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Adjuvant Chemotherapy of Superficial Transitional Cell Bladder Carcinoma:Preliminary Results of a European Organization for Research onTreatment of Cancer Randomized Trial Comparing Doxorubicin Hydrochloride, Ethoglucid and Transurethral Resection Alone
0022-534 7/84/1322-0258$02.00/0 Vol. 132, August Printed in U.S.A.
THE JOURNAL OF UROLOGY
Copyright© 1984 by The Williams & Wilkins Co.
ADJUV ANT CHEMOTHERAPY OF SUPERFICIAL TRANSITIONAL CELL BLADDER CARCINOMA: PRELIMINARY RESULTS OF A EUROPEAN ORGANIZATION FOR RESEARCH ON TREATMENT OF CANCER RANDOMIZED TRIAL COMPARING DOXORUBICIN HYDROCHLORIDE, ETHOGLUCID AND TRANSURETHRAL RESECTION ALONE KARL HEINZ KURTH, FRITZ H. SCHRODER, ULF TUNN, REGINALD AY, MICHELE PAVONEMACALUSO, FRANS DEBRUYNE, MARLEEN DEPAUW, OTILIA DALESIO, FIBO TEN KATE AND MEMBERS OF THE EUROPEAN ORGANIZATION FOR RESEARCH ON TREATMENT OF CANCER, GENITOURINARY TRACT CANCER COOPERATIVE GROUP* From Erasmus University, Rotterdam, and University Clinics of Nijmegen, Nijmegen, The Netherlands; Ruhr University, Bochum and City Hospital, Weiden, West Germany; University Clinics of Palermo, Palermo, Italy, and European Organization for Research on Treatment of Cancer Data Center, Brussels, Belgium
ABSTRACT
Patients with superficial transitional cell carcinoma of the bladder were entered in a randomized clinical trial to compare the efficacies of transurethral resection alone or followed by bladder instillation of doxorubicin hydrochloride or ethoglucid (Epodyl) for 1 year. Results showed that adjuvant chemotherapy with the selected drugs prolonged the mean interval between recurrences. Mild systemic toxicity and chemical cystitis were observed in 3 and 3 per cent, respectively, of the patients given ethoglucid, and in 5 and 4 per cent, respectively, of those taking doxorubicin. When first detected the majority of bladder tumors are superficial in nature. According t.o the tumor, nodes and metastasis classification of the International Union Against Cancer superficial tumors are classified as stages Tis, Ta and T (or stages O and A according to Jewett's classification). Transurethral resection is the first treatment modality for superficial bladder lesions. One of the most common problems encountered in cases of superficial bladder transitional cell carcinoma is the high incidence of recurrence after initial management by transurethral resection. Of these patients 50 to 70 per cent can be expected to have recurrence after complete resection of all visible lesions. 1 Multicentricity in space and time may aGcount for such a high incidence of recurrence. 2 Neoplastic cells also might be spread and implanted at the time of endoscopic resection. 3 Animal studies have stimulated renewed interest in the latter mechanism. 4 Adjuvant intravesical chemotherapy following transurethral resection has been advocated to reduce the incidence of recurrence by destroying floating tumor cells remaining in contact with the bladder urothelium after endoscopic resection. Cytotoxic agents instilled into the bladder also might destroy abnormal mucosal cells not visible to the endoscopist. The cytotoxic agents used most commonly for intravesical chemotherapy are thiotepa, 5 - 8 doxorubicin,9 • 10 mitomycin c 11- 13 and ethoglucid.14· 15 The superiority of one drug over another has yet to
TABLE
1. Patient distribution by treatment group, initial stage and
stratification
Doxorubicin Stage: Tis Ta Tl Totals
3 23 22
48
Primary
Recurrent
Ethoglucid
DoxoEthoglurubicid cin
Control
Control
Totals
1
1
11
13
9 129 102 240
30 28
1 26 16
3 26 9
15
12
58
43
38
27
26
be proved. We decided to compare doxorubicin and ethoglucid. Because ethoglucid has never been used in a randomized trial this study was started with transurethral resection alone as the control arm. MATERIALS AND METHODS
Objectives of the study. The objectives of the study were to compare the interval to first recurrence and the recurrence rate after transurethral resection alone or followed by local doxorubicin or ethoglucid chemotherapy, and also to compare the stage and grade of malignancy of recurrent tumors. The interval to first recurrence is defined as the interval from initial transurethral resection until the first cystoscopy at which a recurAccepted for publication March 23, 1984. rence was observed. Recurrence rate was defined as the total * P. J. Carpentier, Zuiderziekenhuis and E. Essed, Bergwegzieken- number of cystoscopies at which recurrences were observed huis, Rotterdam, R. V. Caubergh, Bleulandziekenhuis, Gouda, J. W. Hoekstra, Groot Ziekengasthuis and W. Alexanderziekenhuis, Den divided by the sum of months of followup from initial transuBosch, H.J. de Voogt, Free University and N. F. Dabhoiwala, Wilhel- rethral resection to the date of the last cystoscopy. mina Gasthuis, Amsterdam, H. J. A. Mensink, University Clinics, Selection of patients. All patients with biopsy proved, transGroningen and J. M. Groen, Maria Stichting, Haarlem, The Nether- urethrally resectable primary or recurrent stages Ta and Tl lands; G. Jakse, University Clinics, Innsbruck, Austria; H.J. Leisinger, Hopital Cantonale, Schaffhausen, Switzerland; D. Newling, Royal In- transitional cell carcinoma of the bladder were considered to firmary, Hull, B. Richards, York District Hospital, York, R. A. Adib, be eligible for the trial. Stages Ta and Tl lesions were defined Pinderfield's General Hospital, Wakefields Yorks, M. Robinson, Nor- according to the 1978 tumor, nodes and metastasis classificamanton and District Hospital, Castleford and P.H. Smith, St. James Hospital, Leeds, England, and L. Denis, Middelheimziekenhuis, Ant- tion. All visible lesions were resected completely. Pathologiwerp, C. Bouffioux, Hopital de Baviere, Liege and C. Schulman, Uni- cally, no tumor infiltrated beyond the lamina propria. versity Clinics, Erasme Hospital, Brussels, Belgium. Design of the trial. Within 1 week after transurethral resec258
