0022-534 7/92/1483-0797$03.00/0 THE JOURNAL OF UROLOGY Copyright© 1992 by AMERICAN UROLOGICAL AsSOCiATION, INC.
MANAGEMENT OF STAGE Tl SUPERFICIAL BLADDER CANCER WITH INTRA VESICAL BACILLUS CALMETTE-GUERIN THERAPY MICHAEL S. COOKSON AND MICHAEL F. SAROSDY* From the Division of Urology, The University of Texas Health Science Center at San Antonio, San Antonio, Texas
ABSTRACT
We reviewed our results with 86 patients who had a pretreatment history of a stage Tl tumor. All patients were treated with transurethral resection of all visible tumor followed by intravesical bacillus Calmette-Guerin (BCG) and many patients received additional maintenance therapy. Local recurrences were treated with repeat transurethral resection followed by additional BCG. Median followup was 59 months, with a range of 9 to 149 months. Overall, 78 of 86 patients (91 %) were free of tumor recurrence with BCG therapy. This result includes 69% of the patients who responded to the initial transurethral resection and intravesical BCG, and 22% who ceased having tumors after additional treatments for local recurrences. Only 7% of the patients had progression to stage T2 tumors after BCG therapy. Grade of the stage Tl tumor, concurrent carcinoma in situ and tumor multiplicity before BCG did not predict tumor recurrence or progression. Of patients with recurrences after BCG therapy, those with stage Tl tumors had a higher rate of progression compared to those with stage Ta tumors but the difference was not statistically significant (p = 0.086). These data clearly support the efficacy of transurethral resection plus intravesical BCG immunotherapy in the treatment of stage Tl tumors as well as in the prevention of disease progression. KEY WORDS:
bladder neoplasms, BCG vaccine, carcinoma in situ
The management of stage Tl superficial bladder cancer that invades the lamina propria continues to be debated. While there is general agreement that stage Tl tumors are associated with a worse prognosis than noninvasive papillary stage Ta tumors, recurrence and progression rates are highly variable. 1- 13 Progression rates in patients with stage Tl tumors have decreased significantly (p = 0.001) when transurethral resection is combined with intravesical bacillus Calmette-Guerin (BCG) or chemotherapy compared to transurethral resection alone (17% versus 29%, respectively). 1 Since many large series of patients with stage Tl tumors were treated with only an initial 6-week course of BCG, patients treated with additional BCG after local recurrence and those treated with maintenance doses of intravesical BCG might be expected to have an even lower rate of stage progression. This is particularly important to consider in the face of a report that implied that the presence of a stage Tl tumor after only an initial 6-week course of BCG is an ominous prognostic indicator, with the implication that some therapy other than BCG should be used for those patients.2 We reviewed the results of 86 patients who underwent resection of a stage Tl bladder tumor immediately before intravesical BCG therapy. The study was performed in an attempt to determine the effectiveness of intravesical BCG in the prevention of local recurrences and progression to muscle invasive disease in patients with stage Tl superficial bladder cancer. MATERIALS AND METHODS
Patients. The records were reviewed of 230 patients with a history of superficial bladder tumors that were treated with therapeutic courses of intravesical BCG after transurethral resection of all visible tumor, and who were not presently enrolled in ongoing protocol studies. Of these patients 86 had a history of a stage Tl bladder tumor immediately before therapy. The available medical records of these 86 patients provided the database for this review. Followup ranged from 9 to 149 months, with a median of 59 months. Only 16 patients
(19%) were followed for less than 36 months and 60 (70%) were followed for 48 months or longer. One patient was followed for less than 1 year, and this patient had progression in stage and died postoperatively with only 9 months of followup. Included are 56 patients with stage Tl tumors who were among a larger group with superficial bladder cancer previously reported; followup at that time ranged from 13 to 120 months.13 Patients were stratified according to pretreatment tumor multiplicity (solitary tumor with or without carcinoma in situ versus multiple tumors) and by grade of stage Tl tumor immediately before BCG therapy. Tumors were staged according to the Marshall modification of Jewett's system 14 and grade was determined according to the criteria of Mostofi. 15 BCG. Pasteur strain BCGt was administered, with each ampule containing 120 mg. to be reconstituted in 50 ml. sterile saline. Treatment. After complete resection of all visible tumors the patients were treated with l ampule of BCG weekly for 6 weeks. All patients received at least an initial 6-week course, and many received additional BCG at 3, 6 and 12 months and/or annual maintenance therapy. The majority of the patients received percutaneous inoculation in addition to intravesical therapy. Patients were followed with cystoscopy and bladder wash cytology studies at regular intervals. For patients who were without evidence of disease these studies were performed quarterly for 2 years, semiannually for 2 years and annually thereafter. Patients with superficial (stages Ta and Tl) recurrences were treated with complete resection of all visible tumor followed by additional courses of BCG. This additional BCG course of therapy was variable, ranging from 6 weekly treatments to 3 treatments every other week or monthly treatments for 12 consecutive months. These patients also received additional maintenance BCG therapy. All patients were followed for as long as possible and, if lost to followup, the date of the last visit was recorded as the last date of followup. Statistical analysis. Comparison of tumor recurrence and progression rates were performed with chi-square analysis. RESULTS
Overall, 78 of 86 patients (91 %) were rendered free of tumor recurrence with BCG therapy after resection of a stage Tl
Accepted for publication February 28, 1992. * Requests for reprints: Division of Urology, The University of Texas Health Science Center at San Antonio, 7703 Floyd Curl Dr., San Antonio, Texas 78284-7845.
t Institute Armand Frappier, Montreal Quebec, Canada. 797
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COOKSON AND SAROSDY
tumor. Included in these patients are 59 (69%) with no recurrence after initial transurethral resection followed by intravesical BCG immunotherapy, and 19 (22%) who ceased having tumors after additional transurethral resection and additional intravesical BCG (see figure). A total of 8 patients failed to remain free of recurrence, with 6 (7%) having progression in stage to muscle invasive (stage T2 or greater) disease. Two patients underwent cystectomy for rapidly recurrent superficial disease. The results were stratified according to the number of previous recurrences before BCG therapy (table 1). A total of 23 patients had an initial solitary stage Tl tumor at presentation, of whom 6 (26%) had recurrences after BCG and 2 (8%) had progression to stage T2 disease. Both of the latter patients had grade 3 histology and represent 33% (2 of 6) of those who presented with this histology in the solitary stage Tl tumor. Carcinoma in situ in the presence of an initial solitary stage Tl tumor was found in 5 patients. One patient (20%) had recurrence and none had progression. A total of 58 patients had a history of multiple superficial tumors before BCG. Twenty patients (35%) had at least 1 recurrence and 4 (7%) had progression to stage T2 disease. There was no significant difference among the patients when stratified according to pretreatment tumor history with respect to recurrence (p = 0.651) or progression (p = 0. 787). Of the 58 patients 25 had a history of multiple stage Ta tumors plus a stage Tl lesion before BCG. In this subset there were 8 patients (32%) with recurrence and 3 (12%) with progression to stage T2. Of the 58 patients 33 had a history of multiple stage Tl tumors, and among these patients there were 12 (36%) who had a recurrence and 1 (3%) who had progression to muscleinvasive disease. There was no significant difference among
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patients with multiple stage Ta versus stage Tl tumors in relation to recurrence (p = 0.729) or progression (p = 0.182). Of the 86 patients 27 (31 %) had tumor recurrence after initial BCG (table 1). Stage of tumor at recurrence relative to progression in stage is shown in table 2. Among the 27 patients 6 (22%) had progression to stage T2 disease, including 4 with muscle invasion at the time of the initial recurrence. Complete tumor histories for these 27 patients are shown in table 3. The median interval to progression was 15 months (range 13 to 52) and the median interval to recurrence was 13 months (range 3 to 84). Of the 27 patients with recurrences 19 eventually achieved a recurrence-free status with additional transurethral resection and intravesical BCG, with a median recurrence-free followup of 47 months (range 31 to 139). Included in the 27 patients with recurrence were 12 with stage Ta and 11 with stage Tl tumors. AH 12 patients with stage Ta recurrences were rendered recurrence-free with local therapy consisting of transurethral resection and additional BCG, and there were no stage progressions in this group. Of the 11 patients with recurrent stage Tl tumors after initiation of BCG therapy 7 (64%) were treated successfully with repeat transurethral resection and additional BCG. Of these 11 patients 2 had progression to stage T2 disease and 2 underwent cystectomy for recurrent superficial disease. There was no statistically significant difference in progression rates between patients with stage Ta (O of 12) versus stage Tl (2 of 11) recurrences (p = 0.086). The relationship between initial stage Tl tumor histology and recurrence is shown in table 4. Of the 86 patients 11 had grade 1, 44 had grade 2, 16 had grade 3 and 15 had any grade disease plus carcinoma in situ before BCG therapy, and tumors recurred in 4 (36%), 14 (32%), 7 (44%) and 2 (13%), respectively. Among the patients with grade 3 histology 7 (44%) had a recurrent tumor and 3 (19%) had progression in stage. With respect to grade of the stage Tl tumor there was no statistically significant difference in patients with grade 3 histology compared with grades 1 and 2 or any grade plus carcinoma in situ (p = 0.178 and p = 0.094, respectively). Of the 15 patients with a stage Tl tumor and carcinoma in situ there was no stage progression and only 2 (13%) had any recurrence .
