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The Use of Intravesical Thio-Tepa in the Management of Non-invasive Carcinoma of the Bladder
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THE JOURNAL OF UROLOGY
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THE USE OF INTRAVESICAL THIO-TEPA IN THE MANAGEMENT OF NON-INVASIVE CARCINOMA OF THE BLADDER WARREN W. KOONTZ, JR.,* GEORGE R. PROUT, JR, WADE SMITH, WILLIAM J. FRABLE JANET K MINNIS
AND
From the Medical College of Virginia, Richmond, Virginia, Massachusetts General Hospital, Boston, Massachusetts, and Georgetown University School of Medicine, Washington, D. C.
ABSTRACT
Two separate uses ofintravesical therapy with thio-tepa were tested: 1) the ablative effect on noninvasive carcinoma of the bladder (that is treatment) and 2) the prophylactic effect in the prevention of new or .recurrent tumors (that is prophylaxis). Of the 95 patients treated with thio-tepa for the ablation of incompletely resected carcinoma of the bladder (stages O and A) 45 (47 per cent) were free of disease after 2 treatment courses. The success rate was not affected by the dose (30 or 60 mg.) or by pathologic assessment of stage and grade. The number of tumors was associated with response to treatment. Patients with 4 or more tumors did not do as well as patients with less than 4 (success rates of 36 and 62 per cent, respectively, which is significant statistically, p equals 0.02). The prophylaxis study included 93 patients: 23 on 30 mg. dose, 23 on 60 mg. and 4 7 controls. The interval free of disease was longer for patients receiving thio-tepa prophylaxis compared to the controls (statistically significant difference). The results with the 30 and 60 mg. regimens were similar. The interval free of disease in the prophylaxis group appeared to be influenced by the presence or absence of cancer cells in the cytology specimens obtained before randomization. Although the difference was not statistically significant for these patients the time to disease recurrence was longer for the patients with negative cytology reports compared to patients with positive (cancer cells present) cytology :reports. Patients who had been treated successfully with thio-tepa for incompletely .resected tumor did well on the prophylaxis regimen (100 per cent were free of disease at 12 months). Of particular interest is the relatively favorable interval free of disease for patients who were treated successfully with thio-tepa for ablation of incompletely resected tumor but did not receive thio-tepa prophylaxis (that is randomized to the control group). In this grou.p 60 per cent of the patients were free of disease at 12 months. In 1961 and 1962 Jones and Swinney,1 and Veenema and associates2 demonstrated that the instillation of thio-tepa into the bladder destroyed low stage bladder carcinoma in some patients. Since then there have been several reports regarding thio-tepa as a therapeutic agent for superficial bladder carcinoma and as a prophylactic agent. 3- 6 Reports on the use of thiotepa as an ablative agent indicated that tumors were destroyed in about a third of the patients but the effect of thio-tepa in preventing recurrence of bladder cancer was not documented clearly. These investigations were a part of the longitudi_nal study of bladder cancer conducted by the National Bladder Cancer Collaborative Group A and were designed to reconfm:n the
therapeutic effectiveness of the intravesical instillation of thiotepa and to test its usefulness as a prophylactic agent. 7 In both aspects of the study 2 dosage levels of the drug were compared. In addition, the prophylaxis study included an untreated control group. Drug instillations were done at weekly intervals in the treatment study and at monthly intervals in the prophylaxis study. A preliminary report on the results of the study was made in 1977. 8 At that time the data were too scanty for a meaningful evaluation of the prophylactic value of thio-tepa. This report provides information for up to 59 months of followup and indicates that thio-tepa is useful as a prophylactic as well as an ablative agent.
Accepted for publication March 28, 19800 The National Bladder Cancer Collaborative Group A is supported by grants from the National Cancer Institute through the National Bladder Cancer Project. The principal investigators and institutions that participated in this study are G. R. Prout, Jr., Massachusetts General Hospital, Boston, Massachusetts (CA 15944); C. E. Cox, University of Tennessee, Memphis, Tennessee (CA 15934); K. B. Cummings, Virginia Mason Research Center, Seattle, Washington (CA 17466); S. J. Cutler, Georgetown University School of Medicine, Washington, D. C. (CA 23078); D. A. Culp, University of Iowa, Iowa City, Iowa (CA 15933); M. J. Flanagan, Rush Presbyterian-St. Luke's Medical Center, Chicago, Illinois (CA 16886); G. H. Friedell, St. Vincent Hospital, Worcester, Massachusetts (CA 15490); C. V. Hodges, University of Oregon, Portland, Oregon (CA 15492); C. E. A. Merrin, Roswell Park Memorial Institute, Buffalo, New York (CA 15937) and R. J. Veenema, Columbia University, New York, New York (CA 16899). * Requests for reprints: Medical College of Virginia, MCV Station Box 118, Richmond, Virginia 23298.
Plan of investigation. All patients were evaluated and classified according to protocols 1 and 2 of the National Bladder Cancer Collaborative Group A. Data concerning size, multiplicity, stage and grade of the tumors, urinary cytology and biopsies of selected mucosa! sites were obtained as part of the initial and subsequent studies. Two separate uses ofintravesical therapy with thio-tepa were tested: 1) the ablative effect on non-invasive carcinoma of the bladder (that is treatment) and 2) the prophylactic effect in the prevention of new or recurrent tumors (that is prophylaxis). Histologic proof of primary carcinoma of the bladder with no evidence of muscle invasion was required for entry to the treatment and prophylaxis regimens. Confirmation of the di-
307
MATERIALS AND METHODS
308
KOONTZ AND ASSOCIATES
agnosis was made by the Central Pathology Laboratory under the direction of Dr. Gilbert Friedell. Eligibility for the treatment regimen was based on 1) incompletely resected visible tumor (single or multiple) remaining in the bladder or 2) presence of carcinoma in situ or carcinoma in a random biopsy specimen. Eligibility to the prophylaxis regimen was based on 1) diagnosis of multifocal carcinoma or history of bladder carcinoma on 3 separate occasions within 18 months, 2) clinical assessment that prophylaxis was warranted (that is 2 tumors within 6 months) or 3) confirmation of a complete response to therapeutic thiotepa. All patients were required to be cystoscopically free of tumor before prophylaxis was started. Patients meeting the aforementioned eligibility criteria did not begin the study if they had any of the following characteristics: white blood count <3,000/mm. 3 , platelet count <100,000/ mm.3, hemoglobin <10 gm., low bladder capacity, urinary extravasation or severe vesicoureteral reflux that might make topical therapy hazardous, pregnancy or chemotherapy within 1 month of the study. In the treatment study patients were randomized to 1 of 2 dose levels: 30 mg. in 30 ml. distilled water or 60 mg. in 60 ml. distilled water. Although the initial concentration of the drug is the same for both dose levels, that is 1 mg./ml., the concentration changes as the bladder fills with urine during the 2 hours tp.e thio-tepa is in the bladder. However, the diluent effect was controlled partially by stipulating that patients were to fast for at least 8 hours before each instillation. The first course of treatment consisted of 4 weekly instillations. Four weeks after the fourth instillation patients were cystoscoped to evaluate response. For patients admitted to the study with visible