurrence developed 69 months after BCG immunoprophylaxis. Pathological evaluation revealed T2a transitional cell carcinoma and a subsequent tumor-free second resection. The patient still refused radical cystectomy and BCG immunoprophylaxis was repeated. T2 GIII bladder carcinoma with multifocal carcinoma in situ was present 21 months later, which was treated with radical cystectomy and urinary diversion with an ileal conduit. Overall only 2 of 22 patients presented with tumor progression for a 5-year progression-free survival rate of 88.8% (fig. 2). In 6 patients superficial transitional cell carcinoma of the bladder developed during followup (Ta GI 1, Ta GII 2, T1 GII 3). These tumors were completely resected with a tumor-free deep layer on second transurethral resection. All patients received a second cycle of BCG immunoprophylaxis. Overall superficial tumor recurrence developed in 8 of 22 patients for a 5-year recurrence-free survival rate of 46.5% (fig. 2). Only 1 severe treatment associated complication was observed. After the last intravesical instillation of BCG 1 patient suf-
FIG. 1. Overall and disease specific survival rates in 22 patients with T2a bladder cancer treated with transurethral resection and BCG immunoprophylaxis.
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FIG. 2. Recurrence-free and progression-free survival rates in 22 patients with T2a bladder cancer treated with transurethral resection and BCG immunoprophylaxis.
fered from BCG pneumonitis with acute respiratory distress syndrome. He completely recovered after steroid therapy and disease is now in complete remission. DISCUSSION
In 1976 Morales et al reported the first encouraging results of intravesical BCG for patients with transitional cell carcinoma of the bladder.1 While the first published studies used mixed populations with superficial and early muscle invasive tumors,3 the majority of later studies focused on the effect of BCG immunoprophylaxis on the recurrence and progression of superficial bladder cancer. Today intravesical BCG instillation can be regarded as the first choice prophylaxis for recurrent superficial transitional cell carcinoma, at least for high risk tumors such as carcinoma in situ. Radical cystectomy is considered the gold standard for muscle invasive transitional cell carcinoma of the bladder. The disease specific survival rate for pT2a bladder cancer ranges between 63% and 82% at 5 years according to larger series.4 –7 Data on the tumor specific survival rate for T2a bladder cancer treated with transurethral resection alone are limited. The 5-year disease specific survival rates in this group range between 45% and 70%.8 –12 These results are 10% to 20% worse compared to those of cystectomy cases. Reasons for this difference are clinical under staging by transurethral resection of bladder tumor alone and lack of information regarding lymph node status. Large cystectomy series have shown that lymph node metastases can be expected in 10% of early muscle infiltrating tumors.13 The staging error in the depth of tumor invasion from T2a to more invasive tumors is estimated to be at least 25%.7, 14 In regard of disease specific survival our results are close to the survival outcome of patients treated with cystectomy. Reasons for this correlation may be a reduced rate of under staging due to an aggressive transurethral resection until the tumor was completely resected and a tumor-free deep muscle layer was confirmed; a reduced rate of recurrent high grade superficial transitional cell carcinoma, and a potential systemic effect of BCG on the disease. Such a systemic effect of BCG was discussed 60 years ago.15 Our data are in accordance with those of Netto and Lemos who reported a partial response rate of 70% following oral BCG in 20 patients with muscle invasive bladder cancer.16 In addition to the risk of systemic disease patients with early
muscle invasive bladder cancer have an increased risk of local recurrence. This finding is supported by the relatively high rate of concomitant carcinoma in situ and multifocal tumors. Therefore, the local recurrence rate can be estimated as high as that of high grade papillary tumors or carcinoma in situ of the bladder. Herr reported a 35% local recurrence rate of muscle invasive tumors in 45 patients with initial T2-4 tumors treated with transurethral resection.11 Our recurrence-free 5-year survival rate was 46.5%. These rates are comparable to those (range 41% to 60%) of aggressive superficial transitional cell carcinoma of the bladder (T1 GIII and carcinoma in situ) treated with transurethral resection of bladder tumor and BCG immunoprophylaxis.17, 18 Similar to patients with high grade superficial transitional cell carcinoma BCG maintenance therapy might have an additional beneficial effect in our cases, since superficial transitional cell carcinoma recurred within 7 to 41 months in at least 5 patients. Until today a significant reduction in the progression rate of superficial transitional cell carcinoma by BCG immunoprophylaxis has not been proven. However, another muscle invasive tumor developed in only 2 of our patients at 17 and 69 months, respectively. This rate does not differ from the progression rates reported for high grade papillary tumors treated with transurethral resection of bladder tumor and BCG immunoprophylaxis. Our overall 5-year survival rate of 69% reflects high comorbidity since only 1 patient died of tumor. The rate of severe complications from BCG immunoprophylaxis was low compared to the reported complication rates of radical cystectomy. Therefore, we assume, that this treatment option might be indicated even for patients with bladder cancer and severe concomitant diseases.