60
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DISCUSSION
40
...
LL -;!?., 0
20 0
A. Initial
B. Initial Plus Retreatment
Treatment Course TABLE
1. Response to BCG immunotherapy stratified according to
pretreatment tumor history Pretreatment Frequency of Tumors Total No. pts. (%) Solitary Tl: Grade 1 Grade 2 Grade 3 Solitary Tl + Ca in situ: Grade 2 + Ca in situ Grade 3 + Ca in situ Multiple tumors: Multiple Ta, single Tl Multiple Tl
No. Pts. 86 23 6 11 6 5 1 4 58 25 33
With Any Recurrences No. Pts. (%)
With Stage Progression (T2 or greater) No. Pts. (%)
27 (31) 6 (26) 1 (17) 2 (18) 3 (50) 1 (20) 0 1 (25) 20 (35) 8 (32) 12 (36)
6 (7) 2 (8) 0 0 2 (33) 0 0 0 4 (7) 3 (12) 1 (3)
This review of 86 patients with stage Tl transitional cell carcinoma of the bladder treated with transurethral resection followed by intravesical BCG suggests that this is an effective form of therapy for these patients. This concept is supported by the finding that 69% of the patients remained free of recurrence after initial therapy alone and that only a small percentage of patients (7%) demonstrated progression in stage to muscle-invasive disease. Included in this review were 33 patients with a history of recurrent Tl tumors before BCG and 11 with stage Tl recurrences after the initiation of BCG therapy. Patients in our series demonstrated an excellent overall response to therapy, including patients with recurrences who were treated with additional intravesical BCG therapy after repeat transurethral resection. When responders to initial BCG are added to those who underwent additional therapy for a TABLE
2. Stage of tumor at recurrence relative to progression in stage
and tumor-free status Tumor Stage at Recurrence Ta Tl T2 Totals
No.(%) 12 11 4 27
(44) (41) (15) (100)
Progression (T2 or greater) No.(%)
Eventually Recurrence-Free No.(%)
0 2 (18) 4 (100) 6 (22)
12 7 (64)* Not ap12licable 19 (70)
Median disease-free followup 47 months (range 31 to 139). * Does not include 2 patients who underwent cystectomy for superficial disease and 1 who underwent cystectomy for stage T2 disease.
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INTRAVESICAL BACILLUS CALMETTE-GUERJN THERAPY TABLE
Pt No.
No. Previous Recurrences
3. Clinical history of 27 patients with recurrences No. Recurrences After BCG
Previous Highest Stage/Grade
Post-BCG Stage/ Grade
Mos. to Recurrence
Disease-Free Followup (mos.)
35 12 27 12 24 61 70 84 6 9 50 12 7 3 9
47 63
Group }-stage Ta recurrences 1 2
0
1
Tl/3 Tl/1
1 2
3 4 5 6 7 8
1 0 6 5 2 0
Tl/2 Tl/2 Tl/2 Tl/1 Tl/2 Tl/1
1 1 1 1 1 2
9 10
3 3 2 5
Tl/+ Ca in situ Tl/2 Tl/1 Tl/2
1 1 1 2
11
12
Ta/1 Ta/1 Ta/1 Ta/1 Ta/1 Ta/2 Ta/1 Ta/1 Ta/1 Ta/2 Ta/1 Ta/1 Ta/1 Ta/2 Ta/1
49 31 119 138 139 89 120 77 45 72
Group 2-stage Tl or T2 recurrences 13 14 15 16 17
0 0 1 2 3
Tl/3 Tl/3 Tl/2 Tl/2 Tl/2
1 1 1 1 2
18
5
Tl/3
4
19 20
4 0
Tl/2 Tl/2
1 2
21 22 23
3 2 5
Tl/2 Tl/2 Tl/2
1 1 2
24 25
0 2
Tl/2 + Ca in situ Tl/2
1 3
26
10
Tl/3
2
27
9
Tl/3
TABLE 4.
Relationship of pretreatment stage Tl tumor histology and response to ECG immunotherapy
Pretreatment Stage Tl Tumor Histology Grade 1 Grade 2 Grade 3 Any grade + Ca in situ Totals
No. Pts.
11
44 16 15
86
With Any Recurrences No.(%) 4 (36) 14 (32) 7 (44)
2 (13) 27 (31)
With Stage Progression (T2 or greater) No.(%) 0 3 (7) 3 (19) 0
6(7)
recurrence after initial BCG therapy, an overall recurrence-free rate of 91 % was noted. The most important objective of intravesical therapy for superficial bladder cancer is the prevention of tumor stage progression. 3 Table 5 summarizes 7 recent series of patients treated with transurethral resection followed by intravesical BCG.'i- 9 From this table it is clear that a wide variety of progression rates have been cited. Among the 309 patients in table 5 the overall rate of progression is 13%, with a range of 2 to 38%. While summaries of reported results in patients with stage Tl tumors may be helpful, the differences in BCG treatment course including additional BCG for stages Ta and Tl recurrences may help to explain the variance in stage progression. For example, Herr et al reported progression rates of 38% and 24% among 13 and 29 patients, respectively, treated with a single 6-week course of BCG. 4 • 5 A single 6-week course of
T2 T2 T2 T2 Tl/1 Tl/2 Tl/3 Ta/1 Ta/2 Ta/1 Tl/2 Tl/2 Tl/2 Tl/2 Tl/2 Tl/2 Tl/2 Tl/2 + Ca in situ Tl/2 Tl/2 T2 Tl/2 T2 Tl/2
TABLE
26 52 13 17 19 12 8 17 12 34 16
112
4
48
26 52 13 17 48 67
7 15 9 26 38 13 6 12 15 12 15 3
58 9 38 36 72 21 46
5. Results of stage Tl tumors treated with transurethral
resection and intravesical ECG Reference Herr et al 4 Herr et al5 Steg et al 6 Martinez-Pineiro et al' Eure et al' Khanna et al8 Dal Bo et al' Present series
No. Patients With Stage Tl Tumor
No. Pts. With Progression (%)
Followup (mos.)
13
5 (38)
29
7 (24) 8 (18) 1 (2)
72* 60*
45 49 30 33 24 86
5 (17) 3 (9) 6 (25) 6 (7)
1st 36t 33t 25t 22* 59*
* Median.
t Mean.