tumor an unchanged or enlarged tumor, or appearance of a new tumor constituted failure. New visible tumor in patients initially having tumors that were not visually evaluable also were classified as failure and they were removed from the study. The remaining patients received a second course of treatment at the same dose level and on the same weekly schedule as the first course. At cystoscopic examination 4 weeks after the fourth instillation in the second course biopsies were taken of new or remaining tumors. In the absence of a visible tumor the previous tumor site was biopsied. Treatment was considtrnd successful if all histology specimens were negative for carcinoma. Successfully treated patients were eligible to begin the prophylaxis regimen. In the prophylaxis study patients were randomized to 1 of the 3 categories: 30 mg. in 30 ml. distilled water, 60 mg. in 60 ml. distilled water and no treatment (control). Instillations were administered every 4 weeks for a maximum of 2 years. Cystoscopic examinations were done every 3 months. The appearance of tumor that was histologically confirmed constituted a failure on prophylaxis. Patients who failed were removed from the study. Completion of 2 years of followup without histologic evidence of tumor recurrence was defined as a success. Before each instillation of thio-tepa a white blood count, platelet count and hemoglobin level were determined. Symptoms of local irritation or infection also were noted. Dosage was reduced or treatment was delayed on the basis of these observations. Treatment was terminated if warranted by the severity of the observed toxicity. Patients. From August 1974 through October 1977, 101 patients began the treatment regimen and 95 began the prophylaxis study. Of the latter group 30 had been treated successfully on the treatment regimen. An additional 15 patients with a successful outcome on the treatment regimen did not begin the prophylaxis study. Six patients on the treatment regimen and 2 on the prophylaxis regimen did not meet all the eligibility criteria and are excluded from analysis. Thus, we herein report on 95 patients in the treatment study and 93 patients in the prophylaxis study. Analytic methods. Patient and tumor characteristics are examined in relation to response to the treatment and the pro-
phylaxis regimens. The primary measure used to assess the efficacy of prophylaxis is the interval free of disease, that is time to first recurrence or to last reported observation in a state free of disease. Since patients were entered into the study through October and the cut-off date for this report was July 1, 1979 all have not been followed for 2 years. To make use of the maximum amount of information available at the cut-off date the modified life table method was used to describe the pattern of disease recurrence. 9 The statistical significance of differences between the free of disease curves was tested by the MantelHaenszel chi-square method. 10 RESULTS
Treatment regimen. The 95 patients from the 9 institutions were randomized to treatment regimens as follows: 50 patients received 30 and 45 received 60 mg. thio-tepa. Of all patients 75 per cent had a history of bladder carcinoma and 82 per cent were men. Patients in the 2 treatment groups were comparable with respect to age, sex and history of bladder carcinoma. The median age was 65 years. Tumor characteristics, that is size, shape, number seen cystoscopically, and the pathologic stage and grade, were similar for the 2 treatment groups. In 88 per cent of the cases patients had incompletely resected visible tumor (single or multiple) remaining in the bladder and in 12 per cent they had positive selected mucosal biopsies or random biopsies. In 61 patients (64 per cent) either a reduction in tumor size or a complete remission was noted after 1 course of therapy. The observed difference in response between the 30 and 60 mg. doses (that is 70 versus 58 per cent) was not statistically significant (p = 0.15). Of the 61 patients who continued treatment 45 were considered free of tumor at the end of 2 courses of treatment. Over-all, 4 7 per cent, or 45 of the 95 patients in the study, were treated successfully (table 1). The ablative effect of thio-tepa was similar for the 2 dose levels: 48 per cent for 30 mg. and 47 per cent for 60 mg. dose levels. Consequently, in examination of the possible influence of other factors no distinction will be made with respect to dose. The sex of the patient did not influence the response rate, 47 per cent of each group being classified as a success. Patients with a history of bladder carcinoma had a lower success rate (45 versus 54 per cent) but this observed difference is not significant statistically. The response rates according to specific characteristics of the tumor when patients were entered into the study were noted (table 2). Patients with i;;:4 tumors did not do as well as patients 1. Thio-tepa treatment-response to first* and second coursest of therapy according to dose of thio-tepa
TABLE
Tumor Response
Thio-tepa-30 mg.: First course Second course Combined Thio-tepa-60 mg.: First course Second course Combined All patients: First course Second course Combined
Success No.(%)
Failure No.(%)
Unknown:j: No.(%)
Totals No.(%)
35 (70.0) 24 (68.5) 24 (48.0)
13 (26.0) 5 (14.3) 18 (36.0)
2 (4.0) 6 (17.2) 8 (16.0)
50 (100.0) 35 (100.0) 50 (100.0)
26 (57.8) 21 (80.8) 21 (46.7)
15 (33.3) 4 (15.4) 19 (42.2)
4 (8.9) 1 (3.8) 5 (11.1)
45 (100.0) 26 (100.0) 45 (100.0)
61 (64.2) 45 (73.8) 45 (47.4)
28 (29.5) 9 (14.8) 37 (38.9)
6 (4.3) 7(11.4) 13 (13.7)
95 (100.0) 61 (100.0) 95 (100.0)
• Success defined as slight or moderate reduction of tumor, or complete remission. Failure defined as an appearance of new tumor(s), or tumor larger or unchanged. t Success defined as complete remission. Failure defined as histological evidence of remaining or new tumor. :j: Includes 4 patients who refused the first course of therapy and 8 patients who refused or did not receive the full second course. Exclusion of these 12 patients from the analysis increases the over-all success rate to 54 per cent, 57 per cent for the 30 mg. dose and 51 per cent for the 60 mg. dose.
-309 Thio~tepa treatraent--sur,unary of response to treatment TABLE according to visible tumor characteristics when the study was begun Tumor Response* Tumor Characteristics No. tumors: 1 2 3
s:;4 No visible tumor Totals Size of largest tumor:4cm. No visible tumor Totals Shape: Flat Sessile Papillary Combination No visible tumor Totals
Success No.(%)
Failure No.(%)
Unknovmt No.(%)
11 7 6 16 5 45
(61.1) (58.3) (66.7) (36.4) (41.7) (47.4)
5 4 2 21 5 37
(27.8) (33.3) (22.2) (47.7) (41.7) (38.9)
2 1 l 7 2 13
(11.1) (15.9) (16.6) (13.7)
18 (100.0) 12 (100.0) 9 (100.0) 44 (100.0) 12:t (100.0) 95 (100.0)
11 19 6 3 6 45
(45.8) (57.6) (46.2) (27.3) (42.9) (47.4)
9 11 5 6 6 37
(37.5) (33.3) (38.5) (54.5) (42.9) (38.9)
4 3 2 2 2 13
(16.7) (9.1) (15.3) (18.2) (14.2) (13.7)
24 33 13 11 14:J: 95
(100.0) (100.0) (100.0) (100.0) (100.0) (100.0)
2 8 20 8 7 45
(50.0) (57.2) (43.5) (47.1) (50.0) (47.4)
2 3 19 8 5 37
(50.0) (21.4) (41.3) (47.1) (35.7) (38.9)
0 3 7 1 2 13
(0.0) (21.4) (15.2) (5.8) (14.3) (13.7)
4 14 46 17 14:J: 95
(100.0) (100.0) (100.0) (100.0) (100.0) (100.0)
(11.1) (8.4)
Totais No.(%)
* Response to total course of treatment, including patients who failed on the first course. t Includes 4 patients who refused the first course of therapy and 8 patients who refused or did not receive the full second course. Exclusion of these 12 patients from the analysis increases the over-all success rate to 54 per cent, 57 per cent for the 30 mg. dose and 51 per cent for the 60 mg. dose. :j: In addition to 11 patients with no visible tumor when the study began, the number of patients with unreported descriptive information include number of tumors-1, tumor size-3 and tumor shape-3.
