Comparison of Transurethral Resection to Radical Therapies for Stage B Bladder Tumors

0022-534 7/88/1405-0964$2.00/0 Vol. 140, November

THE JOURNAL OF UROLOGY

Printed in U.S.A.

Copyright © 1988 by The Williams & Wilkins Co.

COMPARISON OF TRANSURETHRAL RESECTION TO RADICAL THERAPIES FOR STAGE B BLADDER TUMORS KATHY HENRY, JEFFREY MILLER, MOTOMI MORI, STEFAN LOENING AND BERNARD FALLON From the Department of Urology, University of Iowa Hospitals and Clinics, Iowa City, Iowa

ABSTRACT

We evaluated the survival rate and time to recurrence for 114 patients in whom an initial histological diagnosis of stage Bl or B2 bladder tumor was made between 1974 and 1983. The 5year survival rates for stages Bl and B2 disease, respectively, were 63 and 38 per cent in 43 patients treated by transurethral resection alone, 48 and 54 per cent in 40 treated by preoperative radiation and radical cystectomy, 33 and 25 per cent in 15 treated by radical cystectomy alone, and 53 and 11 per cent in 16 treated by definitive radiation therapy alone. Similar results were found among the groups with regard to time to development of metastases. The distribution of stage, grade and number of tumors was not significantly different among the treatment groups. Patients in the transurethral resection group were older, and had smaller tumors and more medical problems. Comparing transurethral resection of muscle invasive bladder tumors to standard radical surgery with or without radiotherapy yielded comparable long-term survival and time to distant recurrence. (J. Urol., 140: 964-967, 1988) Ideal therapy for stage B transitional cell cancer of the bladder is a controversial issue. The most experience has been accumulated with transurethral resection, radiation therapy and radical cystectomy with or without preoperative irradiation. In the last 10 to 15 years numerous studies have been reported detailing the results of these individual therapeutic modalities. O'Flynn and associates reported 5-year survival rates of 54 and 20 per cent for stages Bl and B2 tumors, respectively, treated by transurethral resection alone. 1 Bredael and associates reported similar 5-year survival rates of 54 and 25 per cent in patients treated by radical cystectomy alone. 2 Rider and Evans, using only radiation therapy, reported 5-year survival rates of 50 and 18 per cent, respectively, for stages Bl and B2 tumors. 3 Whitmore and associates reported 5-year survival rates of 48 and 32 per cent for stages Bl and B2 disease, respectively, with 4,000 to 6,000 rad of preoperative radiation followed by radical cystectomy. 4 These reports and many others have failed to indicate a consistent major advantage for any 1 modality of therapy. However, a trend has developed towards increasing use of radical cystectomy as the primary mode of therapy. This trend -may be owing to the disappointing cure rates in an apparently localized tumor and to more sensitive clinical staging methods as well as medical, surgical and anesthestic advances that allow for a more aggressive surgical approach in the older population in whom the disease is most likely to develop. Increasing life expectancy of the population also affects the urologist's therapeutic approach and perhaps results in the more aggressive treatment of stage B bladder cancer. Because of these numerous and fluctuating factors, we thought that it would be of interest to review and to analyze the results of treatment during a recent 9-year period at 1 institution in patients presenting with an initial histological diagnosis of stage B transitional cell bladder cancer. MATERIALS AND METHODS

All patients with a histological diagnosis of transitional cell carcinoma of the bladder treated at the University of Iowa from 1974 to 1983 were followed as part of the National Bladder Accepted for publication February 9, 1988. Read at annual meeting of American Urological Association, Anaheim, California, May 17-21, 1987.