BCG was used in the series of Steg6 and Dal Bo9 et al as well, with progression rates of 25% and 18%, respectively. The lowest rates of progression in stage have been reported in those series treated with repeat courses of intravesical BCG for superficial stages Ta and Tl recurrences. 7 • 9 In the series by Martinez-Pineiro et al patients received 4 weekly treatments of BCG and then monthly for 1 year, and a second 4-week course was administered for recurrences (stage Ta or Tl). 3 Their study showed a progression rate of 2% with a mean followup of 34 months (range 3 to 92). Khanna et al demonstrated a 9% progression rate in patients with stage Tl tumors and concluded that "therapy beyond an initial course of 6 weekly treatments increases the percentage of complete re-
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COOKSON AND SAROSDY
sponses." 8 Eure et al used a repeat course of BCG for incomplete responders and no maintenance therapy was given.7 Their progression rate of 17% despite retreatment can be explained partly by the fact that 17 of 30 patients were "felt to have incomplete resection" of tumor and 24 of 30 had grade 3 histology. Our series as well as results of others demonstrate a clear advantage in decreasing the rate of progression to muscle invasive disease in the majority of patients with stage Tl tumors treated with transurethral resection and intravesical BCG. These results are further enhanced when patients with superficial stages Ta and Tl recurrences undergo retreatment including additional transurethral resection and intravesical BCG as evidenced by the 7% stage progression rate observed in our series. The results of patients stratified according to number of recurreric:esliefore RCG therapy were a1so better in our series than in those reported previously. Patients with recurrent stage Tl tumors are believed to have an overall progression rate of about 35%, and those treated with transurethral resection and BCG had a progression rate of 28% (9 of 32) in 1 series. 1 Only 4 of our 58 patients (7%) with a pretreatment history of multiple tumors had progression in stage. This is in comparison to 2 of 23 patients (8%) with a solitary stage Tl tumor. There was no significant difference among patients with pretreatment solitary versus multiple tumors with respect to progression in stage after BCG treatment (p = 0.787). Also, multiple stage Tl tumors were not associated with a significantly higher rate of progression when compared with multiple stage Ta tumors in our series (p = 0.729). These data clearly support the efficacy of intravesical BCG in the prevention of progression to muscleinvasive disease in patients with stages Ta and Tl tumors, regardless of a history of pretreatment tumor multiplicity. A second important objective in treatment of superficial bladder cancer is to decrease the rate of recurrence. The ability of intravesical BCG to decrease the rate of recurrence has been well documented. 10• 18 • 16- 20 Our results support this concept in patients with stage Tl tumors, with 69% of the patients having no recurrence after initial therapy. This is remarkable when one considers that our series included 58 patients with a history of multiple tumors, 65% of whom had no recurrences after the initial course of BCG. Even among the 33 patients with multiple stage Tl tumor before therapy 64 % had no recurrence after initial BCG therapy. Several reports have shown that additional therapy with BCG after recurrence following initial therapy may increase the overall response rate. 13• 21 In our series 91 % of the patients with stage Tl tumors were eventually rendered recurrence-free with additional BCG therapy. Similarly, in patients with stage Tl tumors treated with additional BCG for local recurrences Martinez-Pineiro et al reported a 12% recurrence rate with a mean followup of 3 years. 3 Khanna et al reported that 50% of the patients in whom initial therapy failed had complete remission with additional BCG therapy. 8 Table 2 demonstrates that 70% of our patients with recurrences were eventually rendered recurrence-free with retreatment, and this proved to be effective irrespective of the stage (Ta versus Tl) at recurrence. A recurrence-free status was achieved in all 12 patients with stage Ta and in 7 of 11 (64%) with stage Tl recurrences, with no statistically significant difference between the 2 groups (p = 0.086). Thus, the majority of our patients with recurrences, including stage Tl recurrences, were successfully managed with transurethral resection and additional BCG therapy. These findings are in contrast to those recently reported by Herr in patients with stage Tl tumors after intravesical BCG. 2 Herr reported an 82% progression rate in 14 of 17 patients with a stage Tl tumor 3 months after initial transurethral resection and BCG therapy. However, these patients were not treated with additional BCG therapy and 12 of 14 had carcinoma in situ after 1 course of BCG. The short interval to progression in that series (median 8.4 months) also is suggestive of a highly
select group of patients not representative of most patients with stage Tl tumors. In our series BCG therapy was effective in the majority of patients with recurrent stage Tl tumors before therapy as well as those who had stage Tl tumors after an initial 6-week course. It is well recognized that patients with a high grade Tl tumor are at increased risk for local recurrence and progression in stage.9 • 12 • 22- 24 In our series patients with an initial pretreatment grade 3 stage Tl tumor demonstrated the highest rates of recurrence and progression in stage: 44% (7 of 16) and 19% (3 of 16), respectively. This is in comparison with initial grade 2 histology in which 32% of the patients had a recurrence and 7% experienced progression in stage. Despite the appearance of an increased rate of progression in patients with grade 3 histology, the difference was not statistically significant when comparea to grades 1 aria-2 or a:riy graae with carcinoma in situ in our series (p = 0.094). Dal Bo et al reported a 25% rate of recurrence (6 of 24) in patients with grade 3 stage Tl tumors treated with BCG and a 25% rate of stage progression. 9 Similarly, Jakse et al reported a 32% stage progression rate in 40 patients with stage Tl tumors and grade 3 histology. 24 Rates of progression in stage as high as 40% were found in 1 series of patients with grade 3 stage Tl tumors treated with transurethral resection alone. 23 It is clear from our data, as well as previously reported studies, that patients with grade 3 histology represent a particularly high risk subset in need of close followup, and a lower threshold to administer more aggressive therapy in these patients who fail to respond to local therapy is justified. These data support the concept that patients with stage Tl transitional cell carcinoma can be treated effectively with transurethral resection followed by intravesical immunotherapy with BCG. Additionally, patients with local recurrences, including those with stage Tl recurrences, can be managed successfully in most instances with repeat transurethral resection followed by additional intravesical BCG. In our series grade of tumor before BCG, concurrent carcinoma in situ and tumor multiplicity before BCG immunotherapy did not predict tumor recurrence or progression. Close followup should allow for identification of those select few patients who fail to respond to transurethral resection followed by intravesical BCG therapy with either rapidly recurrent superficial disease or progression to muscle invasion. Once these patients are identified a change in therapeutic strategy is, indeed, warranted to prevent further progression and ultimately enhance disease-free survival. Michael F. Luther performed the statistical analysis. REFERENCES 1. Herr, H. W., Jakse, G. and Sheinfeld, J.: The Tl bladder tumor. Sem. Urol., 8: 254, 1990. 2. Herr, H. W.: Progression of stage Tl bladder tumors after intravesical bacillus Calmette-Guerin. J. Urol., 145: 40, 1991. 3. Martinez-Pineiro, J. A., Leon, J. J., Martinez-Pineiro, L., Jr., Fiter, L., Mosteiro, J. A., Navarro, J., Matres, M. J. G. and Carcamo, P.: Bacillus Calmette-Guerin versus doxorubicin versus thiotepa: a randomized prospective study in 202 patients with superficial bladder cancer. J. Urol., 143: 502, 1990. 4. Herr, H. W., Laudone, V. P., Badalament, R. A., Oettgen, H. F., Sogani, P. C., Freedman, B. D., Melamed, M. R. and Whitmore, W. F., Jr.: BCG therapy alters the progression of superficial bladder cancer. J. Clin. Oncol., 6: 1450, 1988. 5. Herr, H. W., Badalament, R. A., Amato, D., Laudone, V. P., Fair, W. R. and Whitmore, W. F., Jr.: Superficial bladder cancer treated with bacillus Calmette-Guerin: a multivariate analysis of factors affecting tumor progression. J. Urol., 141: 22, 1989. 6. Steg, A., Belas, M. and Leleu, C.: Intravesical BCG therapy in patients with superficial bladder cancer. In: Immunotherapy of Urological Tumours. Edited by J. B. deKernion. New York: Churchill Livingstone, vol. 1, chapt. 11, pp. 107-112, 1990. 7. Eure, G. R., Ladaga, L. E. and Schellhammer, P. F.: BCG therapy for stage Tl superficial bladder cancer. J. Urol., part 2, 143: 341A, abstract 611, 1990.