with <4 tumors, the success rates being 36 and 62 per cent, respectively. This observed difference was significant statistically (p = 0.02). Although the difference was not significant statistically (p = 0.14) patients with tumors that cystoscopically appeared >4 cm. had a lower response rate compared to those with tumors <4 cm. The visible shape of the tumor does not appear to influence response to treatment. The response of patients with papillary tumors was compared to that of patients with non-papillary tumors, including various combinations of shape categories. No statistically significant differences were found. The Central Pathology Laboratory's histologic diagnosis of tumor stage and grade, according to response, is presented in table 3. In this series there was no statistically significant variation in response wi.th respect to histologic characteristics. status when the patients were entered into the study (presence or absence of cancer cells in bladder washings or urine specimens) was not associated with :response to treatment. The classification of :response to thio-tepa treatment was based on cystoscopic and histologic evi.dence. Of the 45 patients considered free of tumor at the end of 2 courses of treatment 22 (49 per cent) were cy1;0H}g1,~aLly negative and 15 (33 per cent) were cytologically positive. Cytology status was not reported for 8 patients (18 per cent). Of the 45 patients reported free of tumor 12 had carcinoma in situ when they wern entered into the study. At the end of 2 courses of treatment 5 of the 12 patients were cytologically negative and 7 were cytologically positive. Prophylaxis regimen. Of the 93 patients from the 9 institutions admitted to the prophylaxis regimen randomization, stratified by institution, was balanced: 23 received 30 mg. and 23 received 60 mg. dose, while 47 received no treatment (controls). The median patient age was 65 years and 88 per cent were men. Patients in the 3 study groups were comparable with respect to age and sex. Patients in the prophylaxis study had the following tumor characteristics: 14 per cent had 3 tumor occurrences in the 18 months before randomization, 20 per cent had been treated for
multifoca1 tumors and 33 per cent were considered to be at risk for a recurrence because of a long history of recurrence tumors within 6 months, large tumor with invasion of lamina propria and so forth). The remaining 33 per cent of the patients on prophylaxis had begun the study after 2 successful courses of thio-tepa treatment. This last group of patients will be referred to as post-therapy prophylaxis patients. All other patients are regular prophylaxis patients. Patients in the 3 study grnups (that is 30 and 60 mg. thiotepa, and the controls) generally were comparable with respect to the aforementioned tumor characteristics (table 4). Of the 93 patients in the study 24 per cent (10 assigned to prophylaxis and 12 assigned to control) had a positive cytology (urine or bladder washings) at the last cystoscopic examination before randomization. According to the eligibility requirements specified in the prophylaxis protocol a patient was not required to have had bladder carcinoma immediately before randomization, as long as the described criteria were met. The interval from the last treated tumor to beginning the study among the regular prophylaxis patients ranged from
Tun1.or Response*
CPLt Stage: Ca in situ (TIS) Stage O (Ta) Stage A (Tl) Stage A plus Ca in situ No CPLt report Totals CPL t pathologic grade:
Success No.(%)
Failure No.(%)
11 (55.0) 20 (45.5) 11 (47.8)
5 19 8 3 2 37
1 (25.0)
2 (50.0) 45 (47.4) 16 (51.6) 13 (39.4) 14 (51.9)
I II III No CPLt report Totais
(25.0) (43.2) (34.8) (75.0) (50.0) (38.9)
Unknown:j: No.(%) 4 (20.0) 5 (11.3) 4 (17.4) 0 (0.0)
__Q__(Q:22_ 13 (13.7)
2 (6.5)
13 (41.9) 14 (42.4)
2 (50.0)
8 (29.6) 2 (50.0)
45 (47.4)
37 (38.9)
6 (18.2) 5 (18.5)
0 (0.0) 13 (13.7)
Totals No.(%) 20 44 23 4 4 95
(100.0) (100.0) (100.0) (100.0) (100.0) (100.0)
31 33 27 4
(100.0) (100.0) (100.0) (100.0)
95 (100.0)
* Response to total course of treatment, including_patients who failed on the first course. t Central Pathology Laboratory. :j: Includes 4 patients who refused the first course of therapy and 8 who refused OT did not :receive the full second course. Exclusion of patients from the analysis increases the ove:r-all success rate to 54 per cent 1 57 per cent for the 30 mg. dose and 51 per cent for the 60 mg. dose. TABLE 4.
Thio-tepa prophylaxis-distribution of patients by type of eligibility according to assignment Assignment
Prophylaxis Type
Regular: 3 tumor occurrences in last 18 mos. Multifocal tumors Investigator's option Subtotals Post-therapy Totals
Prophylaxis 30Mg. No.(%)
60Mg. No.(%)
5 (21.7)
3 (13.0)
5 (21.7) 5 (21.7) 15 (65.2) 8 (34.8) 23 (100.0)
4 (17.4) 9 (39.2) 16 (69.6) 7 (30.4) 23 (100.0)
Control No.(%)
Totals No.(%)
5 (10.6)
13
(14.0)
10 (21.3)
19 31 63 30 93
(20.4) (33.3) (67.7) (32.3) (100.0)
17 32 15 47
(36.2) (68.1) (31.9) (100.0)
310
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bladder carcinoma. To maximize the amount of information available to examine the prophylactic effect of thio-tepa, the modified life table method9 was used to describe the pattern of disease recurrence. The time of tumor recurrence for the prophylaxis group was compared to the control group (fig. 1). The patients who received prophylaxis did significantly better than the controls. The Mantel-Haenszel chi-square test 10 permits assessment of the statistical significance of an observed difference between 2 survival curves. The 2 curves were significantly different at the end of 7 months (p = 0.025) and thereafter. At 12 months 66 per cent of the prophylaxis group compared to 40 per cent of the control group were reported free of disease (p = 0.02). Comparisons also were made between the 30 and 60 mg. dose levels of thio-tepa. There was no significant difference in the time to first recurrence. At 12 months 63 per cent of the 30 mg. dose group were free of disease compared to 69 per cent of the 60 mg. dose group. As a result a distinction between the 2 dose levels will not be made in the subsequent analyses. Table 5 presents the interval free of disease at 12 months for the prophylaxis and the control groups according to the Central Pathology Laboratory classification of the cytology specimens obtained before randomization. For patients with negative cytologies the percentage free of disease for the prophylaxis group was significantly better than for the control group (68 versus 40 per cent, p = 0.02). Among patients with positive cytologies the observed difference in response between the prophylaxis and control groups was not significant statistically. Among patients assigned to prophylaxis the observed percentage free of disease was higher for patients with negative cytology but the difference was not significant statistically. Among patients assigned to the control group there was no observed difference in the time to disease recurrence with respect to the cytology findings. We made a comparison of the prophylaxis and control groups in the regular prophylaxis study (fig. 2). The curve for the prophylaxis group clearly is at a higher level, that is 50 per cent free of disease at 12 months compared to 31 per cent for the control group. Although the observed difference between the curves is not significant statistically (p = 0.20) the observed advantage for the prophylactically treated group warrants attention. As previously indicated 31 of the 93 patients began the prophylaxis regimen at the option of the investigator. Exclusion of these patients from the analysis had little effect on the levels of the curves depicting duration of the status free of disease. The patients referred to as post-therapy prophylaxis did significantly better than the post-therapy controls (fig. 3). The chi-square method was significant statistically at 12 months and beyond (p = 0.05). At 12 months of observation 100 per
TABLE 5. Thio-tepa prophylaxis-percentage of patients free of disease at 12 months according to assignment and cytology status
% Free of Disease At 12 Mos.*
No. Pts. Cytology Status Prophylaxis Pos.t Neg. Totals
Control
Prophylaxis
Control
10
12
35 45t
35 47
56 69 66
40 40 40
* Calculated by the modified life table method. t Cancer cells present. t Excludes 1 patient who died free of disease 2 weeks after randomization.
cent of the post-therapy prophylaxis patients compared to 60 per cent of the post-therapy controls were free of disease. The interval free of disease of the 15 successfully treated patients from the treatment study, who were not randomized to the prophylaxis study, was compared to the 2 randomized groups. Of these patients 5 continued to receive instillations of thio-tepa. These patients had an interval free of disease roughly similar to the post-therapy controls; at 12 months 43 per cent of the patients were free of disease (fig. 3). The time to first recurrence of the regular prophylaxis study patients was compared to that of the post-therapy controls combined with the 9 successfully treated patients on therapy who were not randomized to prophylaxis and did not continue to receive thio-tepa. The interval free of disease of the latter group was similar to the regular prophylaxis group and clearly better than the regular controls. The successful patients on therapy who did not continue to receive thio-tepa prophylactically appear to experience a beneficial carry-over effect. Toxicity and deviations from protocol. Treatment regimen: toxicity, which included leukopenia, thrombocytopenia and urinary tract symptoms, was observed in 17 per cent of the 95 patients. Of the 16 patients with reported toxicity the severity of the toxicity led to termination of the treatment in 4 patients. The course of treatment was interrupted in the other 12 patients. No deaths were attributed to receipt of thio-tepa. The observed toxicity was similar for the 2 dose levels (table 6). The response to therapy, according to the observed toxicity, is presented in table 7. The response rate did not appear to be affected by the manifestation of toxicity. Protocol deviations, which included patient refusal of treatment, variation in the assigned dose and termination of treatment (without evidence of toxicity), were reported in 21 per cent of the 95 patients on treatment. The number of instillations administered also varied from the number specified in the protocol. Of the 95 patients on the first course of treatment 4 received <4 instillations and 7 received >4. On the second course of therapy 9 of the 61 patients did not receive 4 instil-
INTRA_VES1CAL Tr-n:o-T·EPA FOR I"JON-·lN"VASIVE CAEtCINOlViA OF BLADDER
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FIG. 3. Duration of status free of disease for patients in post-therapy thio-tepa prophylaxis group TABLE
6. Thio-tepa treatment-frequency of observed toxicity by dose Observed Protocol Toxicity*
Leukopeniaj" No.(%)
1 (2.0) 6 (13.4) 7 (7.4)
Thio-tepa-30 mg. Thio-tepa-60 mg. Totals
Thrombocytopenia:j: No.(%)
Urinary Tract Symptoms+ No.(%)
Combination§ No.(%)
Observed Toxicity No.(%)
No Reported Toxicity No.(%)
3 (6.0) 0 (0.0)
I (2.0)
3 (6.0)
8 (16.0)
42 (84.0)
1 (2.2) 2 (2.1)
8 (18.8) 16 (16.9)
37 (82.2)
3 (3.2)
1 (2.2) 4 (4.2)
79 (83.1)
Totals No.(%) 50 (100.0) 45 (100.0) 95 (100.0)
., Of the 16 patients ,vith reported protocol toyjcity treatment was tem'linated in 4 cases and intenupted in the other 12. t Leukopenia-white blood count <3,000/mm. 3 and thrombocytopenia-platelets <100,000/mn,. 3 • Includes 1 patient w:ith pyuria, hematuria and urinary tract infection, and l with hematuria. § Includes 1 patient with a low hemoglobin and urinary tract infection, 1 with lower back pain and mild hematuria, l with leukopenia and a low hemoglobin and 1 with hematuria and cerebrovascular accident.