ADJUVANT CHEMOTHERAPY OF SUPERFICIAL TRANSITIONAL CELL BLADDER CARCINOMA
tion the following treatments were allocated randomly: 1) intravesical doxorubicin, 2) intravesical ethoglucid and 3) no further treatment after transurethral resection (control). Doxorubicin and ethoglucid were administered weekly for 1 month and then monthly thereafter. Recurrent tumors, if observed ~1 year after start of treatment, were resected and intravesical treatment was restarted as described. However, the total duration of intravesical treatment was limited to 1 year after the first transurethral resection. Patients entering the trial were followed until the first recurrence had been detected after completion of 1 year of treatment or until progression of stage was observed. Therapeutic regimens. The drugs (50 mg. doxorubicin diluted in 50 ml. normal saline or 1.13 gm. ethoglucid diluted in 100 ml. sterile water) were instilled into the bladder and retained for 1 hour. Nitrofurantoin was given after each instillation at a dose of 100 mg. 3 times daily for 3 days. White blood cell and platelet counts, blood urea and creatinine levels, and urinalysis were obtained before each chemotherapy administration. Chemotherapy was delayed until the white blood count was ~4,000/mm. 3 and the platelet count was ~150,000/mm. 3 • Chemotherapy also was delayed whenever bacterial cystitis was present until control of the infection was achieved. If drug-induced cystitis occurred the drug was given in a solution that was twice the normal volume. Evaluation of therapy. Cystoscopy was repeated every 12 weeks during year 1, every 16 weeks during year 2 and every 24 weeks thereafter. All visible lesions seen on cystoscopy were biopsied, with recurrence being established only by histological
TABLE 2.
Recurrence rate by treatment group Doxorubicin/ Ethoglucid
No. pts. randomized No. pts. with followup No. pts. with recurrences (%) Total No. recurrences Total mos. followup Recurrence rate/100 pt.-mos. Significance
71 47
135 73 16 (22)
22 (47) 41 755 447 2.91 9.17 p <0.001 22
Totals
Control
206 120 38 (32) 63 1,202 5.24
Probability
-
--.-
1.00 . 90
---6--
.80
examination of the biopsy material. If cytology was positive and no lesion was visible on cystoscopy a random biopsy was done. Clinical material. Between December 1979 and March 1983, 369 patients were randomized, with followup data available for 240. Mean followup was 11.69 months. The distribution of patients by treatment group and initial stage, and by stratification for primary or recurrent tumor is shown in table 1. Of the 240 patients analyzed 86 were randomized to receive doxorubicin, 85 ethoglucid and 69 transurethral resection only (control). Fewer patients were randomized to the control group because the control arm was dropped from the protocol in 1982. RESULTS
The 3 treatment groups were compared with respect to the 2 principal endpoints. However, in April 1982 the control arm was closed to patient entry based on the results of an interim analysis that showed a recurrence rate per 100 patient-months of 9.17 in the transurethral resection-only group compared to 2.91 in patients receiving adjuvant doxorubicin or ethoglucid (table 2, p <0.001). Interval to first recurrence. Curves representing the interval to first recurrence have been estimated by the Kaplan-Meier method and compared using the log-rank test. 16 A global comparison by treatment group was highly significant (p = 0.014, fig. 1). Paired comparisons yielded a significant difference between the ethoglucid and control groups (p = 0.0042) in favor of ethoglucid. In patients with primary tumors (fig. 2) a paired comparison indicated no difference between the ethoglucid and doxorubicin groups but there was a significant difference between the ethoglucid and control groups (p = 0.02). Figure 3 shows the curves for patients with recurrent tumors. Over-all, no significant difference was detected among the 3 treatment arms in this subgroup. Recurrence rate/mean interval between recurrences. Tables 2 and 3 present the recurrence rates in different groups of patients and the significant levels of the treatment comparisons based on a permutation test. For easier presentation the recurrence rates are multiplied by 100. The inverse of the recurrence rate, which can be interpreted as the mean number of months between 2 recurrences, also is presented but should be interTreatment
Total Fail. 86 85 69
259
adriam epodyl control
31 20 33
p= .014 (logrank overall)
. 70 .60 .50
.40 .30
.20 . 10
30 24 18 12 6 0 Number of patients at risk at the corresponding times:
36 months
86
50
27
14
7
4
O adriam
85 69
55 40
26 23
15 7
8 3
3 2
O epodyl
O control
FIG. 1. Comparison of Kaplan-Meier curves for interval to first recurrence in all patients (primary and recurrent cancer). adriam, doxorubicin. epodyl, ethoglucid.
260
KURTH AND ASSOCIATES Probability 1. 00
. 90 .80 . 70 .60 Prim/Rec = primary Total Fa ii. Treatment _ . _ 48 12 adriam 7 epodyl 58 -.6.- 43 14 control
. 50 .. 40 .30
p=
.20
. 063 ( log rank overall)
. 10
0 6 12 18 24 30 Number of the patients at risk at the corresponding times: 48 30 15 8 5 3 58 39 17 10 6 2 17 43 30 4 0
36
months
0 0 0
adriam epodyl control
FIG. 2. Comparison of Kaplan-Meier curves for interval to first recurrence in patients with primary disease. adriam, doxorubicin. epodyl, ethoglucid. Prim /rec Probability 1.00
Total Fail.