INTRAVESICAL BACILLUS CALrvrnTTE-GUERIN THERAPY
8. Khanna, 0. P., Son, D. L., Mazer, H., Read, J., Nugent, D., Cottone, R., Heeg, M., Rezvan, M., Viek, N., Uhlman, R. and Friedmann, M.: Multicenter study of superficial bladder cancer treated with intravesical bacillus Calmette-Guerin or adriamycin. Urology, 35: 101, 1990. 9. Dal Bo, V., Belmonte, P., Veronesi, A., Lo Re, G., Miotto, E., Merlo, A., Volpe, R. and Francini, M.: Intravesical BCG instillations in patients with carcinoma in situ and pTl G3 transitional cell carcinoma of the bladder. Eur. Urol., suppl. 1, 18: 43, abstract 82, 1990. 10. Lamm, D. L., Thor, D. E., Harris, S. C., Reyna, J. A., Stogdill, V. D. and Radwin, H. M.: Bacillus Calmette-Guerin immunotherapy of superficial bladder cancer. J. Urol., 124: 38, 1980. 11. Lutzeyer, W., Rubben, H. and Dahm, H.: Prognostic parameters in superficial bladder cancer: an analysis of 315 cases. J. Urol., 127: 250, 1982. 12. Heney, N. M., Ahmed, S., Flanagan, M. J., Frable, W., Corder, M. P., Hafermann, M. D. and Hawkins, I. R. for National Bladder Cancer Collaborative Group A: Superficial bladder cancer: progression and recurrence. J. Urol., 130: 1083, 1983. 13. Sarosdy, M. F. and Lamm, D. L.: Long-term results of intravesical bacillus Calmette-Guerin therapy for superficial bladder cancer. J. Urol., 142: 719, 1989. 14. Marshall, V. F.: The relation of the preoperative estimate to the pathologic demonstration of the extent of vesical neoplasms. J. Urol., 68: 714, 1952. 15. Mostofi, F. K.: Standardization of nomenclature and criteria for the diagnosis of epithelial tumors of urinary bladder. Acta Un. Int. Cancer, 16: 310, 1960. 16. Morales, A., Eidinger, D. and Bruce, A. W.: Intracavitary bacillus Calmette-Guerin in the treatment of superficial bladder tumors. J. Urol., 116: 180, 1976. 17. Pinsky, C. M., Camacho, F. J., Kerr, D., Braun, D. W., Jr., Whitmore, W. F., Jr. and Oettgen, H.F.: Treatment of superficial bladder cancer with intravesical BCG. In: Immunotherapy of Human Cancer. Edited by W. D. Terry and S. T. Rosenberg. New York: Elsevier North Holland, sect. 7, pp. 309-313, 1982. 18. Adolphs, H.-D. and Bastian, H.P.: Chemoimmune prophylaxis of superficial bladder tumors. Results after treatment of more than 130 patients in 4 years. Read at annual meeting of American Urological Association, Las Vegas, Nevada, abstract 34 7, p. 178, April 17-21, 1983. 19. Brosman, S. A.: Experience with bacillus Calmette-Guerin in patients with superficial bladder carcinoma. J. Urol., 128: 27, 1982. 20. Kowalkowski, T. S. and Lamm, D.: Intravesical therapy of superficial bladder cancer. Curr. Trends Urol., 4: 89, 1988. 21. Haaff, E. 0., Dresner, S. M., Ratliff, T. L. and Catalona, W. J.: Two courses of intravesical bacillus Calmette-Guerin for transitional cell carcinoma of the bladder. J. Urol., 136: 820, 1986. 22. England, H. R., Paris, A. M. I. and Blandy, J. P.: The correlation of Tl bladder tumour history with prognosis and follow-up requirements. Brit. J. Urol., 53: 593, 1981. 23. Birch, B. R. P. and Harland, S. J.: The pTl G3 bladder tumour. Brit. J. Urol., 64: 109, 1989. 24. Jakse, G., Loidl, W., Seeber, G. and Hofstadter, F.: Stage Tl, grade 3 transitional cell carcinoma of the bladder: an unfavorable tumor? J. Urol., 137: 39, 1987.
EDITORIAL COMMENTS The authors present strong evidence that most cases of primary and recurrent stage Tl bladder tumor can be managed successfully by transurethral resection and BCG therapy. This appears to be true whether stage Tl tumors are solitary or multiple and associated or not with carcinoma in situ. Current progression rates for stage Tl tumors range from 7 (present series) to 38% (reference 4 in article). The difference is that the authors resected recurrent stage Tl tumors and gave additional BCG, whereas among the series reporting higher pro-
801
gression such recurrences were resected only and the patient did not receive further BCG. This is the main message of this important article and others (reference 2 in article), namely that primary and especially recurrent stage Tl tumors deserve aggressive, albeit conservative, therapy and that a transurethral resection alone is inadequate. An important caveat is that the stage Tl tumor must first be controlled endoscopically, since it is unlikely that topical therapy can reliably eradicate unresected invasive disease. If true, this suggests that neoplastic alterations within the remaining bladder mucosa (that is carcinoma in situ) define the malignant bladder and are more important than the stage Tl tumor per se in causing tumor progression. This supposition is supported by the fact that such important prognostic variables for progression (that is tumor multiplicity, high grade and carcinoma in situ) become less significant because they are eclipsed by their durable response to BCG. Harry W. Herr Department of Urology Memorial Sloan-Kettering Cancer Institute New York, New York This excellent experience with 86 patients clearly documents the remarkable long-term efficacy of BCG in the treatment of stage Tl transitional cell carcinoma. With 5 years of average followup, 69% of the patients had not even a single tumor recurrence. With the addition of further BCG treatment protection from tumor recurrence was increased to 91 % overall. Only 7% of the patients had stage progression and cancer death occurred in only 1 patient (1%). These findings are particularly impressive when one considers that 31 patients (36%) with stage Tl disease had grade 3 tumors or associated carcinoma in situ, which in my opinion is tantamount to grade 3 disease. Importantly, in contrast to the chemotherapy treated or natural history of grade 3 stage Tl disease, with BCG immunotherapy tumor recurrence and progression rate in high and low grade tumors are not significantly different and are, in fact, remarkably low. In our Southwest Oncology Group trial neither grade 3 nor stage Tl disease influenced tumor recurrence or progression in patients treated with BCG. 1 These results should clearly cause those who routinely recommend radical cystectomy for grade 3 stage Tl transitional cell carcinoma to reconsider their position. I would take exception to the statement that intravesical chemotherapy has been shown to decrease progression in stage Tl tumors. While Herr et al noted an apparent decrease in progression in nonrandomized historical series from 29% with transitional resection alone to 17% overall with intravesical therapy (19% chemotherapy and 14 % BCG), as stated in their review no controlled chemotherapy trial has ever demonstrated a statistically significant decrease in tumor recurrence (reference 1 in article). 2 In our recent review the overall incidence of progression in 1,423 patients from 7 randomized controlled series was 6.6% with chemotherapy and 7.2% with surgery alone. 3 In contrast, 3 BCG immunotherapy trials have documented a statistically significant decrease in tumor progression. 3 Finally, it is a great pleasure to read that our patients in San Antonio are continuing to do so well and the remarkably good results that were previously reported have not only been independently confirmed but, with further BCG treatment, even improved. Donald L. Lamm Department of Urology West Virginia University Morgantown, West Virginia 1. Lamm, D. L., Blumenstein, B. A., Crawford, E. D., Montie, J. E., Scardino, P., Grossman, H. B., Stanisic, T. H., Smith, J. A., Sullivan, J., Sarosdy, M. F., Crissman, J. D. and Coltman, C. A.: A randomized trial of intravesical doxorubicin and immunotherapy with bacille Calmette-Guerin for transitional-cell carcinoma of the bladder. New Engl. J. Med., 325: 1205, 1991. 2. Herr, H. W., Laudone, V. P. and Whitmore, W. F., Jr.: An overview of intravesical therapy for superficial bladder tumors. J. Urol., 138: 1363, 1987. 3. Lamm, D. L. and Griffith, J. G.: Intravesical therapy: does it affect the natural history of superficial bladder cancer? Sem. Urol., 10: 39, 1992.