Cancer Colloborative Group A surveillance protocol. Patient followup included physical examination, chest x-ray and cystoscopy with cytologies every 3 months for 2 years, then every 6 months for patients with a bladder. Patients who underwent cystectomy had standard followup every 3 to 6 months. Multiple tumor and treatment characteristics were recorded in a prospective fashion at each visit. For this study we reviewed the treatment and outcome for all patients in whom the initial histological diagnosis of stage Bl or B2 bladder cancer was made between March 1974 and November 1983. Followup records were systematically kept as part of the study until December 1983. Thereafter progression of the disease and the survival status were determined from medical charts at the institution until August 1986. Patients were excluded from analysis if they had a history of muscle invasion, metastasis was noted during metastatic studies or within 4 months of diagnosis or they had been treated by partial cystectomy. After these exclusions 114 patients were available for study. These patients were placed retrospectively within 1 of 4 treatment groups: group 1-transurethral resection alone (43 patients), group 2-6,500 to 7,500 rad radiation therapy alone (16 patients), group 3-radical cystectomy alone (15 patients) and group 4-4,000 to 6,000 rad preoperative irradiation in 4 to 6 weeks followed by radical cystectomy (40 patients). To be included in the treatment group the patient must have received the designated treatment within 4 months of the initial diagnosis of muscle invasive disease. The stage, grade, number and size of the largest tumor, and age and sex of the patients were considered as the potential prognostic factors that may confound the treatment effects. The stage, grade, number of visible tumors and size of the largest tumor were determined by the original transurethral resection biopsy. Tumor size was defined as the greatest diameter of the largest tumor. Patient age was determined at the initial diagnosis of the stage B bladder cancer. The incidence of concurrent carcinoma in situ at the initial diagnosis of stage B disease and concurrent significant medical problems also were reviewed. Although the accuracy of the differentiation of stage Bl from B2 may be unsatisfactory, we believe that the amount of staging error is about the same for all treatment groups. Therefore, this inaccuracy is not considered to be a significant bias factor in this study which focuses on treatment efficacy.

964

965

TRANSURETHRAL RESECTION VERSUS RADICAL THERAPIES FOR STAGE B BLADDER TUMORS

For each patient the following medical conditions were tabulated and a score of 1 point was assessed for each condition present: congestive heart failure/arrhythmia, history of myocardial infarction, history of stroke, diabetes mellitus, concurrent cancer (other than skin) with a progressive status, chronic obstructive pulmonary disease/significant asthma, hypertension/severe vascular disease and severe renal disease. The total number of points in each group was then divided by the number of patients in the group to allow comparison of the over-all health status of the 4 groups. Treatment groups were evaluated for the percentage of patients with a history of superficial tumors and the percentage who presented with invasive cancer as the first tumor. Within the transurethral resection alone group 2 subgroups were constructed and compared: those who were subsequently treated by salvage radiation and/or radical cystectomy, and those who had no subsequent radical treatment. Statistical methods. The Kaplan-Meier method was used to estimate survival functions, 5-year survival rate and 3-year metastasis rate. Differences in the survival distributions among the 4 treatment groups were tested by the logrank test. 5 The p values of less than 0.05 were considered statistically significant. All statistical analyses were performed by the LIFETEST procedure in Statistical Analysis System (Version 5).6

Patient and tumor characteristics. Table 1 summarizes the 1, 3 and 5-year followup status for each treatment group after entry into the study. Of the 13 patients with a followup of less than 5 years 4 were lost to followup and 9 had less than 5 years of followup owing to late entry into the study. Table 1 also provides censoring information for the survival analysis presented in figures 1 and 2. The censored population consisted of those who died of causes unrelated to bladder cancer and those who had incomplete followup. Patient characteristics within each group are presented in table 2. With respect to sex, age, medical condition and history of bladder cancer, the groups were relatively similar but there appears to be some selection bias away from radical surgery in older patients with more medical illnesses and in those with no history of transitional cell carcinoma of the bladder. Of the group 1 patients 37 per cent were older than 75 years, compared to 25 per cent of group 2, 0 per cent of group 3 and 5 per cent of group 4. Tumor characteristics within each group are presented in table 3. Significant differences were noted in the size of the largest tumor. Of the tumors in group 1, 72 per cent were 3 cm. or less in diameter, compared to 33 per cent in group 2, 25 per cent in group 3 and 44 per cent in group 4. No statistically significant differences were noted with respect to stage, grade, number of tumors or incidence of carcinoma in situ among the groups. TABLE

1. Survival/followup

1 2 3 4 Over-all

1 3 5 1 3 5 1 3 5 1 3 5 1 3 5

5 (12) 12 (28) 14 (33) 5 (31) 11 (69) 11 (69) 4 (27) 8 (53) 9 (60) 6 (15) 17 (43) 17 (43) 20 (18) 48 (42) 51 (45)

No. Deaths of Other Causes (%)

No. Alive (%)

No. Lost to Followup (%)

7 (16) 13 (30) 13 (30) 1 (6) 2 (13) 3 (19) 1 (7) 1 (7) 1 (7) 3 (8) 6 (15) 6 (15) 12 (11) 22 (19) 23 (20)

30 (70) 16 (37) 12 (28) 10 (63) 3 (19) 2 (13) 10 (67) 4 (27) 3 (20) 30 (75) 15 (38) 10 (25) 80 (70) 38 (33) 27 (24)

1 (2) 2 (5) 4 (9) 0 (0) 0 (0) 0 (0) 0 (0) 2 (13) 2 (13) 1 (3) 2 (5) 7 (18) 2 (2) 6 (5) 13 (11)

Total No. (%)

43 (100) 16 (100) 15 (100) 40(100) 114 (100)

ii

,.,j;_

90

----- TUR - - RAD/SURG

I

j L.

