British Journal of Urology (19!91),61, 70-73 01991 British Journal of Urology

Adjuvant Topical Chemotherapy versus lmmunotherapy in Primary Superficial Transitional Cell Carcinoma of the Bladder J. FLAMM and A.

BUCHER

Departments of Urology, Wilhelminen and Hanusch Hospitals, Vienna, Austria

Summary-In a prospective randomised controlled study, the efficacy of ethoglucid was compared with that of keyhole-limpet haemocyanin (KLH) in preventing recurrent tumours following transurethral resection of primary superficial transitional cell carcinoma of the bladder. Patients treated with ethoglucid (n = 39) received 0.565 g (1% solution) ethoglucid weekly for 6 weeks and then monthly for 1 year. Patients treated with KLH (n = 38) were immunised subcutaneously with 1 mg KLH; bladder instillations of 30 mg were then given weekly for 6 weeks and thereafter monthlyfor 1 year. The recurrence rates, disease-free intervals and tumour progression rates were evaluated. The end-point of the study was either progression in stage or grade or more than 1 recurrence during the observation period. The minimum length of follow-up was 1 year. The recurrence rates, mean disease-free intervals and progression rates in the 2 groups showed no statistically significant differences.

Superficial transitional cell carcinoma (STCC) of the bladder is classified in stages pTa-pT1 and grades 1-3 according to the recommendations of the International Union against Cancer (UICC, 1987) and the World Health Organisation (Mostofi, 1973). Transurethral resection (TUR) of all visible lesions with separate biopsies of the tumour margin and tumour base to confirm the completeness of resection are the first treatment modalities for STCC. Even after complete TUR, 50 to 80% of tumours recur (Cutler et al., 1982; Heney et al., 1982; Lutzeyer et al., 1982; Dalesio et al., 1983). Adjuvant intravesical chemotherapy and immunotherapy have been advocated to reduce tumour recurrences and prolong the time to recurrence (Kurth et al., 1985). Ethoglucid is one of the most frequently used cytotoxic agents (Riddle, 1973; Fitzpatrick et al., 1987). There are, however, few reports on immunotherapy in bladder cancer with keyhole-limpet haemocyanin (immucocynine : ImmucothelR; Biosyn Technology, Stuttgart, GerAccepted for publication 9 March 1990

70

many) (Klippel, 1985; Jurincic et al., 1988; Kalble et al., 1989; Weymann, 1989). The aim of this study was to compare the efficacy of standard ethoglucid therapy with that of KLH irnmunotherapy in patients with primary STCC of the bladder.

Patients and Methods

Histological specimens and follow-up data were available on 77 of 80 patients included in the study. After histological confirmation of stage pTa or pT1 (regardless of tumour grade), treatment began within 1 week of TUR. Group E (n = 39) received 0.565 g ethoglucid in 50 ml saline weekly for 6 weeks and then monthly for 1 year. Group K (n= 38) was immunised with 1 mg keyhole-limpet haemocyanin subcutaneously and received 30 mg (30 ml solution) weekly for 6 weeks and afterwards monthly for 1 year. T UR was performed with separate resection of the tumour base and the tumour margin to confirm the completeness of the

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CHEMOTHERAPY VERSUS IMMUNOTHERAPY IN PRIMARY STCC OF THE BLADDER

Table 1 Details of Patients Treatment group

Males (%)

Stage Age (years) (Mean fSO) pTa

Ethoglucid KLH

69.2 78.9

67.3k 11.7 65.9+ 12.4

46.2 42.1

(%I

Grade (%)

pTI

I

2

3

53.8 57.9

41.0 42.1

43.6 47.4

15.4 10.5

Comparisons of frequencies were based on Pearson’s x2 test or Yates’ corrected xz test (P>O,l).

resection. Bladder mapping was performed in each case. In addition to tumour stage and grade, the age and sex of the patients, multiplicity of tumours, number of bladder quadrants with visible tumour, tumour weight, dysplasia and carcinoma in situ (TIS) in the bladder biopsies were evaluated. Each patient was followed up by cystoscopy every 3 months for a minimum period of 12 months (mean 26.18k5.7). The end-point of the study was progression in stage or grade or a second recurrence. In the case of a non-progressive recurrence, T U R with histological confirmation and a further 6-week course of treatment were performed. The objectives of the study were to compare the percentage of recurrences, recurrence rate, disease-free interval and tumour progression rate in both therapeutic arms.

