© 1991 S Karger AG. Basel 0302-2838/91/0203-0184$2.75/0
Eur Urol 1991;20:184-191
Superficial Bladder Cancer: Survival and Prognostic Factors P. Sànchez de la Muela, D. Roseli, L. Agitera, F. De Castro, W. Isa, J.E. Robles, JJ. Zudaire, J.M. Beriân Department of Urology, University Hospital, Navarra University, Pamplona, Spain
1605992
Key Words. Bladder cancer • Prognostic factors • Survival • Increasing grade of anaplasia Abstract. Two hundred and seventeen consecutive patients with superficial bladder cancer stages Ta-Tj were analyzed for survival and prognostic factors. The overall 5-year survival was 88 ± 5.3%. Factors that impacted significantly on survival were: grade of anaplasia (GI 92 ± 5.9% vs. GII 87 ± 7.5% vs. Gill 68 ± 20.7%; p = 0.01); increasing grade of anaplasia (98 ± 1.9% vs. 55 ± 15.6%; p < 0.0001); progression in tumor stage (100% vs. 58 ± 12.5%; p < 0.0001); index of recurrences >0.7 (100% vs. 71 ± 10%; p < 0.0001); the presence of urothelial dysplasia (98 ± 1.7% vs. 77 ± 9.8%; p < 0.05); inflammatory infiltrate (90 ± 7% vs. 83 ± 7.3%; p < 0.01), and residual tumor post-TUR (89 ± 5.5% vs. 68 ± 18.6%; p < 0.001). Tumor stage did not impact on survival (p > 0.05). Using multivariate statistical analysis only the grade of anaplasia (p < 0.0001) and increasing grade of anaplasia (p = 0.001) demonstrated significant prognostic value. Eight percent of patients died because of tumor progression. Of these patients, 87% were Ti and had concomitant urothelial dysplasia. Twenty-five percent had carcinoma in situ and the mean index of recurrence was 1.59. Seventy-five percent of patients dying because of tumor progression developed muscle-infiltrating cancer (>T2GIII) and 25% developed previously metastatic spread without evidence of local progression (TiGIII). The grade of anaplasia and increasing grade of anaplasia predict accurately the likelihood of death secondary to local progression and/or metastatic spread. However, in the evalua tion of individual patients, factors as tumor stage, urothelial dysplasia, carcinoma in situ and mean index of recur rence should also be considered.
Bladder cancer is one of the most highly prevalent malignancies in the middle-aged population and ac counts for more than 45,000 new cases diagnosed per year [1]. Eighty percent of these newly diagnosed tumors are superficial, i.e., they are limited to the urothelium (Ta) or infiltrate no deeper than the lamina propia (TO [1], Generally, the prognosis of superficial bladder can cer (SBC) is good. Survival rates at 5 years are higher than 80%, and less than 10% of patients will have recur rences with progression [2], However, the likelihood of developing recurrences ranges from 30 to 90% and the possibilities of tumor
progression range from 5 to 50% [1], This variability depends on the presence of significant prognostic factors as the stage of the tumor [3, 4], the grade of anaplasia [5], tumor size [6], number of primary tumors [6, 7], growth pattern [8], the presence of associated dysplasia [9] and lymphatic and vascular permeation [10]. Skinner et al. [11] have recently shown that radical surgery could be a successful approach handling selected cases of superficial bladder cancer. However, cystectomy is always available and produces immediate and long term morbidity with permanent changes in the quality of life that only 10% of patients require. To avoid over treatment, it is necessary to understand sufficiently the biological behavior of the tumor. Then, accurate disease Downloaded by: University of Exeter 144.173.6.94 - 5/7/2020 7:16:52 PM
Introduction
Superficial Bladder Cancer: Survival and Prognostic Factors
Table 1. Distribution of growth pattern, tumoral size and num ber of primary tumors among 194 patients with SBC Variable
Growth pattern Size
Material and Methods Number
papillar nodular < 3 cm > 3 cm
1 2 3 4 >4