-
_._
38 27 - A - 26
.90 .80
19 13 19
=recurrent Treatment adriam epodyl control
p= . 170 ( logrank overall)
. 70 .60 .50 . 40 . . 30 .20 . 10
0
6 12 18 24 30 Number of patients at risk at the corresponding times: 38 20 12 6 2 1 27 16 9 5 2 10 26 . 6 3 2 2
36
months
0 0 0
adriam epodyl control
FIG. 3. Comparison of Kaplan-Meier curves for interval to first recurrence in patients with recurrent disease. adriam, doxorubicin. epodyl, ethoglucid.
preted with caution, since the average followup is only about 1 year. Comparisons have been performed globally for all patients and separately for patients with primary and recurrent tumors. The study of the recurrence rate is preferred, since all information available for each patient is considered and not only the interval until the first recurrence. No difference was detected between the doxorubicin and ethoglucid groups but both drugs reduced the recurrence rate significantly compared to the control group (table 3). Among patients with primary tumors a significant difference was found when the ethoglucid group was
compared to controls in favor of ethoglucid (p = 0.008), while no difference was found between the doxorubicin and ethoglucid groups. Treatment comparison in patients with recurrent tumors yielded no significant difference between the doxorubicin and ethoglucid groups. However, there was a significant advantage of doxorubicin over controls (p = 0.026), while the difference between ethoglucid and controls did not reach significance (p = 0.084). Prognostic factors. Several factors of potential prognostic importance were analyzed by comparing the recurrence rates
ADJUVANT CHEMOTHERAPY OF SUPERJ:"1:CIAL TRANSITWNAL CELL BLADDER CARCIJ\,QMA TABLE 3.
Recurrence rate by treatment group Doxorubicin
Ethogiucid
Control
Totals
Over-all* No. pts. Mean followup (mos.) Recurrence rate/100 pt.-mos. Mean interval between recurrences
86 lL:ll 4.11 24.33
85 1L47 2.97 33.62
69 12.42 7.58 13.18
240 1L69 4.78 20.93
43 1L60 4.81 20.79
149 1L32 2.96 33.74
Pts. with primary diseaset No. pts. Mean followup (mos.) Recurrence rate/100 pt.-mos. Mean interval between recurrences (mos.)
48 1L42 3.10 32.24
58 1L03 L41 7Lll
The occurrence of locai and reactions after instillation of doxorubicin and ethoglucid was low: 4 of 98 patients after a total of 1,118 instillations of doxorubicin and 3 of 96 patients after a total of 1,087 instillations of ethoglucid had complaints of chemical cystitis. Further instillation was stopped in only 1 patient because of excessive toxicity after the first instillation of ethoglucid 6 days after transurethral resection. Systemic side effects, such as allergic reaction, mild nausea, diarrhea and vomiting, were seen in 5 of 98 patients after instillation of doxorubicin, while fever and allergic skin reaction were noted in 3 of 96 patients after instillation of ethoglucid. Neither leukopenia nor thrombocytopenia was seen in this study. DISCUSSION
Pts. with recurrent disease:j:. No. pts. Mean followup (mos.) Recurrence rate/100 pt.-mos. Mean interval between recurrences (mos.)
38 1U8 5.41 18.48
27 12.41 5.97 16.76
26 13.77 11.45 8.73
91 12.29 7.51 13.31
* p = 0.018 for doxorubicin versus control, 0.002 for ethoglucid versus control and not significant for doxorubicin versus ethogfocid. tp = 0.008 for ethoglucid versus control, and not significant for doxorubicin versus ethoglucid and controL :j: p = 0.026 for doxorubicin versus control, 0.084 for ethoglucid versus control and not significant for doxorubicin versus ethoglucid.
TABLE 4. Recurrence rate by number of tumors; stage, grade and size of largest tumor at entry into study, and by recurrence rate before entry into study
No. tumors at entry:* 1 2-3 ;;;4 Totals Recurrence rate before entry:t Primary <1/yr. >1/yr. Totals Stage:+ Ta Tl Totals Grade:§ 1 2 3 Totals Tumor size (cm.):11 <1 1-3 >3 Totals
No. Pts.
Mean Followup (mos.)
Recurrence Rate/ 100 PLMos.
Mean Interval Between Recurrences (mos.)
98 84 58 240
12.36 10.83 1L79 1L69
2.39 5.27 8.33 4.78
4L76 18.96 12.00 20.93
149 22 54 225
11.32 12.27 12.65 1L73
2.96 5.19 7.47 4.36
33.74 19.29 13.39 22.96
129 231
12.57 10.47 1L65
3.64 6.65 4.83
27.49 15.04 20.69
95 78 17 190
13.03 10.27 8.12 1L46
3.07 7.24 8.70 4.96
32.58 13.81 1L50 20.16
130 56 54 240
13.08 9.59 10.52 1L69
4.59
2L79 18.52 2L04 20.93
102
SAO 4.75 4.78
* p = 0.016 for 1 versus 2 to 3 tumors, <0.00001 for 1 versus ;;;4 tumors and 0.08 for 2 to 3 versus ;;;4 tumors. t p = 0.006 for primary versus > 1 tumor per year, and not significant for 1 tumor per year. :j: p = 0.006 for stages Ta versus Tl disease. § p = 0.004 for grades 1 versus 2, 0.064 for grades 1 versus 3 and not significant for grades 2 versus 3 disease. II Difference was not significant for all groups.
associated with different levels of the variable. In this analysis the distribution of the other factors has been disregarded. With the recurrence rate as the primary endpoint of interest, it appeared that the number of tumors at presentation was the most significant prognostic factor. Likewise, recurrence rate before entry, and stage and grade were found to be of prognostic importance. The size of the tumor had no influence on the recurrence rate (table 4).
