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Keywords:

  • bacillus Calmette-Guérin;
  • superficial bladder cancer;
  • intravesical therapy;
  • immunotherapy

Abstract

  1. Top of page
  2. Abstract
  3. Introduction
  4. Patients and methods
  5. Results
  6. Discussion

Objectives To determine the efficacy of a three-fold reduced dose (RD, 27 mg) of intravesical bacille Calmette-Gue´rin (BCG) against the standard dose (81 mg) in patients with superficial bladder cancer, assessing recurrence, progression and differences in toxicity.

Patients and methods Five hundred patients with superficial bladder cancer (Ta, T1, Tis) were enrolled and randomly assigned to be treated after transurethral resection of all visible lesions with intravesical BCG Connaught strain (weekly×six and thereafter fortnightly×six) either with the standard or RD instillation.

Results All but one of the 500 patients were evaluable for efficacy and toxicity (252 in the standard arm and 247 in the RD arm). The median follow-up was 69 months (maximum 104); 71 (28%) patients in the standard arm and 76 (31%) in the RD arm developed recurrences; the median time to recurrence has not yet been attained, but at 5 years the mean (sd) percentage of recurrence-free patients was 70.5 (3.12) and 70.4 (3.1) for the standard and RD arms, respectively. In patients presenting with multifocal tumours, the standard dose was more effective against recurrences than the RD (P=0.0151). In those with G3 and high-risk tumours overall, the superiority of the standard dose was marginal (P=0.060 and P=0.082). Twenty-nine (11.5%) tumours in the standard arm and 33 (13.3%) in the RD arm progressed to invasive disease; the median time to progression has not yet been attained, but the percentage of progression-free patients at 5 years was 88.8 (2.23) and 86.9 (2.31) for the standard and RD arms, respectively. The standard dose was more effective than the RD against progression only in patients with multifocal disease (P=0.048). Twelve (4.8%) cystectomies were performed in the standard and 15 (6.1%) in the RD arm. Currently, 106 (21.2%) patients have died, but only 38 (7.6%) from bladder cancer, i.e. 20 (7.9%) in the standard and 18 (7.5%) in RD arm. Overall the disease-specific death rate was lower for those patients who completed the scheduled treatment. The cause-specific survival at 5 years did not differ between the arms (P=0.76) but there was a trend toward better cause-specific survival for patients with multifocal tumours in the standard arm. Toxicity differed between the arms, significantly more patients having no toxicity in the RD arm, and fewer having delayed instillations or withdrawing. However, severe systemic toxicity occurred even in patients treated with the RD, in a similar proportion to those receiving the standard dose.

Conclusion Overall, the RD gave similar results for recurrence and progression but with significantly less toxicity. However, patients with multifocal tumours fared better with the standard dose and there was a trend towards better recurrence rates in patients with high-risk tumours. We recommend continuing to use the standard dose for high-risk tumours, while we consider the reduced dose safe and effective for intermediate-risk lesions and for maintenance schedules.


Introduction

  1. Top of page
  2. Abstract
  3. Introduction
  4. Patients and methods
  5. Results
  6. Discussion

Since the introduction of BCG in the mid 1970s for the treatment and prophylaxis of superficial bladder TCC, it has become the biological response modifier of choice for tumours at high-risk of recurrence and progression. Nevertheless, the most adequate regimen and adequate dose have not yet been determined. The schedules and dosage used either by Martı´nez-Pin˜eiro and Muntan˜ola in 1975 [1] (intralesional injection plus intradermal scarification) and by Morales et al.[2] in 1976 (intravesical instillation plus intradermal multiple punctures) were mostly arbitrary, although derived from previous animal studies, and in human clinical studies which suggested that high doses of living BCG bacilli for local or intratumoral application (at 106–108 c.f.u) were needed to obtain antitumour activity.

The intralesional and intradermal routes were soon abandoned in favour of the intravesical route but the dose has not yet been optimized for the balance of efficacy and toxicity; the lowest dose which is still active remains unknown.

The main disadvantages of BCG are its toxic effects, local or systemic, which depend on the dose and number of instillations. By the late 1980s two groups were trying lower doses than normal in an attempt to decrease the frequency and intensity of adverse reactions [3,4]. The lack of agreement among these studies, using the same strain, the same dose per instillation and similar schedules, together with the need to find less toxic treatment schedules, induced our group (Club Urológico Espan˜ol de Tratamiento Oncológico, CUETO) to undertake a prospective randomized study to ascertain the therapeutic value and toxic effects of a three-fold lower dose of BCG compared with the standard dose; herein we report the final analysis of our trial, as of April 2000.