From January 1976 to December 1990, 217 patients with SBC were treated at the University Hospital of Navarra. One hundred and ninety-four patients who met the requirements were selected for retrospective study. Patient Characteristics and Treatment Schedule One hundred and seventy-four patients were males (90%) and 20 females (10%), with a male to female ratio of 8.7:1. Their age ranged from 18 to 93 years with a mean of 62. Thirty percent of patients (52/171) had been previously treated for SBC. Require ments for entering the study were: (1) stage Ta-Ti urothelial blad der cancer (primary carcinoma in situ of the bladder was excluded); (2) patients who had completed, at least, the first endoscopic study of follow-up, and (3) no previous local or systemic treatments with chemotherapy or radiotherapy. Treatment protocol and follow-ups include diagnosis and tumor staging by urinary cytology, IVP, TUR biopsy and randomized coldcup biopsies. Cold-cup biopsies of the tumor base and TUR margins were systematically performed in order to ensure the complete removal of the tumor. Afterwards, patients were randomly assigned to receive either thiotepa 40 mg i.c. weekly during 8 weeks, or doxo rubicin 50 mg i.c. weekly during 14 weeks. Patients with high grade or highly recurrent tumors were treated with i.c. BCG (Pasteur chain) at 120 mg weekly during 6 weeks. Patients who refused intravesical chemotherapy constituted the control group. Cytology and cystoscopy with randomized cold-cup biopsies were performed at 3, 9 and 12 months from diagnosis and once yearly during the following 5 years. If there was no evidence of macroscopic or cytologic recurrence, follow-ups were maintained by yearly cytology and cystoscopy every 2 years for another 5 years. Patients with evidence of cytological or macroscopic recurrence reentered the protocol as they were newly diagnosed. Patients that died because of unrelated causes or were lost of follow-up as those initially treated by radical surgery were dis charged from the study. One hundred and seventy-five tumors (90%) were papillar, 153 (79%) were smaller than 3 cm in size, 76 (39%) were multiple, and 23 patients had more than 4 synchronic tumors (12%) (table 1). One hundred and twenty-four tumors (64%) were GI, 49 GII (25%) and 21 GUI (11 %). Ninety patients were staged as Ta (46%) and 104 as T! (54%). The remaining characteristics are summarized in table 2. Forty-six patients (24%) did not receive intravesical chemother apy (control group), and 148 received complementary treatment with intravesical chemotherapy or immunotherapy (76%). Seventy patients completed treatment with thiotepa (37%), 57 with doxoru bicin (30%) and 15 with other agents (7%). Six patients did not
Patients n
%
175/194 19/194
90
153/194 41/194
79
118/194 27/194 22/194 4/194 23/194
61 14
10 21
11
2 12
Table 2. Distribution of grade of anaplasia, tumoral stage, cellu lar type, péritumoral and disseminated dysplasia among 194 pa tients with SBC Variable
Patients n
%
GI GII GUI
124/194 49/194 21/194
64 25
Stage
Ta T,
90/194 104/194
46 54
Cellular type
urothelial squamous metaplasia
117/194 17/194
91 9
Péritumoral dysplasia
yes no
79/194 115/194
41 59
Distant dysplasia
yes no
48/139 91/139
34 66
Grade
11
finish the scheduled treatment because of side effects (3%). Rela tionships between variables are shown in tables 3 and 4. Vascular and lymphatic permeation were not considered for statistical analy sis because of their low incidence. Definition of Variables and Data Collected Variables recorded for statistical analysis were: previous history of urothelial bladder cancer, number of tumors, size of the greatest tumor, growth pattern, grade of anaplasia and tumor stage. The presence of concomitant urothelial dysplasia, squamous metaplasia, inflammatory infiltrate and residual bladder cancer were considered for analysis. Also, the annual index of recurrence, increasing grade of anaplasia and progression in tumor stage were included for anal ysis. The end-point of the study was the actuarial survival adjusted for cause-specific death. Downloaded by: University of Exeter 144.173.6.94 - 5/7/2020 7:16:52 PM
progression can be anticipated when radical surgery will still cure the patient. In this paper, predictors for Ta-T! bladder cancer were analyzed in order to identify those patients at high risk of progression and death. Patients with a high likeli hood of progression must be treated early and energically in order to increase their possibilities of survival.