From our study one can conclude that adjuvant chemotherapy with the drugs used has reduced the recurrence rate significantly. In other words, the incidence of hospitalization for transurethral resection of a recurrent tumor decreased significantly. The interval to first recurrence was prolonged by adjuvant chemotherapy. Globally, doxorubicin and ethoglucid appeared to be equally effective. As in an earlier study by our group 17 the number of tumors at presentation was the most important prognostic factor. Surprisingly, and in contrast to the previous study, the size of the tumor was of no prognostic importance when the recurrence rate was analyzed as the primary endpoint of interest. This finding may be due to the fact that this analysis has not been adjusted for other factors. At the time of the final multivariate analysis the relative importance of all prognostic factors will be studied. Local and systemic side effects observed after instillation were remarkably low. Serious toxicity, as has been reported for thiotepa 18 and cis-platinum, 19 was not seen, which may be owing to the low or negligible resorption of doxorubicin and ethoglucid through the bladder wa!L~ 0 However, bone marrow depression has been described after ethoglucid instillation. 21 As reported previously,8 our trial has shown the superiority of adjuvant chemotherapy over transurethral resection alone. Therefore, a control arm with transurethral resection alone is not indispensable in future studies. From the first analysis in 1982 it became obvious that both adjuvantly treated groups have a significant lower recurrence rate than the control group. Therefore, it seemed justified to continue the study without further recruitment into the control arm. Because of the short median followup of 11.6 months in this preliminary report no attempt has been made to include a comparison of progression in stage in the 3 treatment groups. Investigational problems not addressed in this study, such as the frequency and duration of chemotherapy, will be examined in future studies. REFERENCES
L Greene, L F., Hanash, KA. and Farrow, G. IvL: Benign papilloma or papillary carcinoma of the bladder? J. Urol., 110: 205, 1973. 2. Soloway, M. S., Murphy, W., Rao, M. K and Cox, C.: Serial multiple-site biopsies in patients with bladder cancer. J. UroL, 120: 57, 1978. 3. Weyrauch, H. M. and Crossfield, J. G.: Dissemination of bladder neoplasms by endoscopic electroresection. J. UroL, 87: 391, 1962. 4. Weldon, T. K and Soloway, M. S.: Susceptibility of urothelium to neoplastic cellular implantation. Urology, 5: 824, 1975. 5. Veenema, R. J., Dean, A. L, Jr., Uson, A. C., Roberts, M. and Longo, F.: Thiotepa bladder instillations: therapy and prophylaxis for superficial bladder tumors. J. UroL, 101: 711, 1969. 6. Byar, D., Blackard, C. and the Veterans Administration Cooperative Urological Research Group: Comparisons of placebo, pyridoxine, and topical thiotepa in preventing recurrence of stage I bladder cancer. Urology, 10: 556, 1977. 7. 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.
262
KURTH AND ASSOCIATES
8. Schulman, C. C., Robinson, M., Denis, L., Smith, P., Viggiano, G., De Pauw, M., Dalesio, 0. and Sylvester, R.: Prophylactic chemotherapy of superficial transitional cell bladder carcinoma: an EORTC randomized trial comparing thiotepa, VM-26 and TUR alone. Eur. Urol., 8: 207, 1982. 9. Banks, M. D., Pontes, J.E., lzbicki, R. M. and Pierce, J. M., Jr.: Topical instillation of doxorubicin hydrochloride in the treatment of recurring superficial transitional cell carcinoma of the bladder. J. Urol., 118: 757, 1977. 10. Jakse, G., Hofstadter, F. and Marberger, H.: Intracavitary doxorubicin hydrochloride therapy for carcinoma in situ of the bladder. J. Urol., 125: 185, 1981. 11. Mishina, T., Oda, K., Murata, S., Ooe, H., Mori, Y. and Takahashi, T.: Mitomycin C bladder instillation therapy for bladder tumors. J. Urol., 114: 217, 1975. 12. DeFuria, M. D., Bracken, R. B., Johnson, D. E., Soloway, M. S., Merrin, C. E., Morgan, L. R., Miller, H. C. and Crooke, S. T.: Phase I-II study of mitomycin C topical therapy for low-grade, low stage transitional cell carcinoma of the bladder: an interim report. Cancer Treat. Rep., 64: 255, 1980. 13. Huland, H. and Otto, U.: Mitomycin instillation to prevent recurrence of superficial bladder carcinoma. Results of a controlled, prospective study in 58 patients. Eur. Urol., 9: 84, 1983. 14. Fitzpatrick, J. M., Khan, 0., Oliver, R. T. D. and Riddle, P. R.: Long-term followup in patients with superficial bladder tumours treated with intravesical epodyl. Brit. J. Urol., 51: 545, 1979.
15. Kurth, K. H., Maksimovic, P. A., Hop, W. C. J., Schroder, F. H. and Bakker, N. J.: Single-dose intravesical epodyl after TUR of Ta TCC bladder carcinoma. World J. Urol., 1: 89, 1983. 16. Buyse, M. E., Staquet, M. J. and Sylvester, R. J.: Cancer Clinical Trials: Methods and Practice. Oxford: Oxford University Press, 1984. 17. Dalesio, 0., Schulman, C. C., Sylvester, R., De Pauw, M., Robinson, M., Denis, L., Smith, P., Viggiano, G. and Members of the European Organization for Research on Treatment of Cancer, Genitourinary Tract Cancer Cooperative Group: Prognostic factors in superficial bladder tumors. A study of the European Organization for Research on Treatment of Cancer: Genitourinary Tract Cancer Cooperative Group. J. Ural., 129: 730, 1983. 18. Grossman, H. B.: Current therapy of bladder carcinoma. J. Urol., 121: 1, 1979. 19. Denis, L.: Anaphylactic reactions to repeated intravesical instillation with cisplatin. Letter to the Editor. Lancet, 1: 1378, 1983. 20. Jacobi, G. H. and Kurth, K.-H.: Studies on the intravesical action of topically administered G3H-doxorubicin hydrochloride in men: plasma uptake and tumor penetration. J. Urol., 124: 34, 1980. 21. Robinson, M. R. G., Shetty, M. B., Richards, B., Bastable, R., Glashan, R. W. and Smith, P. H.: Intravesical epodyl in the management of bladder tumors: combined experience of the Yorkshire Urological Cancer Research Group. J. Urol., 118: 972, 1977.
