Prognostic Factors Influencing Survival of Patients Receiving Intravesical Epodyl

0022-534 7/82/ 1273-0430$02.00/0 Vol. 127, March Printed in U.S.A.

THE JOURNAL OF UROLOGY

Copyright© 1982 by The Williams & Wilkins Co.

PROGNOSTIC FACTORS INFLUENCING SURVIVAL OF PATIENTS RECEIVING INTRAVESICAL EPODYL P. R. RIDDLE, 0. KHAN, J.M. FITZPATRICK

AND

R. T. D. OLIVER

From St. Peter's Hospitals and Institute of Urology, London, England

ABSTRACT

Results from a retrospective analysis of 139 patients with recurrent superficial bladder tumors treated by intravesical epodyl are reviewed. Of patients who had complete clearance of tumor from the bladder 95 per cent became free of disease within 12 months of starting intravesical therapy. No patient who had persistent tumors at 2 years was free of tumor subsequently. The majority of complete responders who suffered recurrences did so within 3 years and 80 per cent of a small series of patients who remained free of tumor after 3 years and then stopped treatment continued to be free of tumor for a further 2 years. Failure to respond within 12 months or early invasion of the submucosa on biopsy (stage Plb tumors) was associated with poor survival. In patients who underwent salvage cystectomy the demonstration that 35 per cent had involved metastatic lymph nodes and 38 per cent had invasion of muscle is a clear indication of the dangers of delaying radical treatment once the patient has failed to respond completely to intravesical therapy. Intravesical epodyl has been established clearly as effective treatment for patients with recurrent superficial bladder tumors who may otherwise have been candidates for total cystectomy and urinary diversion. 1- 4 Two-thirds of the patients responded completely with clearance of tumor from the bladder but the majority of partial or nonresponders died of invasive cancer. In an attempt to define risk factors and enable better selection of patients who would benefit from this therapy we herein analyze the total experience at our hospital since 1968.

ted to the hospital and received 12 daily treatments). Urine culture was performed before each instillation and treatment was stopped temporarily if the urine became infected. After the first check cystoscopy treatment then was continued monthly for the first year, every other month for the second year and every 3 months thereafter, provided the patient remained without tumors. If tumors recurred a further reinduction was performed. In patients who failed to respond a trial of 2 per cent epodyl sometimes was attempted before cystectomy was performed.

PATIENTS AND METHODS

RESULTS

We treated 139 patients (including those reported previously5) with intravesical epodyl at our hospital from 1968 to June 1978. These patients had been treated for an average of 4 years before referral and had widespread superficial papillary bladder tumors that had ceased to be controlled by endoscopic resection or closed cystodiathermy, and were candidates for cystourethrectomy. Histological studies of the bladder tumor were done with particular reference to the extent of superficial invasion, and the disease was staged according to the criteria of the International Union Against Cancer,6 including the subdivisions of the Pl category proposed by Pugh: 7 Pis-flat, preinvasive carcinoma (carcinoma in situ), Pa-papillary, noninvasive carcinoma, Fla-tumor infiltrating the stromal cores of the papillae, Plb-tumor infiltrating the lamina propria, P2tumor infiltrating the superficial muscle, P3a-tumor infiltrating the deep muscle, P3b-tumor infiltrating the extravesical tissues, P4a-tumor infiltrating the prostate, uterus or vagina, P4b-tumor infiltrating the pelvic or abdominal wall and Pxno tissue available for review. Response to treatment was established by cystoscopy, although in more recent cases random biopsies of normal mucosa also have been performed. Treatment schedule. One ml. epodyl was reconstituted in 100 ml. sterile distilled water and instilled into the bladder using a fine SF gauge Jaques catheter. Treatment was begun immediately in patients who received the drug but was delayed for 4 weeks if diathermy was necessary at any subsequent cystoscopy. The first course of treatment was weekly instillations for 12 weeks (although some patients who lived far away were admit-

Patient survival and response to treatment. Comparison of tumor response to treatment and survival at 5 years after the start of epodyl treatment in both series is shown in table 1. Although the percentage of patients alive at 5 years and with bladders free of tumor at 1 year is slightly less in the second series this difference is not statistically significant. Therefore, the results of the 2 series have been pooled to assess the influence of pathological tumor stage on survival. Since the initial diagnostic and pre-epodyl histology studies were not available in all cases analysis has been made using either source of histological information (table 2). Only those patients with stage Plb tumors (41 per cent 5-year survival) had a worse survival than all other categories (68 per cent 5-year survival). The majority of patients (70 of 74) who had complete disappearance of tumor from the bladder after treatment were free of disease within 1 year. No patient who failed to respond completely by 2 years had clearance of all tumor from the bladder subsequently. Initial response to treatment was an important indication of long-term survival (see figure). Patients who failed to show any response by 1 year had the worse survival (41 per cent at 5 years and 19 per cent at 8 years). Partial responders, although they initially had survival similar to complete responders up to 5 years, died later, which did not occur in patients with a complete response. Duration of response. The majority of patients who had recurrences after complete response were free of disease by 3 years, although 17 of these 46 patients suffered a recurrence subsequently. Initially, all patients continued to receive monthly treatment for the first 2 years and then every 3 months thereafter, since

Accepted for publication April 16, 1981.