185
Sanchez de la Muela/Rosell/Agüera/De Castro/Isa/Robles/Zudaire/Beriân
186
Table 3. Relationship between grade of anaplasia and predictors (n = 194) GII
GI n Growth pattern Papillar 109 Nodular 15
%
n
%
n
56
33 16
17
7 14
4 7 7 4
%
n
%
Growth pattern Papillar Nodular
77 13
40 7
72 32
37 16
3 cm
81 9
42 5
72 32
37 16
1
60 30
31 15
58 46
30 24
NS
88
45
2
1
89 15
46
Eur Urol 1991;20:184-191
Superficial Bladder Cancer: Survival and Prognostic Factors P. Sànchez de la Muela, D. Roseli, L. Agitera, F. De Castro, W. Isa, J.E. Robles, JJ. Zudaire, J.M. Beriân Department of Urology, University Hospital, Navarra University, Pamplona, Spain
1605992
Key Words. Bladder cancer • Prognostic factors • Survival • Increasing grade of anaplasia Abstract. Two hundred and seventeen consecutive patients with superficial bladder cancer stages Ta-Tj were analyzed for survival and prognostic factors. The overall 5-year survival was 88 ± 5.3%. Factors that impacted significantly on survival were: grade of anaplasia (GI 92 ± 5.9% vs. GII 87 ± 7.5% vs. Gill 68 ± 20.7%; p = 0.01); increasing grade of anaplasia (98 ± 1.9% vs. 55 ± 15.6%; p < 0.0001); progression in tumor stage (100% vs. 58 ± 12.5%; p < 0.0001); index of recurrences >0.7 (100% vs. 71 ± 10%; p < 0.0001); the presence of urothelial dysplasia (98 ± 1.7% vs. 77 ± 9.8%; p < 0.05); inflammatory infiltrate (90 ± 7% vs. 83 ± 7.3%; p < 0.01), and residual tumor post-TUR (89 ± 5.5% vs. 68 ± 18.6%; p < 0.001). Tumor stage did not impact on survival (p > 0.05). Using multivariate statistical analysis only the grade of anaplasia (p < 0.0001) and increasing grade of anaplasia (p = 0.001) demonstrated significant prognostic value. Eight percent of patients died because of tumor progression. Of these patients, 87% were Ti and had concomitant urothelial dysplasia. Twenty-five percent had carcinoma in situ and the mean index of recurrence was 1.59. Seventy-five percent of patients dying because of tumor progression developed muscle-infiltrating cancer (>T2GIII) and 25% developed previously metastatic spread without evidence of local progression (TiGIII). The grade of anaplasia and increasing grade of anaplasia predict accurately the likelihood of death secondary to local progression and/or metastatic spread. However, in the evalua tion of individual patients, factors as tumor stage, urothelial dysplasia, carcinoma in situ and mean index of recur rence should also be considered.
Bladder cancer is one of the most highly prevalent malignancies in the middle-aged population and ac counts for more than 45,000 new cases diagnosed per year [1]. Eighty percent of these newly diagnosed tumors are superficial, i.e., they are limited to the urothelium (Ta) or infiltrate no deeper than the lamina propia (TO [1], Generally, the prognosis of superficial bladder can cer (SBC) is good. Survival rates at 5 years are higher than 80%, and less than 10% of patients will have recur rences with progression [2], However, the likelihood of developing recurrences ranges from 30 to 90% and the possibilities of tumor
progression range from 5 to 50% [1], This variability depends on the presence of significant prognostic factors as the stage of the tumor [3, 4], the grade of anaplasia [5], tumor size [6], number of primary tumors [6, 7], growth pattern [8], the presence of associated dysplasia [9] and lymphatic and vascular permeation [10]. Skinner et al. [11] have recently shown that radical surgery could be a successful approach handling selected cases of superficial bladder cancer. However, cystectomy is always available and produces immediate and long term morbidity with permanent changes in the quality of life that only 10% of patients require. To avoid over treatment, it is necessary to understand sufficiently the biological behavior of the tumor. Then, accurate disease Downloaded by: University of Exeter 144.173.6.94 - 5/7/2020 7:16:52 PM
Introduction
Superficial Bladder Cancer: Survival and Prognostic Factors
Table 1. Distribution of growth pattern, tumoral size and num ber of primary tumors among 194 patients with SBC Variable
Growth pattern Size
Material and Methods Number
papillar nodular < 3 cm > 3 cm
1 2 3 4 >4