THE JOURNAL OF UROLOGY
Copyright© 1984 by The Williams & Wilkins Co.
ADJUV ANT CHEMOTHERAPY OF SUPERFICIAL TRANSITIONAL CELL BLADDER CARCINOMA: PRELIMINARY RESULTS OF A EUROPEAN ORGANIZATION FOR RESEARCH ON TREATMENT OF CANCER RANDOMIZED TRIAL COMPARING DOXORUBICIN HYDROCHLORIDE, ETHOGLUCID AND TRANSURETHRAL RESECTION ALONE KARL HEINZ KURTH, FRITZ H. SCHRODER, ULF TUNN, REGINALD AY, MICHELE PAVONEMACALUSO, FRANS DEBRUYNE, MARLEEN DEPAUW, OTILIA DALESIO, FIBO TEN KATE AND MEMBERS OF THE EUROPEAN ORGANIZATION FOR RESEARCH ON TREATMENT OF CANCER, GENITOURINARY TRACT CANCER COOPERATIVE GROUP* From Erasmus University, Rotterdam, and University Clinics of Nijmegen, Nijmegen, The Netherlands; Ruhr University, Bochum and City Hospital, Weiden, West Germany; University Clinics of Palermo, Palermo, Italy, and European Organization for Research on Treatment of Cancer Data Center, Brussels, Belgium
ABSTRACT
Patients with superficial transitional cell carcinoma of the bladder were entered in a randomized clinical trial to compare the efficacies of transurethral resection alone or followed by bladder instillation of doxorubicin hydrochloride or ethoglucid (Epodyl) for 1 year. Results showed that adjuvant chemotherapy with the selected drugs prolonged the mean interval between recurrences. Mild systemic toxicity and chemical cystitis were observed in 3 and 3 per cent, respectively, of the patients given ethoglucid, and in 5 and 4 per cent, respectively, of those taking doxorubicin. When first detected the majority of bladder tumors are superficial in nature. According t.o the tumor, nodes and metastasis classification of the International Union Against Cancer superficial tumors are classified as stages Tis, Ta and T (or stages O and A according to Jewett's classification). Transurethral resection is the first treatment modality for superficial bladder lesions. One of the most common problems encountered in cases of superficial bladder transitional cell carcinoma is the high incidence of recurrence after initial management by transurethral resection. Of these patients 50 to 70 per cent can be expected to have recurrence after complete resection of all visible lesions. 1 Multicentricity in space and time may aGcount for such a high incidence of recurrence. 2 Neoplastic cells also might be spread and implanted at the time of endoscopic resection. 3 Animal studies have stimulated renewed interest in the latter mechanism. 4 Adjuvant intravesical chemotherapy following transurethral resection has been advocated to reduce the incidence of recurrence by destroying floating tumor cells remaining in contact with the bladder urothelium after endoscopic resection. Cytotoxic agents instilled into the bladder also might destroy abnormal mucosal cells not visible to the endoscopist. The cytotoxic agents used most commonly for intravesical chemotherapy are thiotepa, 5 - 8 doxorubicin,9 • 10 mitomycin c 11- 13 and ethoglucid.14· 15 The superiority of one drug over another has yet to
TABLE
1. Patient distribution by treatment group, initial stage and
stratification
Doxorubicin Stage: Tis Ta Tl Totals
3 23 22
48
Primary
Recurrent
Ethoglucid
DoxoEthoglurubicid cin
Control
Control
Totals
1
1
11
13
9 129 102 240
30 28
1 26 16
3 26 9
15
12
58
43
38
27
26
be proved. We decided to compare doxorubicin and ethoglucid. Because ethoglucid has never been used in a randomized trial this study was started with transurethral resection alone as the control arm. MATERIALS AND METHODS
Objectives of the study. The objectives of the study were to compare the interval to first recurrence and the recurrence rate after transurethral resection alone or followed by local doxorubicin or ethoglucid chemotherapy, and also to compare the stage and grade of malignancy of recurrent tumors. The interval to first recurrence is defined as the interval from initial transurethral resection until the first cystoscopy at which a recurAccepted for publication March 23, 1984. rence was observed. Recurrence rate was defined as the total * P. J. Carpentier, Zuiderziekenhuis and E. Essed, Bergwegzieken- number of cystoscopies at which recurrences were observed huis, Rotterdam, R. V. Caubergh, Bleulandziekenhuis, Gouda, J. W. Hoekstra, Groot Ziekengasthuis and W. Alexanderziekenhuis, Den divided by the sum of months of followup from initial transuBosch, H.J. de Voogt, Free University and N. F. Dabhoiwala, Wilhel- rethral resection to the date of the last cystoscopy. mina Gasthuis, Amsterdam, H. J. A. Mensink, University Clinics, Selection of patients. All patients with biopsy proved, transGroningen and J. M. Groen, Maria Stichting, Haarlem, The Nether- urethrally resectable primary or recurrent stages Ta and Tl lands; G. Jakse, University Clinics, Innsbruck, Austria; H.J. Leisinger, Hopital Cantonale, Schaffhausen, Switzerland; D. Newling, Royal In- transitional cell carcinoma of the bladder were considered to firmary, Hull, B. Richards, York District Hospital, York, R. A. Adib, be eligible for the trial. Stages Ta and Tl lesions were defined Pinderfield's General Hospital, Wakefields Yorks, M. Robinson, Nor- according to the 1978 tumor, nodes and metastasis classificamanton and District Hospital, Castleford and P.H. Smith, St. James Hospital, Leeds, England, and L. Denis, Middelheimziekenhuis, Ant- tion. All visible lesions were resected completely. Pathologiwerp, C. Bouffioux, Hopital de Baviere, Liege and C. Schulman, Uni- cally, no tumor infiltrated beyond the lamina propria. versity Clinics, Erasme Hospital, Brussels, Belgium. Design of the trial. Within 1 week after transurethral resec258