MANAGEMENT OF STAGE Tl SUPERFICIAL BLADDER CANCER WITH INTRA VESICAL BACILLUS CALMETTE-GUERIN THERAPY MICHAEL S. COOKSON AND MICHAEL F. SAROSDY* From the Division of Urology, The University of Texas Health Science Center at San Antonio, San Antonio, Texas
ABSTRACT
We reviewed our results with 86 patients who had a pretreatment history of a stage Tl tumor. All patients were treated with transurethral resection of all visible tumor followed by intravesical bacillus Calmette-Guerin (BCG) and many patients received additional maintenance therapy. Local recurrences were treated with repeat transurethral resection followed by additional BCG. Median followup was 59 months, with a range of 9 to 149 months. Overall, 78 of 86 patients (91 %) were free of tumor recurrence with BCG therapy. This result includes 69% of the patients who responded to the initial transurethral resection and intravesical BCG, and 22% who ceased having tumors after additional treatments for local recurrences. Only 7% of the patients had progression to stage T2 tumors after BCG therapy. Grade of the stage Tl tumor, concurrent carcinoma in situ and tumor multiplicity before BCG did not predict tumor recurrence or progression. Of patients with recurrences after BCG therapy, those with stage Tl tumors had a higher rate of progression compared to those with stage Ta tumors but the difference was not statistically significant (p = 0.086). These data clearly support the efficacy of transurethral resection plus intravesical BCG immunotherapy in the treatment of stage Tl tumors as well as in the prevention of disease progression. KEY WORDS:
bladder neoplasms, BCG vaccine, carcinoma in situ
The management of stage Tl superficial bladder cancer that invades the lamina propria continues to be debated. While there is general agreement that stage Tl tumors are associated with a worse prognosis than noninvasive papillary stage Ta tumors, recurrence and progression rates are highly variable. 1- 13 Progression rates in patients with stage Tl tumors have decreased significantly (p = 0.001) when transurethral resection is combined with intravesical bacillus Calmette-Guerin (BCG) or chemotherapy compared to transurethral resection alone (17% versus 29%, respectively). 1 Since many large series of patients with stage Tl tumors were treated with only an initial 6-week course of BCG, patients treated with additional BCG after local recurrence and those treated with maintenance doses of intravesical BCG might be expected to have an even lower rate of stage progression. This is particularly important to consider in the face of a report that implied that the presence of a stage Tl tumor after only an initial 6-week course of BCG is an ominous prognostic indicator, with the implication that some therapy other than BCG should be used for those patients.2 We reviewed the results of 86 patients who underwent resection of a stage Tl bladder tumor immediately before intravesical BCG therapy. The study was performed in an attempt to determine the effectiveness of intravesical BCG in the prevention of local recurrences and progression to muscle invasive disease in patients with stage Tl superficial bladder cancer. MATERIALS AND METHODS
Patients. The records were reviewed of 230 patients with a history of superficial bladder tumors that were treated with therapeutic courses of intravesical BCG after transurethral resection of all visible tumor, and who were not presently enrolled in ongoing protocol studies. Of these patients 86 had a history of a stage Tl bladder tumor immediately before therapy. The available medical records of these 86 patients provided the database for this review. Followup ranged from 9 to 149 months, with a median of 59 months. Only 16 patients
(19%) were followed for less than 36 months and 60 (70%) were followed for 48 months or longer. One patient was followed for less than 1 year, and this patient had progression in stage and died postoperatively with only 9 months of followup. Included are 56 patients with stage Tl tumors who were among a larger group with superficial bladder cancer previously reported; followup at that time ranged from 13 to 120 months.13 Patients were stratified according to pretreatment tumor multiplicity (solitary tumor with or without carcinoma in situ versus multiple tumors) and by grade of stage Tl tumor immediately before BCG therapy. Tumors were staged according to the Marshall modification of Jewett's system 14 and grade was determined according to the criteria of Mostofi. 15 BCG. Pasteur strain BCGt was administered, with each ampule containing 120 mg. to be reconstituted in 50 ml. sterile saline. Treatment. After complete resection of all visible tumors the patients were treated with l ampule of BCG weekly for 6 weeks. All patients received at least an initial 6-week course, and many received additional BCG at 3, 6 and 12 months and/or annual maintenance therapy. The majority of the patients received percutaneous inoculation in addition to intravesical therapy. Patients were followed with cystoscopy and bladder wash cytology studies at regular intervals. For patients who were without evidence of disease these studies were performed quarterly for 2 years, semiannually for 2 years and annually thereafter. Patients with superficial (stages Ta and Tl) recurrences were treated with complete resection of all visible tumor followed by additional courses of BCG. This additional BCG course of therapy was variable, ranging from 6 weekly treatments to 3 treatments every other week or monthly treatments for 12 consecutive months. These patients also received additional maintenance BCG therapy. All patients were followed for as long as possible and, if lost to followup, the date of the last visit was recorded as the last date of followup. Statistical analysis. Comparison of tumor recurrence and progression rates were performed with chi-square analysis. RESULTS
Overall, 78 of 86 patients (91 %) were rendered free of tumor recurrence with BCG therapy after resection of a stage Tl
Accepted for publication February 28, 1992. * Requests for reprints: Division of Urology, The University of Texas Health Science Center at San Antonio, 7703 Floyd Curl Dr., San Antonio, Texas 78284-7845.
t Institute Armand Frappier, Montreal Quebec, Canada. 797
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COOKSON AND SAROSDY
tumor. Included in these patients are 59 (69%) with no recurrence after initial transurethral resection followed by intravesical BCG immunotherapy, and 19 (22%) who ceased having tumors after additional transurethral resection and additional intravesical BCG (see figure). A total of 8 patients failed to remain free of recurrence, with 6 (7%) having progression in stage to muscle invasive (stage T2 or greater) disease. Two patients underwent cystectomy for rapidly recurrent superficial disease. The results were stratified according to the number of previous recurrences before BCG therapy (table 1). A total of 23 patients had an initial solitary stage Tl tumor at presentation, of whom 6 (26%) had recurrences after BCG and 2 (8%) had progression to stage T2 disease. Both of the latter patients had grade 3 histology and represent 33% (2 of 6) of those who presented with this histology in the solitary stage Tl tumor. Carcinoma in situ in the presence of an initial solitary stage Tl tumor was found in 5 patients. One patient (20%) had recurrence and none had progression. A total of 58 patients had a history of multiple superficial tumors before BCG. Twenty patients (35%) had at least 1 recurrence and 4 (7%) had progression to stage T2 disease. There was no significant difference among the patients when stratified according to pretreatment tumor history with respect to recurrence (p = 0.651) or progression (p = 0. 787). Of the 58 patients 25 had a history of multiple stage Ta tumors plus a stage Tl lesion before BCG. In this subset there were 8 patients (32%) with recurrence and 3 (12%) with progression to stage T2. Of the 58 patients 33 had a history of multiple stage Tl tumors, and among these patients there were 12 (36%) who had a recurrence and 1 (3%) who had progression to muscleinvasive disease. There was no significant difference among
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patients with multiple stage Ta versus stage Tl tumors in relation to recurrence (p = 0.729) or progression (p = 0.182). Of the 86 patients 27 (31 %) had tumor recurrence after initial BCG (table 1). Stage of tumor at recurrence relative to progression in stage is shown in table 2. Among the 27 patients 6 (22%) had progression to stage T2 disease, including 4 with muscle invasion at the time of the initial recurrence. Complete tumor histories for these 27 patients are shown in table 3. The median interval to progression was 15 months (range 13 to 52) and the median interval to recurrence was 13 months (range 3 to 84). Of the 27 patients with recurrences 19 eventually achieved a recurrence-free status with additional transurethral resection and intravesical BCG, with a median recurrence-free followup of 47 months (range 31 to 139). Included in the 27 patients with recurrence were 12 with stage Ta and 11 with stage Tl tumors. AH 12 patients with stage Ta recurrences were rendered recurrence-free with local therapy consisting of transurethral resection and additional BCG, and there were no stage progressions in this group. Of the 11 patients with recurrent stage Tl tumors after initiation of BCG therapy 7 (64%) were treated successfully with repeat transurethral resection and additional BCG. Of these 11 patients 2 had progression to stage T2 disease and 2 underwent cystectomy for recurrent superficial disease. There was no statistically significant difference in progression rates between patients with stage Ta (O of 12) versus stage Tl (2 of 11) recurrences (p = 0.086). The relationship between initial stage Tl tumor histology and recurrence is shown in table 4. Of the 86 patients 11 had grade 1, 44 had grade 2, 16 had grade 3 and 15 had any grade disease plus carcinoma in situ before BCG therapy, and tumors recurred in 4 (36%), 14 (32%), 7 (44%) and 2 (13%), respectively. Among the patients with grade 3 histology 7 (44%) had a recurrent tumor and 3 (19%) had progression in stage. With respect to grade of the stage Tl tumor there was no statistically significant difference in patients with grade 3 histology compared with grades 1 and 2 or any grade plus carcinoma in situ (p = 0.178 and p = 0.094, respectively). Of the 15 patients with a stage Tl tumor and carcinoma in situ there was no stage progression and only 2 (13%) had any recurrence .