+
TABLE
7. Thio-tepa treatment-summary of response to treatment
according to the occurrence of toxicity Tumor Response* Toxicity Present Absent Totals
Success No.(%)
Failure No.(%)
Unknown No.(%)
Totals No.(%)
8 (50.0) 37 (46.8) 45 (47.4)
1 (6.3) 36 (45.6) 37 (38.9)
7 (43.7) ~ 13 (13.7)
16 (100.0) 79 (100.0) 95 (100.0)
* Response to total course of treatment, including patients who failed on the first course.
lations (6 received <4 and 3 received >4). The number of patients is too small for assessing the effect of the different types of deviation from protocol on the outcome. Prophylaxis regimen: toxicity was reported in 11 per cent of
the 93 patients. The toxicity was observed more frequently in the 60 mg. group but the difference is not significant statistically (table 8). The severity of the toxicity led to termination of prophylaxis in 6 patients and interruption of instillations in 4. No deaths were attributed to the use of thio-tepa. Protocol deviations, that is refusal of prophylaxis, alteration of the prophylaxis assignment and termination of prophylaxis, were reported in 25 per cent of the 93 patients. In view of the reported deviation from regimen the clear advantage of prophylactic treatment compared to no treatment is particularly impressive. DISCUSSION
Previous reports on the use of thio-tepa for superficial bladder carcinoma indicate that tumors will be destroyed in about a
312
KOONTZ AND ASSOCIATES TABLE
8. Thio-tepa prophylaxis-frequency of observed toxicity by dose Observed Protocol Toxicity*
Leukopeniat No.(%) Thio-tepa-30 mg. Thio-tepa-60 mg. Control Totals
0 1 0 1
(0.0) (4.3) (0.0) (1.1)
Thrombocytopeniat No.(%) 0 1 0 1
(0.0) (4.3) (0.0) (1.1)
Low Remoglobint No.(%) 1 (4.3) 0 (0.0) 0 (0.0) 1 (1.1)
Urinary Tract Symptomst No.(%) 0 4 0 4
(0.0) (17.4) (0.0) (4.3)
Other No.(%) 0 (0.0) 1 (4.3) 0 (0.0) 1 (1.1)
Combination§ No.(%) 0 2 0 2
(0.0) (8.8) (0.0) (2.0)
Observed Toxicity No.(%) 1 9 0 10
No Reported ToXIcity No.(%)
(4.3) (39.1) (0.0) (10.7)
22 14 47 83
(95.7) (60.9) (100.0) (89.3)
Totals No.(%)
23 23 47 93
(100.0) (100.0) (100.0) (100.0)
* Of the 10 patients with reported protocol toxicity prophylaxis was terminated in 6 cases and interrupted in the other 4. t Leukopenia-white blood count <3,000/mm. 3 , thrombocytopenia-platelets <100,000/mm. 3 and low hemoglobin-hemoglobin< 10 gm. t Includes 2 patients with urinary tract infections, 1 with irritative symptoms-frequency, dysuria and urgency, and 1 with moderate dysuria, frequency and severe urgency. § Includes 1 patient with low blood values, pain and abdominal tenderness and 1 with low white blood count and low hematocrit.
third of the patients, diminished in size and number in another third and unaltered in the remaining third. In our study destruction of superficial tumor after therapeutic intravesical thio-tepa was reported in 47 per cent of the patients. The classification of a patient free of tumor was based on visual and histologic evidence. It is noteworthy that 15 of the 45 patients reported to be free of tumor at the end of treatment had positive cytology specimens (urine or bladder washing). The prognostic significance of this observation remains to be determined. It appears that there is no difference in the incidence of ablation of tumor between the 30 and 60 mg. dosage. There also was no difference in the level of toxicity demonstrated with either dose and this is somewhat different from that reported by Nieh and associates, in which there was a slight increase in response to the 60 mg. dosage. 11 Patients with more widespread disease, that is Ei;;4 tumors, did not do as well as those who had <4 tumors. The observed differences in response with respect to history of bladder cancer, sex, size and shape of tumor, histologic grade and stage were not significant statistically. In the prophylaxis study the interval free of disease clearly was longer among patients who received prophylaxis compared to the controls. Patients who had been treated successfully with therapeutic intravesical thio-tepa with complete ablation of their tumors and who then continued to receive thio-tepa prophylactically did extremely well during the first 12 months offollowup. In addition, there was an apparent continued effect of the therapeutic thio-tepa in those patients who had exhibited complete ablation of the tumors and who were then placed in the control group in the prophylaxis study. The results suggest the desirability of investigating the possible advantage of leaving behind a clearly superficial tumor for use as a marker in assessing the effectiveness of thio-tepa as a potential prophylactic agent in an individual patient. If there is complete ablation of this marker as a result of intravesical thiotepa therapy then this patient would be continued on thio-tepa prophylaxis and one would expect a prolonged interval free of disease. If there was no response by the marker tumor to the therapeutic course of thio-tepa then other modalities could be instituted. Thus, a long and fruitless prophylactic course of thio-tepa would be avoided.
Reported toxicity to prophylactic thio-tepa was greater in those patients receiving the higher 60 mg. monthly instillations of the drug, although the observed difference was not significant statistically. Since there appears to be no difference in the prophylactic effect between the 30 and 60 mg. dosage, and no difference in the therapeutic effect between these 2 dosages, the 30 mg. intravesical thio-tepa dosage appears to be preferable. This study describes the successes and failures in treating superficial bladder carcinoma with thio-tepa. After suitable animal testing other agents should be studied singly in phase 2 trials and the sequential use of effective agents should be considered. REFERENCES 1. Jones, H. C. and Swinney, J.: Thio-TEPA in the treatment of tumours of the bladder. Lancet, 2: 615, 1961. 2. Veenema, R. J., Dean, A. L., Jr., Roberts, M., Fingerhut, B., Chowhury, B. K. and Tarassoly, H.: Bladder carcinoma treated by direct instillations of thio-tepa. J. Urol., 88: 60, 1962. 3. Abbassian, A. and Wallace, D. M.: Intracavitary chemotherapy of diffuse non-infiltrating papillary carcinoma of the bladder. J. Urol., 96: 461, 1965. 4. Edsmyr, F. and Boman, J.: Instillation of thio-tepa (Tifosyl) in vesical papillomatosis. Acta Rad. Ther. Phys. Biol., 9: 395, 1970. 5. Pavone-Macaluso, M.: Chemotherapy of vesical and prostatic tumours. Brit. J. Urol., 43: 701, 1971. 6. Veenema, R. J., Dean, A. L., Jr., Uson, A. C., Roberts, M. and Longo, F.: Thio-tepa bladder instillations: therapy and prophylaxis for superficial bladder tumors. J. Urol., 101: 711, 1969. 7. National Bladder Collaborative Group A: Development of a strategy for a longitudinal study of patients with bladder cancer. Cancer Res., 37: 2898, 1977. 8. National Bladder Cancer Collaborative Group A: The role of intravesical thio-tepa in the management of superficial bladder cancer. Cancer Res., 37: 2916, 1977. 9. Cutler, S. J. and Ederer, F.: Maximum utilization of the life table method in analyzing survival. J. Chron. Dis., 8: 699, 1958. 10. Mantel, M. and Haenszel, W.: Statistical aspects of the analysis of data from retrospective studies of disease. J. Natl. Cancer Inst., 22: 719, 1959. 11. Nieh, P. T., Daly, J. J., Heaney, J. A., Heney, N. M. and Prout, G. R., Jr.: The effect of intravesical thio-tepa on normal and tumor urothelium. J. Urol., 119: 59, 1978.
THE JOURNAL OF UROLOGY
Iviarch
Printed in
Copyright© 19el by The VV:illiarns & 1,iVilkin.s Co.