80

-,

L-.J

f·-i·~

70

----,

---····-·- RAD

L-,•-,

L1 _______ ,

LL 60

Percent Survival

Ll---·-,

L--------

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Li

50

1

i

L--·1

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I

40

i

30

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L---·--------···-·-··-----

.

20

l

500

DaysO

11500

10001

Years 1

2000 5

4 3 Survival Time

2

I

2500

6

FIG. 1. Kaplan-Meier analysis of survival estimates. TUR, group 1.

RAD, group 2. SURG, group 3. RAD/SURG, group 4.

100 ----- TUR

90

- - RAD/SURG -·-·-·· SURG -··-·····-·· RAD

80 ·, 1

-r,

70

·····--E, t_,

60 Percent Survival

RESULTS

Duration No. Deaths Treatment of Bladder of Groups Followup Ca (%) (yrs.)

100

""t-~--

50

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40

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i. . .;. .'. . . . .

30

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20

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1

10

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o~-~~-~~~-~--~~--~---.--, Days O 500 1500 2000 1000 3000 250~ Years 1

2

4

3

5

6

8

7

Survival Time

FIG. 2. Survival analysis on total mortality. TUR, group 1. RAD, group 2. SURG, group 3. RAD/SURG, group 4.

TABLE 2.

Patient characteristics in each group

Treatment Group

No. Pts.

Male/ Female

1 2

43

3 4

15 40

37/6 14/2 13/2 35/5

16

Age (mean± standard error)

73.02 69.13 62.00 61.45

± ± ± ±

1.67 1.82 2.22 1.46

Medical Condition Score 1.2 1.06 0.4 0.7

No. Pts. With History of Stage O or A Transitional Cell Ca(%) 22 5 10 28

(51) (31) (66) (70)

Prognostically significant factors. Table 4 summarizes survival differences among the 4 treatment groups as well as various tumor and patient characteristics. Survival curves among the 4 treatment groups were significantly different (p <0.05). Survival in group 1 patients was comparable to group 4 (p >0.30) and significantly better than groups 2 (p <0.01) and 3 (p <0.05). These data are illustrated graphically in figure 1. Tumor stage appeared to be a significant prognostic factor, with patients with stage Bl tumors having a better prognosis than those with stage B2 tumors (p <0.05). There appeared to be no significant survival differences owing to grade, number or size of the tumors, or patient sex or age. Similar results were obtained from analysis of time to metastasis. Table 5 shows that a significant difference in time to metastasis occurred among the 4 treatment groups (p <0.05) and the 2 stages (p <0.05). Group 1 patients appeared to have a significantly longer time to metastasis than group 2 (p <0.05) but the difference between groups 1 and 4 was not statistically significant (p >0.90). The difference between groups 1 and 3 alone approached statistical significance (p = 0.11).

966

HENRY AND ASSOCIATES TABLE

3. Tumor characteristics in each group

TABLE

No. Pts. (%)

Stage: Bl B2 Grade: I II III No. tumors: 1 >1 Mean± standard deviation Diameter of largest tumor (cm.): <3.0 >3.0 Mean± standard deviation Associated Ca in situ

Group 1

Group 2

Group 3

Group4

28 (65) 15 (35)

5 (31) 11 (69)

7 (47) 8 (53)

23 (57) 17 (43)

2 (5) 13 (31) 27 (64)

0 (0) 5 (33) 10 (67)

0 (0) 5 (38) 8 (62)

1 (2) 10 (26) 28 (72)

29 (67) 14 (33) 1.63 ± 0.16

12 (80) 3 (20) 1.53 ± 0.29

10 (83) 2 (17) 1.33 ± 0.26

21 (66) 11 (34) 1.63 ± 0.18

31 (72) 12 (28) 2.26 ± 0.28

5 (33) 10 (67) 3.77 ± 0.47

3 (25) 9 (75) 4.17 ± 0.51

15 (44) 19 (56) 3.28 ± 0.34

8 (18)

2 (12)