ADJUVANT CHEMOTHERAPY OF SUPERFICIAL TRANSITIONAL CELL BLADDER CARCINOMA
tion the following treatments were allocated randomly: 1) intravesical doxorubicin, 2) intravesical ethoglucid and 3) no further treatment after transurethral resection (control). Doxorubicin and ethoglucid were administered weekly for 1 month and then monthly thereafter. Recurrent tumors, if observed ~1 year after start of treatment, were resected and intravesical treatment was restarted as described. However, the total duration of intravesical treatment was limited to 1 year after the first transurethral resection. Patients entering the trial were followed until the first recurrence had been detected after completion of 1 year of treatment or until progression of stage was observed. Therapeutic regimens. The drugs (50 mg. doxorubicin diluted in 50 ml. normal saline or 1.13 gm. ethoglucid diluted in 100 ml. sterile water) were instilled into the bladder and retained for 1 hour. Nitrofurantoin was given after each instillation at a dose of 100 mg. 3 times daily for 3 days. White blood cell and platelet counts, blood urea and creatinine levels, and urinalysis were obtained before each chemotherapy administration. Chemotherapy was delayed until the white blood count was ~4,000/mm. 3 and the platelet count was ~150,000/mm. 3 • Chemotherapy also was delayed whenever bacterial cystitis was present until control of the infection was achieved. If drug-induced cystitis occurred the drug was given in a solution that was twice the normal volume. Evaluation of therapy. Cystoscopy was repeated every 12 weeks during year 1, every 16 weeks during year 2 and every 24 weeks thereafter. All visible lesions seen on cystoscopy were biopsied, with recurrence being established only by histological
TABLE 2.
Recurrence rate by treatment group Doxorubicin/ Ethoglucid
No. pts. randomized No. pts. with followup No. pts. with recurrences (%) Total No. recurrences Total mos. followup Recurrence rate/100 pt.-mos. Significance
71 47
135 73 16 (22)
22 (47) 41 755 447 2.91 9.17 p <0.001 22
Totals
Control
206 120 38 (32) 63 1,202 5.24
Probability
-
--.-
1.00 . 90
---6--
.80
examination of the biopsy material. If cytology was positive and no lesion was visible on cystoscopy a random biopsy was done. Clinical material. Between December 1979 and March 1983, 369 patients were randomized, with followup data available for 240. Mean followup was 11.69 months. The distribution of patients by treatment group and initial stage, and by stratification for primary or recurrent tumor is shown in table 1. Of the 240 patients analyzed 86 were randomized to receive doxorubicin, 85 ethoglucid and 69 transurethral resection only (control). Fewer patients were randomized to the control group because the control arm was dropped from the protocol in 1982. RESULTS
The 3 treatment groups were compared with respect to the 2 principal endpoints. However, in April 1982 the control arm was closed to patient entry based on the results of an interim analysis that showed a recurrence rate per 100 patient-months of 9.17 in the transurethral resection-only group compared to 2.91 in patients receiving adjuvant doxorubicin or ethoglucid (table 2, p <0.001). Interval to first recurrence. Curves representing the interval to first recurrence have been estimated by the Kaplan-Meier method and compared using the log-rank test. 16 A global comparison by treatment group was highly significant (p = 0.014, fig. 1). Paired comparisons yielded a significant difference between the ethoglucid and control groups (p = 0.0042) in favor of ethoglucid. In patients with primary tumors (fig. 2) a paired comparison indicated no difference between the ethoglucid and doxorubicin groups but there was a significant difference between the ethoglucid and control groups (p = 0.02). Figure 3 shows the curves for patients with recurrent tumors. Over-all, no significant difference was detected among the 3 treatment arms in this subgroup. Recurrence rate/mean interval between recurrences. Tables 2 and 3 present the recurrence rates in different groups of patients and the significant levels of the treatment comparisons based on a permutation test. For easier presentation the recurrence rates are multiplied by 100. The inverse of the recurrence rate, which can be interpreted as the mean number of months between 2 recurrences, also is presented but should be interTreatment
Total Fail. 86 85 69
259
adriam epodyl control
31 20 33
p= .014 (logrank overall)
. 70 .60 .50
.40 .30
.20 . 10
30 24 18 12 6 0 Number of patients at risk at the corresponding times:
36 months
86
50
27
14
7
4
O adriam
85 69
55 40
26 23
15 7
8 3
3 2
O epodyl
O control
FIG. 1. Comparison of Kaplan-Meier curves for interval to first recurrence in all patients (primary and recurrent cancer). adriam, doxorubicin. epodyl, ethoglucid.
260
KURTH AND ASSOCIATES Probability 1. 00
. 90 .80 . 70 .60 Prim/Rec = primary Total Fa ii. Treatment _ . _ 48 12 adriam 7 epodyl 58 -.6.- 43 14 control
. 50 .. 40 .30
p=
.20
. 063 ( log rank overall)
. 10
0 6 12 18 24 30 Number of the patients at risk at the corresponding times: 48 30 15 8 5 3 58 39 17 10 6 2 17 43 30 4 0
36
months
0 0 0
adriam epodyl control
FIG. 2. Comparison of Kaplan-Meier curves for interval to first recurrence in patients with primary disease. adriam, doxorubicin. epodyl, ethoglucid. Prim /rec Probability 1.00
Total Fail.