THE USE OF INTRAVESICAL THIO-TEPA IN THE MANAGEMENT OF NON-INVASIVE CARCINOMA OF THE BLADDER WARREN W. KOONTZ, JR.,* GEORGE R. PROUT, JR, WADE SMITH, WILLIAM J. FRABLE JANET K MINNIS
AND
From the Medical College of Virginia, Richmond, Virginia, Massachusetts General Hospital, Boston, Massachusetts, and Georgetown University School of Medicine, Washington, D. C.
ABSTRACT
Two separate uses ofintravesical therapy with thio-tepa were tested: 1) the ablative effect on noninvasive carcinoma of the bladder (that is treatment) and 2) the prophylactic effect in the prevention of new or .recurrent tumors (that is prophylaxis). Of the 95 patients treated with thio-tepa for the ablation of incompletely resected carcinoma of the bladder (stages O and A) 45 (47 per cent) were free of disease after 2 treatment courses. The success rate was not affected by the dose (30 or 60 mg.) or by pathologic assessment of stage and grade. The number of tumors was associated with response to treatment. Patients with 4 or more tumors did not do as well as patients with less than 4 (success rates of 36 and 62 per cent, respectively, which is significant statistically, p equals 0.02). The prophylaxis study included 93 patients: 23 on 30 mg. dose, 23 on 60 mg. and 4 7 controls. The interval free of disease was longer for patients receiving thio-tepa prophylaxis compared to the controls (statistically significant difference). The results with the 30 and 60 mg. regimens were similar. The interval free of disease in the prophylaxis group appeared to be influenced by the presence or absence of cancer cells in the cytology specimens obtained before randomization. Although the difference was not statistically significant for these patients the time to disease recurrence was longer for the patients with negative cytology reports compared to patients with positive (cancer cells present) cytology :reports. Patients who had been treated successfully with thio-tepa for incompletely .resected tumor did well on the prophylaxis regimen (100 per cent were free of disease at 12 months). Of particular interest is the relatively favorable interval free of disease for patients who were treated successfully with thio-tepa for ablation of incompletely resected tumor but did not receive thio-tepa prophylaxis (that is randomized to the control group). In this grou.p 60 per cent of the patients were free of disease at 12 months. In 1961 and 1962 Jones and Swinney,1 and Veenema and associates2 demonstrated that the instillation of thio-tepa into the bladder destroyed low stage bladder carcinoma in some patients. Since then there have been several reports regarding thio-tepa as a therapeutic agent for superficial bladder carcinoma and as a prophylactic agent. 3- 6 Reports on the use of thiotepa as an ablative agent indicated that tumors were destroyed in about a third of the patients but the effect of thio-tepa in preventing recurrence of bladder cancer was not documented clearly. These investigations were a part of the longitudi_nal study of bladder cancer conducted by the National Bladder Cancer Collaborative Group A and were designed to reconfm:n the
therapeutic effectiveness of the intravesical instillation of thiotepa and to test its usefulness as a prophylactic agent. 7 In both aspects of the study 2 dosage levels of the drug were compared. In addition, the prophylaxis study included an untreated control group. Drug instillations were done at weekly intervals in the treatment study and at monthly intervals in the prophylaxis study. A preliminary report on the results of the study was made in 1977. 8 At that time the data were too scanty for a meaningful evaluation of the prophylactic value of thio-tepa. This report provides information for up to 59 months of followup and indicates that thio-tepa is useful as a prophylactic as well as an ablative agent.
Accepted for publication March 28, 19800 The National Bladder Cancer Collaborative Group A is supported by grants from the National Cancer Institute through the National Bladder Cancer Project. The principal investigators and institutions that participated in this study are G. R. Prout, Jr., Massachusetts General Hospital, Boston, Massachusetts (CA 15944); C. E. Cox, University of Tennessee, Memphis, Tennessee (CA 15934); K. B. Cummings, Virginia Mason Research Center, Seattle, Washington (CA 17466); S. J. Cutler, Georgetown University School of Medicine, Washington, D. C. (CA 23078); D. A. Culp, University of Iowa, Iowa City, Iowa (CA 15933); M. J. Flanagan, Rush Presbyterian-St. Luke's Medical Center, Chicago, Illinois (CA 16886); G. H. Friedell, St. Vincent Hospital, Worcester, Massachusetts (CA 15490); C. V. Hodges, University of Oregon, Portland, Oregon (CA 15492); C. E. A. Merrin, Roswell Park Memorial Institute, Buffalo, New York (CA 15937) and R. J. Veenema, Columbia University, New York, New York (CA 16899). * Requests for reprints: Medical College of Virginia, MCV Station Box 118, Richmond, Virginia 23298.
Plan of investigation. All patients were evaluated and classified according to protocols 1 and 2 of the National Bladder Cancer Collaborative Group A. Data concerning size, multiplicity, stage and grade of the tumors, urinary cytology and biopsies of selected mucosa! sites were obtained as part of the initial and subsequent studies. Two separate uses ofintravesical therapy with thio-tepa were tested: 1) the ablative effect on non-invasive carcinoma of the bladder (that is treatment) and 2) the prophylactic effect in the prevention of new or recurrent tumors (that is prophylaxis). Histologic proof of primary carcinoma of the bladder with no evidence of muscle invasion was required for entry to the treatment and prophylaxis regimens. Confirmation of the di-
307
MATERIALS AND METHODS
308
KOONTZ AND ASSOCIATES
agnosis was made by the Central Pathology Laboratory under the direction of Dr. Gilbert Friedell. Eligibility for the treatment regimen was based on 1) incompletely resected visible tumor (single or multiple) remaining in the bladder or 2) presence of carcinoma in situ or carcinoma in a random biopsy specimen. Eligibility to the prophylaxis regimen was based on 1) diagnosis of multifocal carcinoma or history of bladder carcinoma on 3 separate occasions within 18 months, 2) clinical assessment that prophylaxis was warranted (that is 2 tumors within 6 months) or 3) confirmation of a complete response to therapeutic thiotepa. All patients were required to be cystoscopically free of tumor before prophylaxis was started. Patients meeting the aforementioned eligibility criteria did not begin the study if they had any of the following characteristics: white blood count <3,000/mm. 3 , platelet count <100,000/ mm.3, hemoglobin <10 gm., low bladder capacity, urinary extravasation or severe vesicoureteral reflux that might make topical therapy hazardous, pregnancy or chemotherapy within 1 month of the study. In the treatment study patients were randomized to 1 of 2 dose levels: 30 mg. in 30 ml. distilled water or 60 mg. in 60 ml. distilled water. Although the initial concentration of the drug is the same for both dose levels, that is 1 mg./ml., the concentration changes as the bladder fills with urine during the 2 hours tp.e thio-tepa is in the bladder. However, the diluent effect was controlled partially by stipulating that patients were to fast for at least 8 hours before each instillation. The first course of treatment consisted of 4 weekly instillations. Four weeks after the fourth instillation patients were cystoscoped to evaluate response. For patients admitted to the study with visible tumor an unchanged or enlarged tumor, or appearance of a new tumor constituted failure. New visible tumor in patients initially having tumors that were not visually evaluable also were classified as failure and they were removed from the study. The remaining patients received a second course of treatment at the same dose level and on the same weekly schedule as the first course. At cystoscopic examination 4 weeks after the fourth instillation in the second course biopsies were taken of new or remaining tumors. In the absence of a visible tumor the previous tumor site was biopsied. Treatment was considtrnd successful if all histology specimens were negative for carcinoma. Successfully treated patients were eligible to begin the prophylaxis regimen. In the prophylaxis study patients were randomized to 1 of the 3 categories: 30 mg. in 30 ml. distilled water, 60 mg. in 60 ml. distilled water and no treatment (control). Instillations were administered every 4 weeks for a maximum of 2 years. Cystoscopic examinations were done every 3 months. The appearance of tumor that was histologically confirmed constituted a failure on prophylaxis. Patients who failed were removed from the study. Completion of 2 years of followup without histologic evidence of tumor recurrence was defined as a success. Before each instillation of thio-tepa a white blood count, platelet count and hemoglobin level were determined. Symptoms of local irritation or infection also were noted. Dosage was reduced or treatment was delayed on the basis of these observations. Treatment was terminated if warranted by the severity of the observed toxicity. Patients. From August 1974 through October 1977, 101 patients began the treatment regimen and 95 began the prophylaxis study. Of the latter group 30 had been treated successfully on the treatment regimen. An additional 15 patients with a successful outcome on the treatment regimen did not begin the prophylaxis study. Six patients on the treatment regimen and 2 on the prophylaxis regimen did not meet all the eligibility criteria and are excluded from analysis. Thus, we herein report on 95 patients in the treatment study and 93 patients in the prophylaxis study. Analytic methods. Patient and tumor characteristics are examined in relation to response to the treatment and the pro-