2 (13)

6 (15)

5. Association between metastasis and tumor/patient characteristics 3-Yr. No. Pts. With Standard Metastasis/Total Metastasis Error No. Pts. (%) Rate

Variable Parameter Over-all Treatment groups: 1 2 3 4 Stage: Bl B2 Grade: I II III No. tumors: 1 >1 Tumor size (cm.): ;;;.3 >3 Sex: M

F

TABLE

4. Association between survival and tumor/patient characteristics

Variable Parameter Over-all Treatment groups: 1 2 3 4 Stage: Bl B2 Grade: I II III No. tumors: 1 >1 Tumor size (cm.): ;;;;3 >3 Sex: M

F Age (yrs.): <55 56-65 66-75 >75

Age (yrs.): <55 56-65 66-75 >75

No. Deaths of Transitional Cell Ca of Bladder/Total No. Pts. (%)

5-Yr. Survival Rate

0.57

0.05

(42) (75) (67) (48)

0.50 0.79 0.71 0.51

0.09 0.11 0.13 0.08

p = 0.0366*

27/63 (43) 32/51 (63)

0.50 0.66

0.07 0.07

p = 0.0261*

1/3 (33) 15/33 (45) 41/73 (56)

0.33 0.46 0.64

0.27 0.09 0.06

p = 0.2793

39/72 (54) 10/30 (33)

0.57 0.44

0.06 0.11

p = 0.3482

23/54 (43) 28/50 (56)

0.48 0.62

0.08 0.07

p = 0.2330

51/99 (52) 8/15 (53)

0.56 0.66

0.05 0.14

p = 0.4865

(56) (48) (51) (55)

0.56 0.50 0.60 0.68

0.12 0.09 0.08 0.11

p = 0.8059

18/43 12/16 10/15 19/40

9/16 15/31 23/45 12/22

Logrank TABLE

Treatment Groups

0.45

0.05

(33) (69) (67) (45)

0.55 0.25 0.28 0.51

0.09 0.12 0.13 0.09

p = 0.0139*

23/63 (37) 30/51 (59)

0.54 0.35

0.07 0.07

p = 0.0140*

1/3 (33) 13/33 (39) 37/73 (51)

0.67 0.56 0.39

0.27 0.10 0.06

p = 0.3085

34/72 (47) 9/30 (30)

0.47 0.52

0.07 0.13

p = 0.3991

19/54 (35) 26/50 (52)

0.58 0.38

0.08 0.08

p = 0.1223

(46) (47)

0.47 0.35

0.06 0.15

p = 0.7566

7/16 (44) 15/31 (48) 21/45 (47) 10/22 (45)

0.54 0.50 0.40 0.38

0.13 0.10 0.09 0.13

p = 0.6292

46/99 7/15

59/114 (52)

* Statistically significant at p = 0.05. Standard Error

53/114 (46) 14/43 11/16 10/15 18/40

Logrank

28 5 7 23

1 2 3 4

• Statistically significant at 0.05.

Logrank over-all 1 2 3 4 Logrank over-all 1 2 3 4

Stage Bl 0.63 ± 0.11 0.53 ± 0.25 0.33 ± 0.25 0.48± 0.11

No. Pts. 15 11 8 17

Grade II 0.40 ± 0.17 0.75 ± 0.22 0.80 ± 0.18 0.56 ± 0.17

Logrank over-all

Age <65 0.78 ± 0.20 ± 0.29 ± 0.55 ±

(p value) 0.14 0.18 (0.0062*) 0.17 (0.0347*) 0.11 (0.1469)

27 10 8 28

Tumor<3 cm. 0.62 ± 0.10 0 0.50 ± 0.35 0.60 ± 0.14 p = 0.0622

Stage B2 (p value) 0.38 ± 0.18 0.11 ± 0.10 (0.0723) 0.25 ± 0.15 (0.5577) 0.54 ± 0.13 (0.2611)

Grade III (p value) 0.57 ± 0.12 (0.0001*) 0 0 (0.0008*) 0.51 ± 0.10 (0.3750) p = 0.0001*