-
_._
38 27 - A - 26
.90 .80
19 13 19
=recurrent Treatment adriam epodyl control
p= . 170 ( logrank overall)
. 70 .60 .50 . 40 . . 30 .20 . 10
0
6 12 18 24 30 Number of patients at risk at the corresponding times: 38 20 12 6 2 1 27 16 9 5 2 10 26 . 6 3 2 2
36
months
0 0 0
adriam epodyl control
FIG. 3. Comparison of Kaplan-Meier curves for interval to first recurrence in patients with recurrent disease. adriam, doxorubicin. epodyl, ethoglucid.
preted with caution, since the average followup is only about 1 year. Comparisons have been performed globally for all patients and separately for patients with primary and recurrent tumors. The study of the recurrence rate is preferred, since all information available for each patient is considered and not only the interval until the first recurrence. No difference was detected between the doxorubicin and ethoglucid groups but both drugs reduced the recurrence rate significantly compared to the control group (table 3). Among patients with primary tumors a significant difference was found when the ethoglucid group was
compared to controls in favor of ethoglucid (p = 0.008), while no difference was found between the doxorubicin and ethoglucid groups. Treatment comparison in patients with recurrent tumors yielded no significant difference between the doxorubicin and ethoglucid groups. However, there was a significant advantage of doxorubicin over controls (p = 0.026), while the difference between ethoglucid and controls did not reach significance (p = 0.084). Prognostic factors. Several factors of potential prognostic importance were analyzed by comparing the recurrence rates
ADJUVANT CHEMOTHERAPY OF SUPERJ:"1:CIAL TRANSITWNAL CELL BLADDER CARCIJ\,QMA TABLE 3.
Recurrence rate by treatment group Doxorubicin
Ethogiucid
Control
Totals
Over-all* No. pts. Mean followup (mos.) Recurrence rate/100 pt.-mos. Mean interval between recurrences
86 lL:ll 4.11 24.33
85 1L47 2.97 33.62
69 12.42 7.58 13.18
240 1L69 4.78 20.93
43 1L60 4.81 20.79
149 1L32 2.96 33.74
Pts. with primary diseaset No. pts. Mean followup (mos.) Recurrence rate/100 pt.-mos. Mean interval between recurrences (mos.)
48 1L42 3.10 32.24
58 1L03 L41 7Lll
The occurrence of locai and reactions after instillation of doxorubicin and ethoglucid was low: 4 of 98 patients after a total of 1,118 instillations of doxorubicin and 3 of 96 patients after a total of 1,087 instillations of ethoglucid had complaints of chemical cystitis. Further instillation was stopped in only 1 patient because of excessive toxicity after the first instillation of ethoglucid 6 days after transurethral resection. Systemic side effects, such as allergic reaction, mild nausea, diarrhea and vomiting, were seen in 5 of 98 patients after instillation of doxorubicin, while fever and allergic skin reaction were noted in 3 of 96 patients after instillation of ethoglucid. Neither leukopenia nor thrombocytopenia was seen in this study. DISCUSSION
Pts. with recurrent disease:j:. No. pts. Mean followup (mos.) Recurrence rate/100 pt.-mos. Mean interval between recurrences (mos.)
38 1U8 5.41 18.48
27 12.41 5.97 16.76
26 13.77 11.45 8.73
91 12.29 7.51 13.31
* p = 0.018 for doxorubicin versus control, 0.002 for ethoglucid versus control and not significant for doxorubicin versus ethogfocid. tp = 0.008 for ethoglucid versus control, and not significant for doxorubicin versus ethoglucid and controL :j: p = 0.026 for doxorubicin versus control, 0.084 for ethoglucid versus control and not significant for doxorubicin versus ethoglucid.
TABLE 4. Recurrence rate by number of tumors; stage, grade and size of largest tumor at entry into study, and by recurrence rate before entry into study
No. tumors at entry:* 1 2-3 ;;;4 Totals Recurrence rate before entry:t Primary <1/yr. >1/yr. Totals Stage:+ Ta Tl Totals Grade:§ 1 2 3 Totals Tumor size (cm.):11 <1 1-3 >3 Totals
No. Pts.
Mean Followup (mos.)
Recurrence Rate/ 100 PLMos.
Mean Interval Between Recurrences (mos.)
98 84 58 240
12.36 10.83 1L79 1L69
2.39 5.27 8.33 4.78
4L76 18.96 12.00 20.93
149 22 54 225
11.32 12.27 12.65 1L73
2.96 5.19 7.47 4.36
33.74 19.29 13.39 22.96
129 231
12.57 10.47 1L65
3.64 6.65 4.83
27.49 15.04 20.69
95 78 17 190
13.03 10.27 8.12 1L46
3.07 7.24 8.70 4.96
32.58 13.81 1L50 20.16
130 56 54 240
13.08 9.59 10.52 1L69
4.59
2L79 18.52 2L04 20.93
102
SAO 4.75 4.78
* p = 0.016 for 1 versus 2 to 3 tumors, <0.00001 for 1 versus ;;;4 tumors and 0.08 for 2 to 3 versus ;;;4 tumors. t p = 0.006 for primary versus > 1 tumor per year, and not significant for
associated with different levels of the variable. In this analysis the distribution of the other factors has been disregarded. With the recurrence rate as the primary endpoint of interest, it appeared that the number of tumors at presentation was the most significant prognostic factor. Likewise, recurrence rate before entry, and stage and grade were found to be of prognostic importance. The size of the tumor had no influence on the recurrence rate (table 4).