430

431

FACTORS INFLUENCING SURVIVAL OF PATIENTS RECEIVING INTRAVESICAL EPODYL

it was uncertain when treatment could be stopped. However, 19 patients stopped treatment after the bladder had been clear of tumor for at least 1 year (12 because of local symptoms and 7 by default). Although the number of patients is small there is a suggestion that recurrence within 2 years of stopping epodyl is less the longer the patients have been on treatment (table 3). Death of bladder cancer was most frequent in patients with stages Pla and Plb tumors (table 4). The type of treatment given after epodyl failure is indicated in table 5. Older patients who were unsuitable for cystectomy were treated by radiotherapy. Survival after cystourethrectomy. Cystourethrectomy was done on 35 patients. Pathological stage, grade and iliac lymph node status were important predictors of survival (table 6). Of interest was the suggestion that the 15 patients who underwent simple cystourethrectomy (whose nodes status was not known) did better than the 13 who underwent radical cystourethrectomy and who had nodes negative for disease. Side effects of treatment. A total of 22 patients (16 per cent) stopped treatment because of side effects (12 without tumor in the bladder and 10 with persistent tumor). Of these patients 2

had an urticaria! skin reaction after treatment for > 1 year, which recurred within 30 minutes of drug instillation, and bronchospasm occurred in 1. The remaining patients stopped treatment because severe symptoms of cystitis (dysuria, frequency and bladder pain) developed after treatment for > 1 year. Most patients had infected urine that only responded to treatment after stopping epodyl, although a minority with sterile urine may have had chemical cystitis. No patient on treatment had problems related to anemia (unexplained by hematuria), leukopenia or thrombocytopenia. TABLE 4.

%Dead

Pa Pla Plb Px

Comparison between earlier and present series

Earlier report' Present series Totals

No. Pts.

% Survival at 5 Yrs.

% Free of Tumor at 1 Yr.

65 74 139

69 67 68

54 48 50

% Alive

83 7 11 38

68 29 27 58

Bladder Ca

Other Cause

27* 71 64 24

6 6 9 18

Influence ofpost-epodyl treatment on survival of patients who failed epodyl therapy No. Alive/No. Treated

Stage

Pa Pla Plb Px

Cystodiathermy Alone

Cystectomy

Radiotherapy

24/26 1/2 0/3 0/3

8/17 0/3 2/6 5/9

0/9 1/2 0/2

Survival by pathological biopsy stage before epodyl

TABLE 2.

No. Pts. 83 7 11 38

Pa Pla Plb Pxt

% Survival* 1 Yr. 98 100 91 100

2 Yrs. 93 100 81 92

(45) (29) (36) (66)

5 Yrs.

(44) (14) (26) (63)

73 67 41 66

Effect of stopping epodyl treatment in patients whose bladder had been free of tumor

Duration of Epodyl Treatment (yrs.)

% Free of Disease 2 Yrs. After Stopping Epodyl

No. Pts.

~2

9

3

10

56 80

6. Survival after cystourethrectomy according to tumor stage and grade, and nodal involvement at cystourethrectomy

TABLE

(26) (0) (13) (55)

* Figures in brackets are per cent of patients free of tumor. t Patients whose histology studies were not reviewed by pathologist. TABLE 3.

No. Pts.

* Includes 2 deaths after cystectomy. TABLE 5.

TABLE 1.

Cause of death in patients receiving epodyl

% Survival (yrs.)

No. Pts. Stage: Pa Pla and Plb P2, P3 and P4 Grades: Gl G2 G3 Nodal involvement: Neg. Pos. Unknown