phylaxis regimens. The primary measure used to assess the efficacy of prophylaxis is the interval free of disease, that is time to first recurrence or to last reported observation in a state free of disease. Since patients were entered into the study through October and the cut-off date for this report was July 1, 1979 all have not been followed for 2 years. To make use of the maximum amount of information available at the cut-off date the modified life table method was used to describe the pattern of disease recurrence. 9 The statistical significance of differences between the free of disease curves was tested by the MantelHaenszel chi-square method. 10 RESULTS
Treatment regimen. The 95 patients from the 9 institutions were randomized to treatment regimens as follows: 50 patients received 30 and 45 received 60 mg. thio-tepa. Of all patients 75 per cent had a history of bladder carcinoma and 82 per cent were men. Patients in the 2 treatment groups were comparable with respect to age, sex and history of bladder carcinoma. The median age was 65 years. Tumor characteristics, that is size, shape, number seen cystoscopically, and the pathologic stage and grade, were similar for the 2 treatment groups. In 88 per cent of the cases patients had incompletely resected visible tumor (single or multiple) remaining in the bladder and in 12 per cent they had positive selected mucosal biopsies or random biopsies. In 61 patients (64 per cent) either a reduction in tumor size or a complete remission was noted after 1 course of therapy. The observed difference in response between the 30 and 60 mg. doses (that is 70 versus 58 per cent) was not statistically significant (p = 0.15). Of the 61 patients who continued treatment 45 were considered free of tumor at the end of 2 courses of treatment. Over-all, 4 7 per cent, or 45 of the 95 patients in the study, were treated successfully (table 1). The ablative effect of thio-tepa was similar for the 2 dose levels: 48 per cent for 30 mg. and 47 per cent for 60 mg. dose levels. Consequently, in examination of the possible influence of other factors no distinction will be made with respect to dose. The sex of the patient did not influence the response rate, 47 per cent of each group being classified as a success. Patients with a history of bladder carcinoma had a lower success rate (45 versus 54 per cent) but this observed difference is not significant statistically. The response rates according to specific characteristics of the tumor when patients were entered into the study were noted (table 2). Patients with i;;:4 tumors did not do as well as patients 1. Thio-tepa treatment-response to first* and second coursest of therapy according to dose of thio-tepa
TABLE
Tumor Response
Thio-tepa-30 mg.: First course Second course Combined Thio-tepa-60 mg.: First course Second course Combined All patients: First course Second course Combined
Success No.(%)
Failure No.(%)
Unknown:j: No.(%)
Totals No.(%)
35 (70.0) 24 (68.5) 24 (48.0)
13 (26.0) 5 (14.3) 18 (36.0)
2 (4.0) 6 (17.2) 8 (16.0)
50 (100.0) 35 (100.0) 50 (100.0)
26 (57.8) 21 (80.8) 21 (46.7)
15 (33.3) 4 (15.4) 19 (42.2)
4 (8.9) 1 (3.8) 5 (11.1)
45 (100.0) 26 (100.0) 45 (100.0)
61 (64.2) 45 (73.8) 45 (47.4)
28 (29.5) 9 (14.8) 37 (38.9)
6 (4.3) 7(11.4) 13 (13.7)
95 (100.0) 61 (100.0) 95 (100.0)
• Success defined as slight or moderate reduction of tumor, or complete remission. Failure defined as an appearance of new tumor(s), or tumor larger or unchanged. t Success defined as complete remission. Failure defined as histological evidence of remaining or new tumor. :j: Includes 4 patients who refused the first course of therapy and 8 patients who refused or did not receive the full second course. Exclusion of these 12 patients from the analysis increases the over-all success rate to 54 per cent, 57 per cent for the 30 mg. dose and 51 per cent for the 60 mg. dose.
-309 Thio~tepa treatraent--sur,unary of response to treatment TABLE according to visible tumor characteristics when the study was begun Tumor Response* Tumor Characteristics No. tumors: 1 2 3
s:;4 No visible tumor Totals Size of largest tumor:
Success No.(%)
Failure No.(%)
Unknovmt No.(%)
11 7 6 16 5 45
(61.1) (58.3) (66.7) (36.4) (41.7) (47.4)
5 4 2 21 5 37
(27.8) (33.3) (22.2) (47.7) (41.7) (38.9)
2 1 l 7 2 13
(11.1) (15.9) (16.6) (13.7)
18 (100.0) 12 (100.0) 9 (100.0) 44 (100.0) 12:t (100.0) 95 (100.0)
11 19 6 3 6 45
(45.8) (57.6) (46.2) (27.3) (42.9) (47.4)
9 11 5 6 6 37
(37.5) (33.3) (38.5) (54.5) (42.9) (38.9)
4 3 2 2 2 13
(16.7) (9.1) (15.3) (18.2) (14.2) (13.7)
24 33 13 11 14:J: 95
(100.0) (100.0) (100.0) (100.0) (100.0) (100.0)
2 8 20 8 7 45
(50.0) (57.2) (43.5) (47.1) (50.0) (47.4)
2 3 19 8 5 37
(50.0) (21.4) (41.3) (47.1) (35.7) (38.9)
0 3 7 1 2 13
(0.0) (21.4) (15.2) (5.8) (14.3) (13.7)
4 14 46 17 14:J: 95
(100.0) (100.0) (100.0) (100.0) (100.0) (100.0)
(11.1) (8.4)
Totais No.(%)
* Response to total course of treatment, including patients who failed on the first course. t Includes 4 patients who refused the first course of therapy and 8 patients who refused or did not receive the full second course. Exclusion of these 12 patients from the analysis increases the over-all success rate to 54 per cent, 57 per cent for the 30 mg. dose and 51 per cent for the 60 mg. dose. :j: In addition to 11 patients with no visible tumor when the study began, the number of patients with unreported descriptive information include number of tumors-1, tumor size-3 and tumor shape-3.
with <4 tumors, the success rates being 36 and 62 per cent, respectively. This observed difference was significant statistically (p = 0.02). Although the difference was not significant statistically (p = 0.14) patients with tumors that cystoscopically appeared >4 cm. had a lower response rate compared to those with tumors <4 cm. The visible shape of the tumor does not appear to influence response to treatment. The response of patients with papillary tumors was compared to that of patients with non-papillary tumors, including various combinations of shape categories. No statistically significant differences were found. The Central Pathology Laboratory's histologic diagnosis of tumor stage and grade, according to response, is presented in table 3. In this series there was no statistically significant variation in response wi.th respect to histologic characteristics. status when the patients were entered into the study (presence or absence of cancer cells in bladder washings or urine specimens) was not associated with :response to treatment. The classification of :response to thio-tepa treatment was based on cystoscopic and histologic evi.dence. Of the 45 patients considered free of tumor at the end of 2 courses of treatment 22 (49 per cent) were cy1;0H}g1,~aLly negative and 15 (33 per cent) were cytologically positive. Cytology status was not reported for 8 patients (18 per cent). Of the 45 patients reported free of tumor 12 had carcinoma in situ when they wern entered into the study. At the end of 2 courses of treatment 5 of the 12 patients were cytologically negative and 7 were cytologically positive. Prophylaxis regimen. Of the 93 patients from the 9 institutions admitted to the prophylaxis regimen randomization, stratified by institution, was balanced: 23 received 30 mg. and 23 received 60 mg. dose, while 47 received no treatment (controls). The median patient age was 65 years and 88 per cent were men. Patients in the 3 study groups were comparable with respect to age and sex. Patients in the prophylaxis study had the following tumor characteristics: 14 per cent had 3 tumor occurrences in the 18 months before randomization, 20 per cent had been treated for
multifoca1 tumors and 33 per cent were considered to be at risk for a recurrence because of a long history of recurrence tumors within 6 months, large tumor with invasion of lamina propria and so forth). The remaining 33 per cent of the patients on prophylaxis had begun the study after 2 successful courses of thio-tepa treatment. This last group of patients will be referred to as post-therapy prophylaxis patients. All other patients are regular prophylaxis patients. Patients in the 3 study grnups (that is 30 and 60 mg. thiotepa, and the controls) generally were comparable with respect to the aforementioned tumor characteristics (table 4). Of the 93 patients in the study 24 per cent (10 assigned to prophylaxis and 12 assigned to control) had a positive cytology (urine or bladder washings) at the last cystoscopic examination before randomization. According to the eligibility requirements specified in the prophylaxis protocol a patient was not required to have had bladder carcinoma immediately before randomization, as long as the described criteria were met. The interval from the last treated tumor to beginning the study among the regular prophylaxis patients ranged from
Tun1.or Response*
CPLt Stage: Ca in situ (TIS) Stage O (Ta) Stage A (Tl) Stage A plus Ca in situ No CPLt report Totals CPL t pathologic grade:
Success No.(%)
Failure No.(%)
11 (55.0) 20 (45.5) 11 (47.8)
5 19 8 3 2 37
1 (25.0)
2 (50.0) 45 (47.4) 16 (51.6) 13 (39.4) 14 (51.9)
I II III No CPLt report Totais
(25.0) (43.2) (34.8) (75.0) (50.0) (38.9)
Unknown:j: No.(%) 4 (20.0) 5 (11.3) 4 (17.4) 0 (0.0)
__Q__(Q:22_ 13 (13.7)
2 (6.5)
13 (41.9) 14 (42.4)
2 (50.0)
8 (29.6) 2 (50.0)
45 (47.4)
37 (38.9)
6 (18.2) 5 (18.5)
0 (0.0) 13 (13.7)
Totals No.(%) 20 44 23 4 4 95
(100.0) (100.0) (100.0) (100.0) (100.0) (100.0)
31 33 27 4
(100.0) (100.0) (100.0) (100.0)
95 (100.0)
* Response to total course of treatment, including_patients who failed on the first course. t Central Pathology Laboratory. :j: Includes 4 patients who refused the first course of therapy and 8 who refused OT did not :receive the full second course. Exclusion of patients from the analysis increases the ove:r-all success rate to 54 per cent 1 57 per cent for the 30 mg. dose and 51 per cent for the 60 mg. dose. TABLE 4.