60
a: 0
Q) Q)
DISCUSSION
40
...
LL -;!?., 0
20 0
A. Initial
B. Initial Plus Retreatment
Treatment Course TABLE
1. Response to BCG immunotherapy stratified according to
pretreatment tumor history Pretreatment Frequency of Tumors Total No. pts. (%) Solitary Tl: Grade 1 Grade 2 Grade 3 Solitary Tl + Ca in situ: Grade 2 + Ca in situ Grade 3 + Ca in situ Multiple tumors: Multiple Ta, single Tl Multiple Tl
No. Pts. 86 23 6 11 6 5 1 4 58 25 33
With Any Recurrences No. Pts. (%)
With Stage Progression (T2 or greater) No. Pts. (%)
27 (31) 6 (26) 1 (17) 2 (18) 3 (50) 1 (20) 0 1 (25) 20 (35) 8 (32) 12 (36)
6 (7) 2 (8) 0 0 2 (33) 0 0 0 4 (7) 3 (12) 1 (3)
This review of 86 patients with stage Tl transitional cell carcinoma of the bladder treated with transurethral resection followed by intravesical BCG suggests that this is an effective form of therapy for these patients. This concept is supported by the finding that 69% of the patients remained free of recurrence after initial therapy alone and that only a small percentage of patients (7%) demonstrated progression in stage to muscle-invasive disease. Included in this review were 33 patients with a history of recurrent Tl tumors before BCG and 11 with stage Tl recurrences after the initiation of BCG therapy. Patients in our series demonstrated an excellent overall response to therapy, including patients with recurrences who were treated with additional intravesical BCG therapy after repeat transurethral resection. When responders to initial BCG are added to those who underwent additional therapy for a TABLE
2. Stage of tumor at recurrence relative to progression in stage
and tumor-free status Tumor Stage at Recurrence Ta Tl T2 Totals
No.(%) 12 11 4 27
(44) (41) (15) (100)
Progression (T2 or greater) No.(%)
Eventually Recurrence-Free No.(%)
0 2 (18) 4 (100) 6 (22)
12 7 (64)* Not ap12licable 19 (70)
Median disease-free followup 47 months (range 31 to 139). * Does not include 2 patients who underwent cystectomy for superficial disease and 1 who underwent cystectomy for stage T2 disease.
799
INTRAVESICAL BACILLUS CALMETTE-GUERJN THERAPY TABLE
Pt No.
No. Previous Recurrences
3. Clinical history of 27 patients with recurrences No. Recurrences After BCG
Previous Highest Stage/Grade
Post-BCG Stage/ Grade
Mos. to Recurrence
Disease-Free Followup (mos.)
35 12 27 12 24 61 70 84 6 9 50 12 7 3 9
47 63
Group }-stage Ta recurrences 1 2
0
1
Tl/3 Tl/1
1 2
3 4 5 6 7 8
1 0 6 5 2 0
Tl/2 Tl/2 Tl/2 Tl/1 Tl/2 Tl/1
1 1 1 1 1 2
9 10
3 3 2 5
Tl/+ Ca in situ Tl/2 Tl/1 Tl/2
1 1 1 2
11
12
Ta/1 Ta/1 Ta/1 Ta/1 Ta/1 Ta/2 Ta/1 Ta/1 Ta/1 Ta/2 Ta/1 Ta/1 Ta/1 Ta/2 Ta/1
49 31 119 138 139 89 120 77 45 72
Group 2-stage Tl or T2 recurrences 13 14 15 16 17
0 0 1 2 3
Tl/3 Tl/3 Tl/2 Tl/2 Tl/2
1 1 1 1 2
18
5
Tl/3
4
19 20
4 0
Tl/2 Tl/2
1 2
21 22 23
3 2 5
Tl/2 Tl/2 Tl/2
1 1 2
24 25
0 2
Tl/2 + Ca in situ Tl/2
1 3
26
10
Tl/3
2
27
9
Tl/3
TABLE 4.
Relationship of pretreatment stage Tl tumor histology and response to ECG immunotherapy
Pretreatment Stage Tl Tumor Histology Grade 1 Grade 2 Grade 3 Any grade + Ca in situ Totals
No. Pts.
11
44 16 15
86
With Any Recurrences No.(%) 4 (36) 14 (32) 7 (44)
2 (13) 27 (31)
With Stage Progression (T2 or greater) No.(%) 0 3 (7) 3 (19) 0
6(7)
recurrence after initial BCG therapy, an overall recurrence-free rate of 91 % was noted. The most important objective of intravesical therapy for superficial bladder cancer is the prevention of tumor stage progression. 3 Table 5 summarizes 7 recent series of patients treated with transurethral resection followed by intravesical BCG.'i- 9 From this table it is clear that a wide variety of progression rates have been cited. Among the 309 patients in table 5 the overall rate of progression is 13%, with a range of 2 to 38%. While summaries of reported results in patients with stage Tl tumors may be helpful, the differences in BCG treatment course including additional BCG for stages Ta and Tl recurrences may help to explain the variance in stage progression. For example, Herr et al reported progression rates of 38% and 24% among 13 and 29 patients, respectively, treated with a single 6-week course of BCG. 4 • 5 A single 6-week course of
T2 T2 T2 T2 Tl/1 Tl/2 Tl/3 Ta/1 Ta/2 Ta/1 Tl/2 Tl/2 Tl/2 Tl/2 Tl/2 Tl/2 Tl/2 Tl/2 + Ca in situ Tl/2 Tl/2 T2 Tl/2 T2 Tl/2
TABLE
26 52 13 17 19 12 8 17 12 34 16
112
4
48
26 52 13 17 48 67
7 15 9 26 38 13 6 12 15 12 15 3
58 9 38 36 72 21 46
5. Results of stage Tl tumors treated with transurethral
resection and intravesical ECG Reference Herr et al 4 Herr et al5 Steg et al 6 Martinez-Pineiro et al' Eure et al' Khanna et al8 Dal Bo et al' Present series
No. Patients With Stage Tl Tumor
No. Pts. With Progression (%)
Followup (mos.)
13
5 (38)
29
7 (24) 8 (18) 1 (2)
72* 60*
45 49 30 33 24 86
5 (17) 3 (9) 6 (25) 6 (7)
1st 36t 33t 25t 22* 59*
* Median.
t Mean.