2

12 13

90 83 69

44 74 43

14 14 7

93 71 71

93 55 40

13 7 15

76 43 100

67 0 93

10

INFLUENCE OF RESPONSE TO TREATMENT ON SURVIVAL OF PATIENTS RECEIVING EPODYL 16

100 90

71

80 70 60

Response %

50 40 30 20

~

o---o

Complete Responders Partial Responders Non-responders

10 4

Survival In Years

3

432

RIDDLE AND ASSOCIATES

DISCUSSION

Two drugs, epodyl and thio-tepa, have been used most in the treatment of recurrent superficial tumors, either as therapy without concomitant resection or as a prophylaxis after resection. Our patients had multiple recurrences that no longer were controllable by cystodiathermy, and epodyl was given initially as therapy and not after clearance of all tumor from the bladder. The response at 3 months8 using this drug was higher (64 per cent) than reported when thio-tepa was used as therapy rather than prophylaxis (46 per cent). 9 However, in this long-term followup only 26 per cent of the patients remain free of tumor at 5 years (table 3) and in 24 per cent cystourethrectomy was necessary. No comparable information has been published on thio-tepa. Nevertheless, the results reported are as good as those achieved using more aggressive therapy, such as cystourethrectomy with or'without radiotherapy. 10 Our current policy is to give all such patients at least a 1-year trial before considering cystectomy, since failure to respond completely by that time was associated with a poor prognosis (see figure). 5 There were insufficient data available from this series to establish unequivocally the influence of pathological stage on survival although the data did suggest that patients with stage Plb tumors did worse (table 2). In addition, although unpublished analysis of a small number of cases did demonstrate poorer survival of patients with positive cytology studies and/ or grade 3 tumors, insufficient cases were available to assess the influence of these pathological variables independent of one another. In this series cystourethrectomy often was undertaken too late since many patients were discovered to have previously unsuspected muscle invasion and lymph node metastases at operation, both of which had grave prognostic significance. Early consideration must be given to more radical treatment if the patient has not responded with complete disappearance of all tumors by 12 months. In the future it will be important to compare the results achieved with epodyl to those of some of the newer drugs, such as doxorubicin and mitomycin C, currently under evaluation for intravesical treatment. In addition, for the patients who have had invasion of muscle or lymphocytes before cystectomy, systemic chemotherapy or preoperative radiotherapy needs to be considered. Drs. K. M. Cameron and W. Highman assisted with histology and cytology studies, respectively. Dr. S. Evans, London Hospital Medical College, assisted in computer analysis. REFERENCES

1. Abbassian, A. and Wallace, D. M.: Intracavitary chemotherapy of diffuse non-infiltrating papillary carcinoma of the bladder. J. Urol., 96: 461, 1966. 2. Riddle, P.R. and Wallace, D. M.: Intracavitary chemotherapy for

3.

4. 5. 6. 7. 8. 9. 10.

multiple non-invasive bladder tumours. Brit. J. Urol., 43: 181, 1971. Robinson, M. R. G., Shetty, M. B., Richards, B., Bastable, J., Glashen, 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. Smith, J.M., Lane, V. and O'Flynn, J. D.: Epodyl in management of noninvasive vesical neoplasms. Urology, 11: 474, 1978. Fitzpatrick, J. M., Khan, 0., Oliver, R. T. D. and Riddle, P. R.: Long-term follow-up in patients with superficial bladder tumours treated with intravesical Epodyl. Brit. J. Urol., 51: 545, 1979. International Union Against Cancer: TNM Classification of Malignant Tumours, 3rd ed. Edited by M. H. Harmer. Geneva: International Union Against Cancer, 1978. Pugh, R. C.: Proceedings: the pathology of cancer of the bladder. Cancer, 32: 1267, 1973. Riddle, P.R.: The management of superficial bladder tumours with intravesical Epodyl. Brit. J. Urol., 45: 84, 1973. 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. Whitmore, W. F., Jr., Batata, M.A., Ghoneim, M.A., Grabstald, H. and Unal, A.: Radical cystectomy with or without prior irradiation in the treatment of bladder cancer. J. Urol., 118: 184, 1977.

EDITORIAL COMMENT Despite the renewed interest in the use of intravesical chemotherapy and the welcomed initiation of studies designed to compare the efficacy of different drugs we lack data on the impact of these agents during an extended period. Although this article does not answer all of our quandries, for example insufficient patients in the stages Pla and Plb (stage A) group, lack of information on tumor grade and no data on cytology, it does provide 5-year data on 83 patients with noninvasive (stage Pa or 0) tumors treated with intravesical epodyl. It should be emphasized that these patients had "widespread" tumors not amenable to endoscopic control. Of these patients 27 per cent subsequently died of bladder cancer; 9 of 17 despite cystectomy and all 9 undergoing radiation therapy. Conservative therapy obviously was continued too long in those dying of bladder cancer. Intravesical chemotherapy was a "last ditch" attempt to avoid cystectomy in this group of 83 patients and the authors emphasize that failure to achieve a lasting complete (? or partial) response necessitates cystectomy. We must continue to search for methods to select which patients initially presenting with superficial tumors will progress to have invasive disease and, just as important, which patients may not require intensive monitoring and intravesical chemotherapy. Although the red cell adherence assay is an attempt to provide this information it has yet to attain sufficient predicative accuracy that will allow the clinician to suggest management based on the presence or absence of surface antigens. Mark S. Soloway Department of Urology University of Tennessee Center for Health Sciences Memphis, Tennessee