CONCLUSIONS
Our data show encouraging results with transurethral resection and BCG immunoprophylaxis in patients with T2a transitional cell carcinoma of the bladder who were unfit for or refused more aggressive therapies. Our data may theoretically support a beneficial systemic effect of BCG for muscle invasive transitional cell carcinoma. However, the real value of this study protocol compared to transurethral resection of bladder tumor alone and radical cystectomy can only be determined by a randomized prospective study. Since radical cystectomy has been accepted as standard therapy for T2a
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transitional cell carcinoma of the bladder, it is unlikely that such a study will be conducted. REFERENCES
1. Morales, A., Eidinger, D. and Bruce, A. W.: Intracavitary bacillus Calmette-Guerin in the treatment of superficial bladder tumors. J Urol, 116: 180, 1976 2. Lamm, D. L., Blumenstein, B. A., Crawford, E. D., Crissmann, J. D., Lowe, B. A., Smith, J. A. et al: Randomized intergroup comparison of bacillus Calmette-Guerin immunotherapy and Mitomycin C chemotherapy prophylaxis in superficial transitional cell carcinoma of the bladder: a Southwest Oncology Group study. Urol Oncol, 1: 119, 1995 3. Lamm, D. L.: Bacillus Calmette-Guerin immunotherapy for bladder cancer. J Urol, 134: 40, 1985 4. Bassi, P., Ferrante, G. D., 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. J Urol, 161: 1494, 1999 5. Gschwend, J. E., Fair, W. R. and Vieweg, J.: Radical cystectomy for invasive bladder cancer: contemporary results and remaining controversies. Eur Urol, 38: 121, 2000 6. Malkowicz, S. B., Nichols, P., Lieskovsky, G., Boyd, S. D., Huffman, J. and Skinner, D. G.: The role of radical cystectomy in the management of high grade superficial bladder cancer (PA, P1, PIS, P2). J Urol, 144: 641, 1990 7. Dutta, S. C., Smith, J. A., Jr., Shappell, S. B., Coffey, C. S., Chang, S. S. and Cookson, M. S.: Clinical understaging of high risk nonmuscle invasive urothelial carcinoma treated with radical cystectomy. J Urol, 166: 490, 2001 8. RUTT (Registry of Urinary Tract Tumors). Harnwegstumorregister, Jahresbericht. Verh Dtsch Ges Urol, 37: 685, 1985 9. Henry, K., Miller, J., Mori, M., Loening, S. and Fallon, B.: Comparison of transurethral resection to radical therapies for stage B bladder tumors. J Urol, 140: 964, 1988 10. O’Flynn, J. D., Smith, J. D. and Hanson, J. S.: Transurethral resection for the assessment and treatment of vesical neoplasms. A review of 800 consecutive cases. Eur Urol, 1: 38, 1975 11. Herr, H. W.: Conservative management of muscle-infiltrating bladder cancer: prospective experience. J Urol, 138: 1162, 1987 12. Herr, H. W.: Transurethral resection of muscle-invasive bladder cancer: 10-year outcome. J Clin Oncol, 19: 89, 2001 13. Vieweg, J., Gschwend, J. E., Herr, H. W. and Fair, W. R.: The impact of primary stage on survival in patients with lymph node positive bladder cancer. J Urol, 161: 72, 1999 14. Lee, R. and Droller, M. J.: The natural history of bladder cancer. Implications for therapy. Urol Clin North Am, 27: 1, 2000 15. Holmgren, I.: La tuberculine et le BCG chez les chance´ reux. Schweiz Med Wochenschr, 65: 1203, 1935 16. Netto, N. R., Jr. and Lemos, G. C.: Bacillus Calmette-Guerin immunotherapy of infiltrating bladder cancer. J Urol, 132: 675, 1984 17. Lamm, D. L., Blumenstein, B. A., Crissman, J. D., Montie, J. E., Gottesman, J. E., Lowe, B. A. et al: Maintenance bacillus Calmette-Guerin immunotherapy for recurrent TA, T1 and carcinoma in situ transitional cell carcinoma of the bladder: a randomized Southwest Oncology Group study. J Urol, 163: 1124, 2000 18. Brake, M., Loertzer, H., Horsch, R. and Keller, H.: Recurrence and progression