Thio-tepa prophylaxis-distribution of patients by type of eligibility according to assignment Assignment
Prophylaxis Type
Regular: 3 tumor occurrences in last 18 mos. Multifocal tumors Investigator's option Subtotals Post-therapy Totals
Prophylaxis 30Mg. No.(%)
60Mg. No.(%)
5 (21.7)
3 (13.0)
5 (21.7) 5 (21.7) 15 (65.2) 8 (34.8) 23 (100.0)
4 (17.4) 9 (39.2) 16 (69.6) 7 (30.4) 23 (100.0)
Control No.(%)
Totals No.(%)
5 (10.6)
13
(14.0)
10 (21.3)
19 31 63 30 93
(20.4) (33.3) (67.7) (32.3) (100.0)
17 32 15 47
(36.2) (68.1) (31.9) (100.0)
310
KOONTZ AND ASSOCIATES 100-----
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bladder carcinoma. To maximize the amount of information available to examine the prophylactic effect of thio-tepa, the modified life table method9 was used to describe the pattern of disease recurrence. The time of tumor recurrence for the prophylaxis group was compared to the control group (fig. 1). The patients who received prophylaxis did significantly better than the controls. The Mantel-Haenszel chi-square test 10 permits assessment of the statistical significance of an observed difference between 2 survival curves. The 2 curves were significantly different at the end of 7 months (p = 0.025) and thereafter. At 12 months 66 per cent of the prophylaxis group compared to 40 per cent of the control group were reported free of disease (p = 0.02). Comparisons also were made between the 30 and 60 mg. dose levels of thio-tepa. There was no significant difference in the time to first recurrence. At 12 months 63 per cent of the 30 mg. dose group were free of disease compared to 69 per cent of the 60 mg. dose group. As a result a distinction between the 2 dose levels will not be made in the subsequent analyses. Table 5 presents the interval free of disease at 12 months for the prophylaxis and the control groups according to the Central Pathology Laboratory classification of the cytology specimens obtained before randomization. For patients with negative cytologies the percentage free of disease for the prophylaxis group was significantly better than for the control group (68 versus 40 per cent, p = 0.02). Among patients with positive cytologies the observed difference in response between the prophylaxis and control groups was not significant statistically. Among patients assigned to prophylaxis the observed percentage free of disease was higher for patients with negative cytology but the difference was not significant statistically. Among patients assigned to the control group there was no observed difference in the time to disease recurrence with respect to the cytology findings. We made a comparison of the prophylaxis and control groups in the regular prophylaxis study (fig. 2). The curve for the prophylaxis group clearly is at a higher level, that is 50 per cent free of disease at 12 months compared to 31 per cent for the control group. Although the observed difference between the curves is not significant statistically (p = 0.20) the observed advantage for the prophylactically treated group warrants attention. As previously indicated 31 of the 93 patients began the prophylaxis regimen at the option of the investigator. Exclusion of these patients from the analysis had little effect on the levels of the curves depicting duration of the status free of disease. The patients referred to as post-therapy prophylaxis did significantly better than the post-therapy controls (fig. 3). The chi-square method was significant statistically at 12 months and beyond (p = 0.05). At 12 months of observation 100 per
TABLE 5. Thio-tepa prophylaxis-percentage of patients free of disease at 12 months according to assignment and cytology status
% Free of Disease At 12 Mos.*
No. Pts. Cytology Status Prophylaxis Pos.t Neg. Totals
Control
Prophylaxis
Control
10
12
35 45t
35 47
56 69 66
40 40 40
* Calculated by the modified life table method. t Cancer cells present. t Excludes 1 patient who died free of disease 2 weeks after randomization.
cent of the post-therapy prophylaxis patients compared to 60 per cent of the post-therapy controls were free of disease. The interval free of disease of the 15 successfully treated patients from the treatment study, who were not randomized to the prophylaxis study, was compared to the 2 randomized groups. Of these patients 5 continued to receive instillations of thio-tepa. These patients had an interval free of disease roughly similar to the post-therapy controls; at 12 months 43 per cent of the patients were free of disease (fig. 3). The time to first recurrence of the regular prophylaxis study patients was compared to that of the post-therapy controls combined with the 9 successfully treated patients on therapy who were not randomized to prophylaxis and did not continue to receive thio-tepa. The interval free of disease of the latter group was similar to the regular prophylaxis group and clearly better than the regular controls. The successful patients on therapy who did not continue to receive thio-tepa prophylactically appear to experience a beneficial carry-over effect. Toxicity and deviations from protocol. Treatment regimen: toxicity, which included leukopenia, thrombocytopenia and urinary tract symptoms, was observed in 17 per cent of the 95 patients. Of the 16 patients with reported toxicity the severity of the toxicity led to termination of the treatment in 4 patients. The course of treatment was interrupted in the other 12 patients. No deaths were attributed to receipt of thio-tepa. The observed toxicity was similar for the 2 dose levels (table 6). The response to therapy, according to the observed toxicity, is presented in table 7. The response rate did not appear to be affected by the manifestation of toxicity. Protocol deviations, which included patient refusal of treatment, variation in the assigned dose and termination of treatment (without evidence of toxicity), were reported in 21 per cent of the 95 patients on treatment. The number of instillations administered also varied from the number specified in the protocol. Of the 95 patients on the first course of treatment 4 received <4 instillations and 7 received >4. On the second course of therapy 9 of the 61 patients did not receive 4 instil-
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< 10 patients under observation beyond this point < 5 patients under observation beyond this point 14
12
10
II
16
18
20
24
22
Months since Randomization
Fm. 2. Duration of status free of disease for patients in regular thio-tepa prophylaxis group
,
fl.a,----------------..