34 11 7 15

p = 0.0087* 31 5 3 15

5-Yr. Survival Rate ± Standard Error

p = 0.0085*

p = 0.7379 9 5 8 25

1 2 3 4

5-Yr: Survival Rate ± Standard Error

p = 0.3564 13 5 5 10

Logrank over-all

Stratified analysis was performed to control for stage, grade and size of tumor, and patient age. The results for survival are summarized in table 6. When treatment groups were compared among patients with stage Bl disease 5-year survival for group 1 patients was greatest (63 per cent) but survival of group 1 patients with stage Bl disease was not statistically different from those of the other treatment groups. For stage B2 disease survival was comparable between groups 4 (45 per cent) and 1 (38 per cent). Significant survival differences were noted among the 4 treatment groups for patients with stage B2 tumors and grade III tumors, and for those younger than 65 years. Survival in group 1 was significantly better than that in group 2 or 3 among patients less than 65 years old (group 1 versus 2 p <0.01,

6. Survival differences among treatment groups No. Pts.

Age 0.46 ± 0.25 ± 0.29 ± 0.43 ±

>65 0.12 0.15 0.22 0.14

p = 0.2839 12 10 9 19

Tumor>3cm. 0.27 ± 0.21 0.35 ± 0.65 0.16 ± 0.14 0.50 ± 0.13 p = 0.5485

• Statistically significant at 0.05.

group 1 versus 3 p <0.05), and those with grade III tumors (group 1 versus 2 p <0.0001, group 1 versus 3 p <0.0005). The 5-year survival in group 1 (62 per cent) was greatest in patients whose largest tumor did not exceed 3 cm. However, survival curves of the 4 treatment groups among these patients were only marginally significant (p = 0.0622). No significant treatment effects on survival were observed among patients whose largest tumor exceeded 3 cm. Similar results were obtained from analysis of time to metastasis (table 7). Significant differences were noted among patients less than 65 years old, those with stage B2, grade III

TRANSURETHRAL RESECTION VERSUS RADICAL THERAPIES FOR STAGE B BLADDER TUMORS TABLE

7. Differences in time to metastasis among treatment groups

Treatment Groups

1 2 3 4

No. Pts.

28 5 7 23 Logrank over-all 13 5 5 23

1 2 3 4 Logrank over-all

Logrank over-all

Stage Bl 0.41 ± 0.10 0.60 ± 0.22 0.67 ± 0.25 0.55 ± 0.11

Stage B2 (p value) 0.65 ± 0.14 0.89 ± 0.10 (0.2957) 11 0.75 ± 0.15 (0.8021) 8 17 0.55 ± 0.13 (0.1176)

Age <65 (p value) 0.33 ± 0.16 0.80 ± 0.18 (0.0298*) 0.71 ± 0.17 (0.0917) 0.48 ± 0.10 (0.3553)

Logrank over-all

p = 0.0364*

Grade III (p value) 0.52 ± 0.11 (0.0005*) 1.00 (0.0042*) 1.00 0.52 ± 0.10 (0.7906) p = 0.0001 *

34 11 7 15

p = 0.0397* Tumor <3 cm. (p value) 31 0.46 ± 0.10 1.00 (0.0168) 5 0.50 ± 0.35 (0.6880) 3 0.39 ± 0.14 (0.6474) 15

1 2 3 4

p = 0.0269*

27 10 8 28

Age >65 0.57 ± 0.10 0.80 ± 0.13 0.71 ± 0.22 0.56 ± 0.14 p = 0.4575

12 10 9

19

salvage therapy

Error

15

p = 0.5707

9 5 8 25

1 2 3 4

No. Pts.

Grade II 0.58 ± 0.15 0.40 ± 0.22 0.20 ± 0.18 0.43 ± 0.16

8. Outcome of transurethral resection patients who required

3-Yr. Metastasis Rate ± Standard

3-Yr. Metastasis Rate ± Standard Error

p = 0.6787

TABLE

Tumor>3 cm. 0.63 ± 0.16 0.65 ± 0.16 0.83 ± 0.15 0.53 ± 0.12 p = 0.6754

* Statistically significant at 0.05.

tumors or tumor size of 3 cm. or less. Patients with grade III tumors in group 1 had a significantly longer time to metastasis than those in group 2 or 3, and they were comparable in prognosis with those in group 4. Among those patients less than 65 years old or those with the largest tumor size of 3 cm. or less time to metastasis was significantly shorter for group 2 compared to the other 3 groups. Salvage therapy/total mortality. Within group 1 a subpopulation was identified of 10 patients (25 per cent of the total) who required salvage therapy owing to local recurrence. Of these 10 patients 8 were treated by radical cystectomy alone and 2 received preoperative radiation, followed by radical cystectomy. The 5-year survival rate of those 10 patients is identical to the over-all group and, while the 3-year metastasis rate appeared to be worse, the difference was not statistically significant (table 8). Figure 2 shows the survival curves obtained from incorporating death of bladder cancer and all other causes for each treatment group. There was no statistical difference in the over-all survival among the 4 treatment groups. DISCUSSION