of stage T1, grade 3 transitional cell carcinoma of the bladder following intravesical immunotherapy with bacillus Calmette-Guerin. J Urol, 163: 1697, 2000 EDITORIAL COMMENT Radical cystectomy is a formidable procedure. The cardiac, vascular and respiratory systems of most patients with bladder cancer have been adversely impacted by years of cigarette smoking. Many are overweight and older than 65 years, representing additional risk factors for major pelvic surgery. The reconstruction must be precise. There are suture and staple anastomoses that must heal without leaking and yet remain patent. Due to dramatic improvements in perioperative care, operative mortality has declined to less than 5%. However, perioperative morbidity hovers around 20% to 25%. Thus, it is no surprise that most of these procedures are performed at large hospital centers with state-of-the-art intensive care units and fellows and residents to help with the intraoperative and postoperative care. A reason that bladder preservation is an attractive option for muscle invasive bladder cancer is the desire on the part of the
patient and the urologist to avoid this major procedure. Although an orthotopic bladder substitute has made radical cystectomy more palatable, approximately 20% to 30% of patients are not candidates because of cancer related factors, age, co-morbidity or altered renal function. Bladder preservation provides the advantages of less surgery, no diversion and the potential to retain a more normal sex life. Volkmer et al provide us with an alternative for a select group of patients with transitional cell carcinoma which has invaded the superficial muscularis propria of the bladder. They performed a thorough transurethral resection followed by intravesical BCG instillation. They suggest that since this approach is reasonable for initial treatment of patients with high grade T1 transitional cell carcinoma, why not for limited T2? The authors were obviously selective, treating 22 patients in 11 years. They excluded patients with prior transitional cell carcinoma, which eliminates patients more likely to have recurrence. Mean patient age was almost 74. In the abstract the authors state that there was “a tumor-free second resection,” however, 1 patient had “minimal residual muscle invasion” (negative deep muscle) and 5 had superficial transitional cell carcinoma (no tumor in the muscularis propria). Thus, only 16 of the 22 patients had no tumor on the re-staging transurethral resection. Thus, assuming the patients did not already have metastasis (in which case cystectomy will not be curative), this approach is not unlike the management of high grade T1 transitional cell carcinoma with a second transurethral resection (to confirm less than T2 and resect residual tumor) followed by intravesical BCG. With careful monitoring and proceeding to radical cystectomy if there is a subsequent high grade tumor, the results for T1 transitional cell carcinoma are comparable to initial cystectomy.1 Is this similar approach comparable for “limited T2” transitional cell carcinoma? According to the table, after completing BCG 5 patients had high grade Ta-T1 transitional cell carcinoma, 1 had a T2a lesion and 2 had T3 lesions. Mean followup is only 45 months and only 16 patients have been followed longer than 2 years, which is to short for me to be confident of this treatment approach based on this limited series. However, Herr retrospectively analyzed the outcome of 99 patients with muscle invasive transitional cell carcinoma who had either no tumor, carcinoma in situ or T1 tumor on a second transurethral resection (reference 12 in article). The bladder was initially preserved, that is no cystectomy, and minimum followup was 10 