Statistical analysis

For statistical analysis BMDP statistical software (University of California) was used. The diseasefree interval was defined as the interval from T U R before randomisation to the first recurrence. Curves presenting the interval to next recurrence were estimated by the Kaplan-Meier method (Kaplan and Meier, 1958). The recurrence rate was defined as the total number of recurrences in each treatment group divided by the total number of follow-up months in each group. These results were multiplied by 100 to simplify the presentation. The levels of significance were assessed by generalised Wilcoxon (Breslow) and generalised Savage (Mantel-Cox) tests. The Kruskal-Wallis test and Mann-Whitney U test were used as nonparametric tests for comparison of the 2 groups. Comparisons between frequencies were based on Pearson’s x2 test or Yates’ corrected x2 test.

of the patients was 66.6 years (range 26-83) and 74% were male; 44% of the tumours were stage pTa and 56% were pT1; 42% of the tumours were grade 1,46% grade 2 and 13% grade 3 ; 66% were solitary. The mean tumour weight was 3.75 g (range 1-9). Dysplasia (grades 1-2) was found in 22% and concomitant TIS in 5% of the tumours. The distribution of risk factors such as stage, grade, multiplicity, dysplasia and TIS in the bladder mapping in the 2 groups was comparable and showed no significant difference (Tables 1 and 2). The mean follow-up period was 26.2 months f 5.7 with a minimum of 12 months (range 12-32).

Recurrences The overall frequency of recurrences was 33%. After ethoglucid instillation therapy the percentage of recurrences was 33% and after KLH it was 32% (P=0.69). One recurrence was found in 21% of patients after ethoglucid treatment and in 26% after KLH instillation. Two recurrences were found in 13% after ethoglucid and in 5% after KLH treatment ( P = 0.47). Multiple recurrences were found in 8% after ethoglucid and in 5% after KLH instillations ( P = 0.69). A recurrence with downstaging was found in 10% after ethoglucid and in 3% after KLH treatment. The rate of histological equal recurrences was 18% after ethoglucid and 26% after KLH and progression was found in 5% after ethoglucid and 3% after KLH ( P = 0.27). The recurrence rate after Table 2 Risk Factors Tumour weight

Quadrant Biopsies with

Treatment group

Multiplicity (%)

Results

Ethoglucid KLH

35.9 31.6

Of 80 patients who entered the study, 77 were evaluated; 3 were lost to follow-up. The mean age

Comparisons of frequencies were based on Pearson’s xz test or Yates’ corrected x2 test (P>0.1).

0.1).

ethoglucid was 3% and after KLH 2% (Tables 3 and 4). Disease-free interval

The overall disease-free interval was 9.4 months 4.6 and there was no difference between the 2 groups (P=0.86). The mean disease-free interval after ethoglucid was 10.3 monthsf5.6 and after KLH 8.4 months k 3.1 (Fig.).

versus 3% after KLH). Progressions were either by stage or by stage plus grade and progression by grade alone was not observed. Comparison of the time to progression showed no statistical difference (P=0.57 Mantel-Cox test). After histological confirmation of progression or a second recurrence, treatment was changed to intravesical instillations of Bacillus-Calmette GuCrin (BCG), systemic chemotherapy or operative treatment according to the nature of the progression and the age of the patient.

Tumour progression rate

Tumour progression was found in 4% of patients. The progression rate showed no significant difference in the treatment groups (5% after ethoglucid 1.o

0.8 z

Side efsects

No severe side effects were found in either of the 2 groups. Chemocystitis was noted in 5 of 39 patients (13%) in the ethoglucid group but in none of the KLH patients. This was not severe and it was not necessary to interrupt treatment. In the KLH group, 3 patients (8%) had a febrile reaction for 1 or 2 days. No systemic side effects were reported.

G 0.6

Bm n 2 0.4

E 33.3%

Discussion

p=0.861 (Mantel-Cox)

n

,1 o.2 0.0

00

5

10

15

20

25

Months

Figure Comparison of Kaplan-Meier curves for time to recurrence. K : KLH group. E: Ethoglucid group.

Ethoglucid is a well known and well documented alkylating cytotoxic agent (Riddle, 1973; Smith et al., 1978; Fitzpatrick et al., 1987). Chemocystitis and the possible development of bladder contracture or reflux in about 4% of patients are the limiting factors in the long-term use of the drug (Smith et al., 1978; Virdi, unpublished data). It is of interest to investigate drugs with similar or greater efficacy which lack the side effects of cytotoxic drugs. BCG

Table 4 Recurrence Rates, Follow-up, Disease-freeIntervals and Progression Rates Treatment group

Recurrence rate (%)

FONOW-UP (months) (Mean fS D )

Disease-jree interval Tumour (months) progression (Mean &SO) (%)

Ethoglucid KLH

2.79 2.33

26.6 f6.0 25.8 f5.3

10.3& 5.6 8.4k 3.2

5.1 2.6

Recurrence rate=number of recurrences divided by the total number of follow-up months multiplied by 100. Disease-free interval = time to first recurrence.

CHEMOTHERAPY VERSUS IMMUNOTHERAPY IN PRIMARY STCC OF THE BLADDER

has a high rate of side effects (Brosman, 1982; Lamm et al., 1982). Keyhole-limpet haemocyanin is a powerful immunogenic compound of high molecular weight (Jurincic et al., 1988). The systemic and topical use of KLH in experimental studies has been shown to reduce tumour growth in animals (Lamm et al., 1981). There are few data on the efficacy of KLH in the prophylactic treatment of patients with STCC. In a prospective randomised trial of KLH and mitomycin C, there was a recurrence rate of 14.2% in the KLH group (mean follow-up 20.7 months) and 39.1% in the mitomycin C group (mean follow-up 18.3 months) (P