From January 1976 to December 1990, 217 patients with SBC were treated at the University Hospital of Navarra. One hundred and ninety-four patients who met the requirements were selected for retrospective study. Patient Characteristics and Treatment Schedule One hundred and seventy-four patients were males (90%) and 20 females (10%), with a male to female ratio of 8.7:1. Their age ranged from 18 to 93 years with a mean of 62. Thirty percent of patients (52/171) had been previously treated for SBC. Require ments for entering the study were: (1) stage Ta-Ti urothelial blad der cancer (primary carcinoma in situ of the bladder was excluded); (2) patients who had completed, at least, the first endoscopic study of follow-up, and (3) no previous local or systemic treatments with chemotherapy or radiotherapy. Treatment protocol and follow-ups include diagnosis and tumor staging by urinary cytology, IVP, TUR biopsy and randomized coldcup biopsies. Cold-cup biopsies of the tumor base and TUR margins were systematically performed in order to ensure the complete removal of the tumor. Afterwards, patients were randomly assigned to receive either thiotepa 40 mg i.c. weekly during 8 weeks, or doxo rubicin 50 mg i.c. weekly during 14 weeks. Patients with high grade or highly recurrent tumors were treated with i.c. BCG (Pasteur chain) at 120 mg weekly during 6 weeks. Patients who refused intravesical chemotherapy constituted the control group. Cytology and cystoscopy with randomized cold-cup biopsies were performed at 3, 9 and 12 months from diagnosis and once yearly during the following 5 years. If there was no evidence of macroscopic or cytologic recurrence, follow-ups were maintained by yearly cytology and cystoscopy every 2 years for another 5 years. Patients with evidence of cytological or macroscopic recurrence reentered the protocol as they were newly diagnosed. Patients that died because of unrelated causes or were lost of follow-up as those initially treated by radical surgery were dis charged from the study. One hundred and seventy-five tumors (90%) were papillar, 153 (79%) were smaller than 3 cm in size, 76 (39%) were multiple, and 23 patients had more than 4 synchronic tumors (12%) (table 1). One hundred and twenty-four tumors (64%) were GI, 49 GII (25%) and 21 GUI (11 %). Ninety patients were staged as Ta (46%) and 104 as T! (54%). The remaining characteristics are summarized in table 2. Forty-six patients (24%) did not receive intravesical chemother apy (control group), and 148 received complementary treatment with intravesical chemotherapy or immunotherapy (76%). Seventy patients completed treatment with thiotepa (37%), 57 with doxoru bicin (30%) and 15 with other agents (7%). Six patients did not
Patients n
%
175/194 19/194
90
153/194 41/194
79
118/194 27/194 22/194 4/194 23/194
61 14
10 21
11
2 12
Table 2. Distribution of grade of anaplasia, tumoral stage, cellu lar type, péritumoral and disseminated dysplasia among 194 pa tients with SBC Variable
Patients n
%
GI GII GUI
124/194 49/194 21/194
64 25
Stage
Ta T,
90/194 104/194
46 54
Cellular type
urothelial squamous metaplasia
117/194 17/194
91 9
Péritumoral dysplasia
yes no
79/194 115/194
41 59
Distant dysplasia
yes no
48/139 91/139
34 66
Grade
11
finish the scheduled treatment because of side effects (3%). Rela tionships between variables are shown in tables 3 and 4. Vascular and lymphatic permeation were not considered for statistical analy sis because of their low incidence. Definition of Variables and Data Collected Variables recorded for statistical analysis were: previous history of urothelial bladder cancer, number of tumors, size of the greatest tumor, growth pattern, grade of anaplasia and tumor stage. The presence of concomitant urothelial dysplasia, squamous metaplasia, inflammatory infiltrate and residual bladder cancer were considered for analysis. Also, the annual index of recurrence, increasing grade of anaplasia and progression in tumor stage were included for anal ysis. The end-point of the study was the actuarial survival adjusted for cause-specific death. Downloaded by: University of Exeter 144.173.6.94 - 5/7/2020 7:16:52 PM
progression can be anticipated when radical surgery will still cure the patient. In this paper, predictors for Ta-T! bladder cancer were analyzed in order to identify those patients at high risk of progression and death. Patients with a high likeli hood of progression must be treated early and energically in order to increase their possibilities of survival.
185
Sanchez de la Muela/Rosell/Agüera/De Castro/Isa/Robles/Zudaire/Beriân
186
Table 3. Relationship between grade of anaplasia and predictors (n = 194) GII
GI n Growth pattern Papillar 109 Nodular 15
%
n
%
n
56
33 16
17
7 14
4 7 7 4
%
n
%
Growth pattern Papillar Nodular
77 13
40 7
72 32
37 16
3 cm
81 9
42 5
72 32
37 16
1
60 30
31 15
58 46
30 24
NS
88
45
2
1
89 15
46