BCG was used in the series of Steg6 and Dal Bo9 et al as well, with progression rates of 25% and 18%, respectively. The lowest rates of progression in stage have been reported in those series treated with repeat courses of intravesical BCG for superficial stages Ta and Tl recurrences. 7 • 9 In the series by Martinez-Pineiro et al patients received 4 weekly treatments of BCG and then monthly for 1 year, and a second 4-week course was administered for recurrences (stage Ta or Tl). 3 Their study showed a progression rate of 2% with a mean followup of 34 months (range 3 to 92). Khanna et al demonstrated a 9% progression rate in patients with stage Tl tumors and concluded that "therapy beyond an initial course of 6 weekly treatments increases the percentage of complete re-
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COOKSON AND SAROSDY
sponses." 8 Eure et al used a repeat course of BCG for incomplete responders and no maintenance therapy was given.7 Their progression rate of 17% despite retreatment can be explained partly by the fact that 17 of 30 patients were "felt to have incomplete resection" of tumor and 24 of 30 had grade 3 histology. Our series as well as results of others demonstrate a clear advantage in decreasing the rate of progression to muscle invasive disease in the majority of patients with stage Tl tumors treated with transurethral resection and intravesical BCG. These results are further enhanced when patients with superficial stages Ta and Tl recurrences undergo retreatment including additional transurethral resection and intravesical BCG as evidenced by the 7% stage progression rate observed in our series. The results of patients stratified according to number of recurreric:esliefore RCG therapy were a1so better in our series than in those reported previously. Patients with recurrent stage Tl tumors are believed to have an overall progression rate of about 35%, and those treated with transurethral resection and BCG had a progression rate of 28% (9 of 32) in 1 series. 1 Only 4 of our 58 patients (7%) with a pretreatment history of multiple tumors had progression in stage. This is in comparison to 2 of 23 patients (8%) with a solitary stage Tl tumor. There was no significant difference among patients with pretreatment solitary versus multiple tumors with respect to progression in stage after BCG treatment (p = 0.787). Also, multiple stage Tl tumors were not associated with a significantly higher rate of progression when compared with multiple stage Ta tumors in our series (p = 0.729). These data clearly support the efficacy of intravesical BCG in the prevention of progression to muscleinvasive disease in patients with stages Ta and Tl tumors, regardless of a history of pretreatment tumor multiplicity. A second important objective in treatment of superficial bladder cancer is to decrease the rate of recurrence. The ability of intravesical BCG to decrease the rate of recurrence has been well documented. 10• 18 • 16- 20 Our results support this concept in patients with stage Tl tumors, with 69% of the patients having no recurrence after initial therapy. This is remarkable when one considers that our series included 58 patients with a history of multiple tumors, 65% of whom had no recurrences after the initial course of BCG. Even among the 33 patients with multiple stage Tl tumor before therapy 64 % had no recurrence after initial BCG therapy. Several reports have shown that additional therapy with BCG after recurrence following initial therapy may increase the overall response rate. 13• 21 In our series 91 % of the patients with stage Tl tumors were eventually rendered recurrence-free with additional BCG therapy. Similarly, in patients with stage Tl tumors treated with additional BCG for local recurrences Martinez-Pineiro et al reported a 12% recurrence rate with a mean followup of 3 years. 3 Khanna et al reported that 50% of the patients in whom initial therapy failed had complete remission with additional BCG therapy. 8 Table 2 demonstrates that 70% of our patients with recurrences were eventually rendered recurrence-free with retreatment, and this proved to be effective irrespective of the stage (Ta versus Tl) at recurrence. A recurrence-free status was achieved in all 12 patients with stage Ta and in 7 of 11 (64%) with stage Tl recurrences, with no statistically significant difference between the 2 groups (p = 0.086). Thus, the majority of our patients with recurrences, including stage Tl recurrences, were successfully managed with transurethral resection and additional BCG therapy. These findings are in contrast to those recently reported by Herr in patients with stage Tl tumors after intravesical BCG. 2 Herr reported an 82% progression rate in 14 of 17 patients with a stage Tl tumor 3 months after initial transurethral resection and BCG therapy. However, these patients were not treated with additional BCG therapy and 12 of 14 had carcinoma in situ after 1 course of BCG. The short interval to progression in that series (median 8.4 months) also is suggestive of a highly
select group of patients not representative of most patients with stage Tl tumors. In our series BCG therapy was effective in the majority of patients with recurrent stage Tl tumors before therapy as well as those who had stage Tl tumors after an initial 6-week course. It is well recognized that patients with a high grade Tl tumor are at increased risk for local recurrence and progression in stage.9 • 12 • 22- 24 In our series patients with an initial pretreatment grade 3 stage Tl tumor demonstrated the highest rates of recurrence and progression in stage: 44% (7 of 16) and 19% (3 of 16), respectively. This is in comparison with initial grade 2 histology in which 32% of the patients had a recurrence and 7% experienced progression in stage. Despite the appearance of an increased rate of progression in patients with grade 3 histology, the difference was not statistically significant when comparea to grades 1 aria-2 or a:riy graae with carcinoma in situ in our series (p = 0.094). Dal Bo et al reported a 25% rate of recurrence (6 of 24) in patients with grade 3 stage Tl tumors treated with BCG and a 25% rate of stage progression. 9 Similarly, Jakse et al reported a 32% stage progression rate in 40 patients with stage Tl tumors and grade 3 histology. 24 Rates of progression in stage as high as 40% were found in 1 series of patients with grade 3 stage Tl tumors treated with transurethral resection alone. 23 It is clear from our data, as well as previously reported studies, that patients with grade 3 histology represent a particularly high risk subset in need of close followup, and a lower threshold to administer more aggressive therapy in these patients who fail to respond to local therapy is justified. These data support the concept that patients with stage Tl transitional cell carcinoma can be treated effectively with transurethral resection followed by intravesical immunotherapy with BCG. Additionally, patients with local recurrences, including those with stage Tl recurrences, can be managed successfully in most instances with repeat transurethral resection followed by additional intravesical BCG. In our series grade of tumor before BCG, concurrent carcinoma in situ and tumor multiplicity before BCG immunotherapy did not predict tumor recurrence or progression. Close followup should allow for identification of those select few patients who fail to respond to transurethral resection followed by intravesical BCG therapy with either rapidly recurrent superficial disease or progression to muscle invasion. Once these patients are identified a change in therapeutic strategy is, indeed, warranted to prevent further progression and ultimately enhance disease-free survival. Michael F. Luther performed the statistical analysis. REFERENCES 1. Herr, H. W., Jakse, G. and Sheinfeld, J.: The Tl bladder tumor. Sem. Urol., 8: 254, 1990. 2. Herr, H. W.: Progression of stage Tl bladder tumors after intravesical bacillus Calmette-Guerin. J. Urol., 145: 40, 1991. 3. Martinez-Pineiro, J. A., Leon, J. J., Martinez-Pineiro, L., Jr., Fiter, L., Mosteiro, J. A., Navarro, J., Matres, M. J. G. and Carcamo, P.: Bacillus Calmette-Guerin versus doxorubicin versus thiotepa: a randomized prospective study in 202 patients with superficial bladder cancer. J. Urol., 143: 502, 1990. 4. Herr, H. W., Laudone, V. P., Badalament, R. A., Oettgen, H. F., Sogani, P. C., Freedman, B. D., Melamed, M. R. and Whitmore, W. F., Jr.: BCG therapy alters the progression of superficial bladder cancer. J. Clin. Oncol., 6: 1450, 1988. 5. Herr, H. W., Badalament, R. A., Amato, D., Laudone, V. P., Fair, W. R. and Whitmore, W. F., Jr.: Superficial bladder cancer treated with bacillus Calmette-Guerin: a multivariate analysis of factors affecting tumor progression. J. Urol., 141: 22, 1989. 6. Steg, A., Belas, M. and Leleu, C.: Intravesical BCG therapy in patients with superficial bladder cancer. In: Immunotherapy of Urological Tumours. Edited by J. B. deKernion. New York: Churchill Livingstone, vol. 1, chapt. 11, pp. 107-112, 1990. 7. Eure, G. R., Ladaga, L. E. and Schellhammer, P. F.: BCG therapy for stage Tl superficial bladder cancer. J. Urol., part 2, 143: 341A, abstract 611, 1990.