years or death. Of the patients 24% died of transitional cell carcinoma and 57% retained the bladder. The series of Herr dates from 1979 to 1989. All patients did not receive BCG and some may not have had a cystectomy at the first sign of a new high grade transitional cell carcinoma. Herr suggests that despite close followup, patients who meet the criteria for this transurethral resection based bladder preservation approach must assume an 8% to 16% risk that a recurrent or new invasive tumor will cause death from transitional cell carcinoma. This figure is reasonable in my view and must be weighed against the operative mortality and morbidity of cystectomy. However, it all begins with the decision to perform a second transurethral resection. A review of the initial transurethral resection specimen with the pathologist along with information garnered from the initial endoscopy will help select patients for bladder preservation. Bladder cancer covers a wide spectrum. The reason that radical transurethral resection followed by chemotherapy and radiationchemotherapy protocols falls is because the entire urothelium has been exposed to the carcinogen and new tumors develop in many patients. Thus, the patient is contemplating bladder removal again if these new or recurrent tumors are high grade or invasive. If he has had radiation as part of a bladder preservation program the morbidity of the salvage cystectomy is higher. My initial impression of this small series was that the risk of under staging is too high and BCG should not be effective if there is residual muscle invasive transitional cell carcinoma. On further reflection, however, the approach is not unreasonable for a well selected population. The separation of T2 classification into superficial and deep muscle invasion is controversial and not terribly accurate. Cheng et al concluded that the size of a muscle invasive tumor was more predictive than the depth.2 Smaller tumors would seem more amenable to complete excision by transurethral resection. There may be another lesson from this article. The authors were prepared to use this bladder preservation approach for patients with limited muscle invasive transitional cell carcinoma, and they only found 2 appropriate candidates a year while treating more than 800 patients with bladder cancer. Most of these 800 patients probably had Ta and T1 transitional cell carcinoma. However, they obviously saw many with T2–T4 and metastatic transitional cell carcinoma. In the broad picture patients with muscle invasive bladder cancer are
BLADDER CARCINOMA AND BACILLUS CALMETTE-GUERIN IMMUNOPROPHYLAXIS being diagnosed too late.3 These tumors either grow rapidly or there is a delay in diagnosis because the patient has no symptoms or the physician does not recognize the need to investigate hematuria promptly and, thus, the tumors are too extensive for a transurethral resection based protocol. In my view this situation requires a public health initiative aimed at patients at high risk of bladder cancer, for example cigarette smokers and industrial exposure. Mark S. Soloway Department of Urology University of Miami School of Medicine Miami, Florida
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1. Soloway, M. S., Sofer, M. and Vaidya, A.: Contemporary management of stage T1 transitional cell carcinoma of the bladder. J Urol, 167: 1573, 2002 2. Cheng, L., Neumann, R. M., Scherer, B. G., Weaver, A. L., Leibovich, B. C., Nehra, A. et al: Tumor size predicts the survival of patients with pathologic stage T2 bladder carcinoma. Cancer, 85: 2638, 1999 3. Vaidya, A., Soloway, M. S., Hawke, C., Tiguert, R. and Civantos, F.: De novo muscle invasive bladder cancer: is there a change in trend? J Urol, 165: 47, 2001