From our study one can conclude that adjuvant chemotherapy with the drugs used has reduced the recurrence rate significantly. In other words, the incidence of hospitalization for transurethral resection of a recurrent tumor decreased significantly. The interval to first recurrence was prolonged by adjuvant chemotherapy. Globally, doxorubicin and ethoglucid appeared to be equally effective. As in an earlier study by our group 17 the number of tumors at presentation was the most important prognostic factor. Surprisingly, and in contrast to the previous study, the size of the tumor was of no prognostic importance when the recurrence rate was analyzed as the primary endpoint of interest. This finding may be due to the fact that this analysis has not been adjusted for other factors. At the time of the final multivariate analysis the relative importance of all prognostic factors will be studied. Local and systemic side effects observed after instillation were remarkably low. Serious toxicity, as has been reported for thiotepa 18 and cis-platinum, 19 was not seen, which may be owing to the low or negligible resorption of doxorubicin and ethoglucid through the bladder wa!L~ 0 However, bone marrow depression has been described after ethoglucid instillation. 21 As reported previously,8 our trial has shown the superiority of adjuvant chemotherapy over transurethral resection alone. Therefore, a control arm with transurethral resection alone is not indispensable in future studies. From the first analysis in 1982 it became obvious that both adjuvantly treated groups have a significant lower recurrence rate than the control group. Therefore, it seemed justified to continue the study without further recruitment into the control arm. Because of the short median followup of 11.6 months in this preliminary report no attempt has been made to include a comparison of progression in stage in the 3 treatment groups. Investigational problems not addressed in this study, such as the frequency and duration of chemotherapy, will be examined in future studies. REFERENCES
L Greene, L F., Hanash, KA. and Farrow, G. IvL: Benign papilloma or papillary carcinoma of the bladder? J. Urol., 110: 205, 1973. 2. Soloway, M. S., Murphy, W., Rao, M. K and Cox, C.: Serial multiple-site biopsies in patients with bladder cancer. J. UroL, 120: 57, 1978. 3. Weyrauch, H. M. and Crossfield, J. G.: Dissemination of bladder neoplasms by endoscopic electroresection. J. UroL, 87: 391, 1962. 4. Weldon, T. K and Soloway, M. S.: Susceptibility of urothelium to neoplastic cellular implantation. Urology, 5: 824, 1975. 5. Veenema, R. J., Dean, A. L, Jr., Uson, A. C., Roberts, M. and Longo, F.: Thiotepa bladder instillations: therapy and prophylaxis for superficial bladder tumors. J. UroL, 101: 711, 1969. 6. Byar, D., Blackard, C. and the Veterans Administration Cooperative Urological Research Group: Comparisons of placebo, pyridoxine, and topical thiotepa in preventing recurrence of stage I bladder cancer. Urology, 10: 556, 1977. 7. 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.
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8. Schulman, C. C., Robinson, M., Denis, L., Smith, P., Viggiano, G., De Pauw, M., Dalesio, 0. and Sylvester, R.: Prophylactic chemotherapy of superficial transitional cell bladder carcinoma: an EORTC randomized trial comparing thiotepa, VM-26 and TUR alone. Eur. Urol., 8: 207, 1982. 9. Banks, M. D., Pontes, J.E., lzbicki, R. M. and Pierce, J. M., Jr.: Topical instillation of doxorubicin hydrochloride in the treatment of recurring superficial transitional cell carcinoma of the bladder. J. Urol., 118: 757, 1977. 10. Jakse, G., Hofstadter, F. and Marberger, H.: Intracavitary doxorubicin hydrochloride therapy for carcinoma in situ of the bladder. J. Urol., 125: 185, 1981. 11. Mishina, T., Oda, K., Murata, S., Ooe, H., Mori, Y. and Takahashi, T.: Mitomycin C bladder instillation therapy for bladder tumors. J. Urol., 114: 217, 1975. 12. DeFuria, M. D., Bracken, R. B., Johnson, D. E., Soloway, M. S., Merrin, C. E., Morgan, L. R., Miller, H. C. and Crooke, S. T.: Phase I-II study of mitomycin C topical therapy for low-grade, low stage transitional cell carcinoma of the bladder: an interim report. Cancer Treat. Rep., 64: 255, 1980. 13. Huland, H. and Otto, U.: Mitomycin instillation to prevent recurrence of superficial bladder carcinoma. Results of a controlled, prospective study in 58 patients. Eur. Urol., 9: 84, 1983. 14. Fitzpatrick, J. M., Khan, 0., Oliver, R. T. D. and Riddle, P. R.: Long-term followup in patients with superficial bladder tumours treated with intravesical epodyl. Brit. J. Urol., 51: 545, 1979.
15. Kurth, K. H., Maksimovic, P. A., Hop, W. C. J., Schroder, F. H. and Bakker, N. J.: Single-dose intravesical epodyl after TUR of Ta TCC bladder carcinoma. World J. Urol., 1: 89, 1983. 16. Buyse, M. E., Staquet, M. J. and Sylvester, R. J.: Cancer Clinical Trials: Methods and Practice. Oxford: Oxford University Press, 1984. 17. Dalesio, 0., Schulman, C. C., Sylvester, R., De Pauw, M., Robinson, M., Denis, L., Smith, P., Viggiano, G. and Members of the European Organization for Research on Treatment of Cancer, Genitourinary Tract Cancer Cooperative Group: Prognostic factors in superficial bladder tumors. A study of the European Organization for Research on Treatment of Cancer: Genitourinary Tract Cancer Cooperative Group. J. Ural., 129: 730, 1983. 18. Grossman, H. B.: Current therapy of bladder carcinoma. J. Urol., 121: 1, 1979. 19. Denis, L.: Anaphylactic reactions to repeated intravesical instillation with cisplatin. Letter to the Editor. Lancet, 1: 1378, 1983. 20. Jacobi, G. H. and Kurth, K.-H.: Studies on the intravesical action of topically administered G3H-doxorubicin hydrochloride in men: plasma uptake and tumor penetration. J. Urol., 124: 34, 1980. 21. Robinson, M. R. G., Shetty, M. B., Richards, B., Bastable, R., Glashan, R. W. and Smith, P. H.: Intravesical epodyl in the management of bladder tumors: combined experience of the Yorkshire Urological Cancer Research Group. J. Urol., 118: 972, 1977.