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80
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10 patients under observation beyond this point 5 patients under observation beyond this point
- Prophylaxis rn, 151 ····· Control ln·l51 --Not Randomized rn·l41
10
12
14
16
18
20
24
22
Months since Randomization
FIG. 3. Duration of status free of disease for patients in post-therapy thio-tepa prophylaxis group TABLE
6. Thio-tepa treatment-frequency of observed toxicity by dose Observed Protocol Toxicity*
Leukopeniaj" No.(%)
1 (2.0) 6 (13.4) 7 (7.4)
Thio-tepa-30 mg. Thio-tepa-60 mg. Totals
Thrombocytopenia:j: No.(%)
Urinary Tract Symptoms+ No.(%)
Combination§ No.(%)
Observed Toxicity No.(%)
No Reported Toxicity No.(%)
3 (6.0) 0 (0.0)
I (2.0)
3 (6.0)
8 (16.0)
42 (84.0)
1 (2.2) 2 (2.1)
8 (18.8) 16 (16.9)
37 (82.2)
3 (3.2)
1 (2.2) 4 (4.2)
79 (83.1)
Totals No.(%) 50 (100.0) 45 (100.0) 95 (100.0)
., Of the 16 patients ,vith reported protocol toyjcity treatment was tem'linated in 4 cases and intenupted in the other 12. t Leukopenia-white blood count <3,000/mm. 3 and thrombocytopenia-platelets <100,000/mn,. 3 • Includes 1 patient w:ith pyuria, hematuria and urinary tract infection, and l with hematuria. § Includes 1 patient with a low hemoglobin and urinary tract infection, 1 with lower back pain and mild hematuria, l with leukopenia and a low hemoglobin and 1 with hematuria and cerebrovascular accident.
+
TABLE
7. Thio-tepa treatment-summary of response to treatment
according to the occurrence of toxicity Tumor Response* Toxicity Present Absent Totals
Success No.(%)
Failure No.(%)
Unknown No.(%)
Totals No.(%)
8 (50.0) 37 (46.8) 45 (47.4)
1 (6.3) 36 (45.6) 37 (38.9)
7 (43.7) ~ 13 (13.7)
16 (100.0) 79 (100.0) 95 (100.0)
* Response to total course of treatment, including patients who failed on the first course.
lations (6 received <4 and 3 received >4). The number of patients is too small for assessing the effect of the different types of deviation from protocol on the outcome. Prophylaxis regimen: toxicity was reported in 11 per cent of
the 93 patients. The toxicity was observed more frequently in the 60 mg. group but the difference is not significant statistically (table 8). The severity of the toxicity led to termination of prophylaxis in 6 patients and interruption of instillations in 4. No deaths were attributed to the use of thio-tepa. Protocol deviations, that is refusal of prophylaxis, alteration of the prophylaxis assignment and termination of prophylaxis, were reported in 25 per cent of the 93 patients. In view of the reported deviation from regimen the clear advantage of prophylactic treatment compared to no treatment is particularly impressive. DISCUSSION
Previous reports on the use of thio-tepa for superficial bladder carcinoma indicate that tumors will be destroyed in about a
312
KOONTZ AND ASSOCIATES TABLE
8. Thio-tepa prophylaxis-frequency of observed toxicity by dose Observed Protocol Toxicity*
Leukopeniat No.(%) Thio-tepa-30 mg. Thio-tepa-60 mg. Control Totals
0 1 0 1
(0.0) (4.3) (0.0) (1.1)
Thrombocytopeniat No.(%) 0 1 0 1
(0.0) (4.3) (0.0) (1.1)
Low Remoglobint No.(%) 1 (4.3) 0 (0.0) 0 (0.0) 1 (1.1)
Urinary Tract Symptomst No.(%) 0 4 0 4
(0.0) (17.4) (0.0) (4.3)
Other No.(%) 0 (0.0) 1 (4.3) 0 (0.0) 1 (1.1)
Combination§ No.(%) 0 2 0 2
(0.0) (8.8) (0.0) (2.0)
Observed Toxicity No.(%) 1 9 0 10
No Reported ToXIcity No.(%)
(4.3) (39.1) (0.0) (10.7)
22 14 47 83
(95.7) (60.9) (100.0) (89.3)
Totals No.(%)
23 23 47 93
(100.0) (100.0) (100.0) (100.0)
* Of the 10 patients with reported protocol toxicity prophylaxis was terminated in 6 cases and interrupted in the other 4. t Leukopenia-white blood count <3,000/mm. 3 , thrombocytopenia-platelets <100,000/mm. 3 and low hemoglobin-hemoglobin< 10 gm. t Includes 2 patients with urinary tract infections, 1 with irritative symptoms-frequency, dysuria and urgency, and 1 with moderate dysuria, frequency and severe urgency. § Includes 1 patient with low blood values, pain and abdominal tenderness and 1 with low white blood count and low hematocrit.
third of the patients, diminished in size and number in another third and unaltered in the remaining third. In our study destruction of superficial tumor after therapeutic intravesical thio-tepa was reported in 47 per cent of the patients. The classification of a patient free of tumor was based on visual and histologic evidence. It is noteworthy that 15 of the 45 patients reported to be free of tumor at the end of treatment had positive cytology specimens (urine or bladder washing). The prognostic significance of this observation remains to be determined. It appears that there is no difference in the incidence of ablation of tumor between the 30 and 60 mg. dosage. There also was no difference in the level of toxicity demonstrated with either dose and this is somewhat different from that reported by Nieh and associates, in which there was a slight increase in response to the 60 mg. dosage. 11 Patients with more widespread disease, that is Ei;;4 tumors, did not do as well as those who had <4 tumors. The observed differences in response with respect to history of bladder cancer, sex, size and shape of tumor, histologic grade and stage were not significant statistically. In the prophylaxis study the interval free of disease clearly was longer among patients who received prophylaxis compared to the controls. Patients who had been treated successfully with therapeutic intravesical thio-tepa with complete ablation of their tumors and who then continued to receive thio-tepa prophylactically did extremely well during the first 12 months offollowup. In addition, there was an apparent continued effect of the therapeutic thio-tepa in those patients who had exhibited complete ablation of the tumors and who were then placed in the control group in the prophylaxis study. The results suggest the desirability of investigating the possible advantage of leaving behind a clearly superficial tumor for use as a marker in assessing the effectiveness of thio-tepa as a potential prophylactic agent in an individual patient. If there is complete ablation of this marker as a result of intravesical thiotepa therapy then this patient would be continued on thio-tepa prophylaxis and one would expect a prolonged interval free of disease. If there was no response by the marker tumor to the therapeutic course of thio-tepa then other modalities could be instituted. Thus, a long and fruitless prophylactic course of thio-tepa would be avoided.
Reported toxicity to prophylactic thio-tepa was greater in those patients receiving the higher 60 mg. monthly instillations of the drug, although the observed difference was not significant statistically. Since there appears to be no difference in the prophylactic effect between the 30 and 60 mg. dosage, and no difference in the therapeutic effect between these 2 dosages, the 30 mg. intravesical thio-tepa dosage appears to be preferable. This study describes the successes and failures in treating superficial bladder carcinoma with thio-tepa. After suitable animal testing other agents should be studied singly in phase 2 trials and the sequential use of effective agents should be considered. REFERENCES 1. Jones, H. C. and Swinney, J.: Thio-TEPA in the treatment of tumours of the bladder. Lancet, 2: 615, 1961. 2. Veenema, R. J., Dean, A. L., Jr., Roberts, M., Fingerhut, B., Chowhury, B. K. and Tarassoly, H.: Bladder carcinoma treated by direct instillations of thio-tepa. J. Urol., 88: 60, 1962. 3. Abbassian, A. and Wallace, D. M.: Intracavitary chemotherapy of diffuse non-infiltrating papillary carcinoma of the bladder. J. Urol., 96: 461, 1965. 4. Edsmyr, F. and Boman, J.: Instillation of thio-tepa (Tifosyl) in vesical papillomatosis. Acta Rad. Ther. Phys. Biol., 9: 395, 1970. 5. Pavone-Macaluso, M.: Chemotherapy of vesical and prostatic tumours. Brit. J. Urol., 43: 701, 1971. 6. Veenema, R. J., Dean, A. L., Jr., Uson, A. C., Roberts, M. and Longo, F.: Thio-tepa bladder instillations: therapy and prophylaxis for superficial bladder tumors. J. Urol., 101: 711, 1969. 7. National Bladder Collaborative Group A: Development of a strategy for a longitudinal study of patients with bladder cancer. Cancer Res., 37: 2898, 1977. 8. National Bladder Cancer Collaborative Group A: The role of intravesical thio-tepa in the management of superficial bladder cancer. Cancer Res., 37: 2916, 1977. 9. Cutler, S. J. and Ederer, F.: Maximum utilization of the life table method in analyzing survival. J. Chron. Dis., 8: 699, 1958. 10. Mantel, M. and Haenszel, W.: Statistical aspects of the analysis of data from retrospective studies of disease. J. Natl. Cancer Inst., 22: 719, 1959. 11. Nieh, P. T., Daly, J. J., Heaney, J. A., Heney, N. M. and Prout, G. R., Jr.: The effect of intravesical thio-tepa on normal and tumor urothelium. J. Urol., 119: 59, 1978.