INTRAVESICAL BACILLUS CALrvrnTTE-GUERIN THERAPY
8. Khanna, 0. P., Son, D. L., Mazer, H., Read, J., Nugent, D., Cottone, R., Heeg, M., Rezvan, M., Viek, N., Uhlman, R. and Friedmann, M.: Multicenter study of superficial bladder cancer treated with intravesical bacillus Calmette-Guerin or adriamycin. Urology, 35: 101, 1990. 9. Dal Bo, V., Belmonte, P., Veronesi, A., Lo Re, G., Miotto, E., Merlo, A., Volpe, R. and Francini, M.: Intravesical BCG instillations in patients with carcinoma in situ and pTl G3 transitional cell carcinoma of the bladder. Eur. Urol., suppl. 1, 18: 43, abstract 82, 1990. 10. Lamm, D. L., Thor, D. E., Harris, S. C., Reyna, J. A., Stogdill, V. D. and Radwin, H. M.: Bacillus Calmette-Guerin immunotherapy of superficial bladder cancer. J. Urol., 124: 38, 1980. 11. Lutzeyer, W., Rubben, H. and Dahm, H.: Prognostic parameters in superficial bladder cancer: an analysis of 315 cases. J. Urol., 127: 250, 1982. 12. Heney, N. M., Ahmed, S., Flanagan, M. J., Frable, W., Corder, M. P., Hafermann, M. D. and Hawkins, I. R. for National Bladder Cancer Collaborative Group A: Superficial bladder cancer: progression and recurrence. J. Urol., 130: 1083, 1983. 13. Sarosdy, M. F. and Lamm, D. L.: Long-term results of intravesical bacillus Calmette-Guerin therapy for superficial bladder cancer. J. Urol., 142: 719, 1989. 14. Marshall, V. F.: The relation of the preoperative estimate to the pathologic demonstration of the extent of vesical neoplasms. J. Urol., 68: 714, 1952. 15. Mostofi, F. K.: Standardization of nomenclature and criteria for the diagnosis of epithelial tumors of urinary bladder. Acta Un. Int. Cancer, 16: 310, 1960. 16. Morales, A., Eidinger, D. and Bruce, A. W.: Intracavitary bacillus Calmette-Guerin in the treatment of superficial bladder tumors. J. Urol., 116: 180, 1976. 17. Pinsky, C. M., Camacho, F. J., Kerr, D., Braun, D. W., Jr., Whitmore, W. F., Jr. and Oettgen, H.F.: Treatment of superficial bladder cancer with intravesical BCG. In: Immunotherapy of Human Cancer. Edited by W. D. Terry and S. T. Rosenberg. New York: Elsevier North Holland, sect. 7, pp. 309-313, 1982. 18. Adolphs, H.-D. and Bastian, H.P.: Chemoimmune prophylaxis of superficial bladder tumors. Results after treatment of more than 130 patients in 4 years. Read at annual meeting of American Urological Association, Las Vegas, Nevada, abstract 34 7, p. 178, April 17-21, 1983. 19. Brosman, S. A.: Experience with bacillus Calmette-Guerin in patients with superficial bladder carcinoma. J. Urol., 128: 27, 1982. 20. Kowalkowski, T. S. and Lamm, D.: Intravesical therapy of superficial bladder cancer. Curr. Trends Urol., 4: 89, 1988. 21. Haaff, E. 0., Dresner, S. M., Ratliff, T. L. and Catalona, W. J.: Two courses of intravesical bacillus Calmette-Guerin for transitional cell carcinoma of the bladder. J. Urol., 136: 820, 1986. 22. England, H. R., Paris, A. M. I. and Blandy, J. P.: The correlation of Tl bladder tumour history with prognosis and follow-up requirements. Brit. J. Urol., 53: 593, 1981. 23. Birch, B. R. P. and Harland, S. J.: The pTl G3 bladder tumour. Brit. J. Urol., 64: 109, 1989. 24. Jakse, G., Loidl, W., Seeber, G. and Hofstadter, F.: Stage Tl, grade 3 transitional cell carcinoma of the bladder: an unfavorable tumor? J. Urol., 137: 39, 1987.
EDITORIAL COMMENTS The authors present strong evidence that most cases of primary and recurrent stage Tl bladder tumor can be managed successfully by transurethral resection and BCG therapy. This appears to be true whether stage Tl tumors are solitary or multiple and associated or not with carcinoma in situ. Current progression rates for stage Tl tumors range from 7 (present series) to 38% (reference 4 in article). The difference is that the authors resected recurrent stage Tl tumors and gave additional BCG, whereas among the series reporting higher pro-
801
gression such recurrences were resected only and the patient did not receive further BCG. This is the main message of this important article and others (reference 2 in article), namely that primary and especially recurrent stage Tl tumors deserve aggressive, albeit conservative, therapy and that a transurethral resection alone is inadequate. An important caveat is that the stage Tl tumor must first be controlled endoscopically, since it is unlikely that topical therapy can reliably eradicate unresected invasive disease. If true, this suggests that neoplastic alterations within the remaining bladder mucosa (that is carcinoma in situ) define the malignant bladder and are more important than the stage Tl tumor per se in causing tumor progression. This supposition is supported by the fact that such important prognostic variables for progression (that is tumor multiplicity, high grade and carcinoma in situ) become less significant because they are eclipsed by their durable response to BCG. Harry W. Herr Department of Urology Memorial Sloan-Kettering Cancer Institute New York, New York This excellent experience with 86 patients clearly documents the remarkable long-term efficacy of BCG in the treatment of stage Tl transitional cell carcinoma. With 5 years of average followup, 69% of the patients had not even a single tumor recurrence. With the addition of further BCG treatment protection from tumor recurrence was increased to 91 % overall. Only 7% of the patients had stage progression and cancer death occurred in only 1 patient (1%). These findings are particularly impressive when one considers that 31 patients (36%) with stage Tl disease had grade 3 tumors or associated carcinoma in situ, which in my opinion is tantamount to grade 3 disease. Importantly, in contrast to the chemotherapy treated or natural history of grade 3 stage Tl disease, with BCG immunotherapy tumor recurrence and progression rate in high and low grade tumors are not significantly different and are, in fact, remarkably low. In our Southwest Oncology Group trial neither grade 3 nor stage Tl disease influenced tumor recurrence or progression in patients treated with BCG. 1 These results should clearly cause those who routinely recommend radical cystectomy for grade 3 stage Tl transitional cell carcinoma to reconsider their position. I would take exception to the statement that intravesical chemotherapy has been shown to decrease progression in stage Tl tumors. While Herr et al noted an apparent decrease in progression in nonrandomized historical series from 29% with transitional resection alone to 17% overall with intravesical therapy (19% chemotherapy and 14 % BCG), as stated in their review no controlled chemotherapy trial has ever demonstrated a statistically significant decrease in tumor recurrence (reference 1 in article). 2 In our recent review the overall incidence of progression in 1,423 patients from 7 randomized controlled series was 6.6% with chemotherapy and 7.2% with surgery alone. 3 In contrast, 3 BCG immunotherapy trials have documented a statistically significant decrease in tumor progression. 3 Finally, it is a great pleasure to read that our patients in San Antonio are continuing to do so well and the remarkably good results that were previously reported have not only been independently confirmed but, with further BCG treatment, even improved. Donald L. Lamm Department of Urology West Virginia University Morgantown, West Virginia 1. Lamm, D. L., Blumenstein, B. A., Crawford, E. D., Montie, J. E., Scardino, P., Grossman, H. B., Stanisic, T. H., Smith, J. A., Sullivan, J., Sarosdy, M. F., Crissman, J. D. and Coltman, C. A.: A randomized trial of intravesical doxorubicin and immunotherapy with bacille Calmette-Guerin for transitional-cell carcinoma of the bladder. New Engl. J. Med., 325: 1205, 1991. 2. Herr, H. W., Laudone, V. P. and Whitmore, W. F., Jr.: An overview of intravesical therapy for superficial bladder tumors. J. Urol., 138: 1363, 1987. 3. Lamm, D. L. and Griffith, J. G.: Intravesical therapy: does it affect the natural history of superficial bladder cancer? Sem. Urol., 10: 39, 1992.