Transurethral resection has been performed since the 1930s as a principal modality of therapy for bladder tumors. As radical surgery became more commonplace with lower morbidity, transurethral resection receded into a position of secondary importance in the management of muscle invasive tumor. This review was undertaken to reassess the proper position of transurethral resection in the spectrum of treatment options. Our analysis is not based on a prospectively randomized study and, therefore, an unknown element of selection bias may be present. However, a comparison of the patient and tumor characteristics within each treatment group revealed that group 1 patients generally were an older and less healthy population. These factors, if anything, should weigh against increased survival in this group of patients. The only tumor factor that would seem to favor the transurethral resection group was the smaller mean size of tumor but size did not appear to be a statistically significant factor in either the 5-

967

Transurethral resection Transurethral resection plus salvage therapy Totals Logrank over-all

No. Pts.

5-Yr. Survival Rate ± Standard Error

3-Yr. Metastasis Rate± Standard Error

33 10

0.56 ± 0.11 0.55 ± 0.17

0.42 ± 0.10 0.70 ± 0.14

43

0.55 ± 0.09 p = 0.8917

0.50 ± 0.09 p = 0.3447

year survival or 3-year metastasis rate. We were somewhat surprised at the over-all results of this study, which indicate that in this population of patients with stage B bladder tumors transurethral resection was as successful as preoperative radiation plus cystectomy and, perhaps, more successful than cystectomy or radiation therapy alone. The potential for effective treatment of invasive disease by transurethral resection was discussed in 1951 by Flocks. 7 Of 126 patients with stage B disease treated transurethrally he reported a control rate of 54 per cent. In 1967 Barnes and associates reported a combined 31 per cent 5-year survival rate in a group of patients with stages Bl and B2 disease who were managed by endoscopic means. 8 Most recently, Herr has reported on 45 patients with muscle invasive disease who were managed initially with transurethral resection. 9 Followup ranged from 3 to 7 years and 9 patients (20 per cent) remained free of disease. Another 21 patients (45 per cent) have required further transurethral or intravesical therapy but not cystectomy. Another encouraging finding in the transurethral resection group was the outcome in those 10 patients whose disease progressed to require more radical treatment and whose prognosis, nevertheless, was not adversely affected in terms of either survival or metastasis rate. Therefore, we conclude that increased consideration should be given to transurethral resection as the primary surgical therapy in patients with stage B bladder tumor. Cystectomy alone certainly does not appear to be an adequate single mode of therapy nor does radiation alone. Perhaps this study provides an adequate basis for conducting a further investigation of stage B tumors using a multiagent chemotherapeutic regimen as adjunctive therapy to transurethral resection and radical cystectomy. Such treatment might ultimately allow the majority of patients with stage B bladder cancer to avoid the morbidity and change in quality of life necessitated by radical cystectomy. REFERENCES

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. Bredael, J. J., Croker, B. P. and Glenn, J. F.: The curability of invasive bladder cancer treated by radical cystectomy. Eur. Urol., 6: 206, 1980. Rider, W. D. and Evans, D. H.: Radiotherapy in the treatment of recurrent bladder cancer. Brit. J. Urol., 48: 595, 1976. Whitmore, W. F., Jr., Batata, M. A., Ghoneim, M. A., Grabstald, H. and Unal, A.: Radical cystectomy with or without prior irradiation in the treatment of bladder cancer. J. Urol., 118: 184, 1977. Lee, E. T.: Statistical Methods for Survival Analysis. Belmont, California: Lifetime Learning Publications, 1980. SAS Institute, Inc.: SAS User's Guide: Statistics, Version 5. Cary, North Carolina: SAS Institute, Inc., pp. 529-557, 1985. Flocks, R.H.: Treatment of patients with carcinoma of the bladder. J.A.M.A., 145: 295, 1951. Barnes, R. W., Dick, A. L., Hadley, H. L. and Johnston, 0. L.: Survival following transurethral resection of bladder carcinoma. Cancer Res., 37: 2895, 1977. Herr, H. W.: Conservative management of muscle-infiltrating bladder cancer: prospective experience. J. Urol., 138: 1162, 1987.

1. O'Flynn,

2. 3. 4.

5. 6. 7.

8. 9.