Patients and methods

  1. Top of page
  2. Abstract
  3. Introduction
  4. Patients and methods
  5. Results
  6. Discussion

The methods were reported previously [5] and are described briefly here. The trial was a joint effort of the urological departments of 18 Spanish hospitals, to compare the efficacy and toxicity of intravesically administered BCG Connaught, at either a standard dose of 81 mg or a reduced dose (RD) of 27 mg. The objectives were to assess, in both arms, the rate of recurrence and progression, the time to first recurrence, the time to progression to > T1N0M0 and the duration of survival, and to compare the frequency and severity of the side-effects.

Five hundred patients with primary or recurrent histologically confirmed superficial urothelial bladder carcinomas treated by TURBT (or laser in eight; two in the standard and six the RD arm) were recruited. The tumours were TaG2,3/T1G1–3 with or without concomitant Tis, or primary Tis; patients with TaG1 tumours were admitted only if recurrent.

Exclusion criteria were any previous treatment with BCG, the presence of severe infection or active tuberculosis, untreatable urinary infection, the presence of a concomitant urothelial tumour of the upper urinary tract, reduced bladder capacity to < 200 mL, blood creatinine, bilirubin and hepatic enzymes of more than double the upper limit of normal in the local laboratory, an expected survival of < 2 years and expected conditions that would make follow-up difficult, and finally the presence of any second malignancy, except non-melanoma skin cancer.

Within 7–10 days after complete resection and pathological confirmation, the patients were randomly assigned to receive one of the two treatments using the method of centralized randomization stratified by participating centre (variable size blocks).

The patient and tumour characteristics are detailed in Table 1; the distribution of age, gender, number of tumours, disease status (primary or relapsing) and size was similar in both treatment arms. However, there were significantly more patients with G3 and slightly more with Tis in the standard arm that, given the few patients, might have influenced the results.

Table 1.  Patient and tumour characteristics
CharacteristicsStandard armRD armTotal
  • *

    Either recurrent Ta of any grade, or Ta G2,3;

  • Significant difference (P=0.012) between arms in the G3 category;

  • An erythematous area of <1 cm in diameter after 1 mg intradermal protein purified derivative is negative.

No. of patients252 248 500 
Mean (sd) age, years64.1 (10.3)62.9 (11.6)
Categories, n (%)
 leqslant R: less-than-or-eq, slant 65 years130 (51.6)131 (52.8)261 (52.2)
 > 65 years122 (43.4)117 (47.2)239 (47.8)
 Male225 (89.3)226 (91.1)451 (90.2)
 Female27 (10.7)22 (8.9)49 (9.8)
Disease status
 Primary153 (60.7)155 (62.5)308 (61.6)
 Recurrent99 (39.3)93 (37.5)192 (38.4)
No. of tumours
 1142 (56.3)141 (56.9)283 (56.6)
 240 (15.9)42 (16.9)82 (16.4)
 324 (9.5)17 (6.9)41 (8.2)
 > 346 (18.2)48 (19.3)94 (18.8)
Tumour size (cm)
 leqslant R: less-than-or-eq, slant 188 (34.9)75 (30.2)163 (32.6)
 253 (21)74 (29.8)127 (25.4)
 357 (22.6)43 (17.3)100 (20)
 > 354 (21.4)56 (22.6)110 (22)
T category
 Ta*61 (24.2)68 (27.4)129 (25.8)
 T1168 (66.7)164 (66.1)332 (66.4)
 Tis primary8 (3.2)5 (2)13 (2.6)
 Tis Ta2 (0.8)3 (1.2)5 (1)
 Tis T113 (5.1)8 (3.2)21 (4.2)
G category
 G142 (16.7)44 (17.7)86 (17.2)
 G2150 (59.5)167 (67.3)317 (63.4)
 G360 (23.8)37 (14.9)97 (19.4)
PPD skin test
 < 1 cm185 (73.4)183 (73.8)367 (73.4)
 geqslant R: gt-or-equal, slanted 1 cm51 (20.2)56 (22.5)107 (21.4)

The first instillation was given 7–14 days after endoscopic treatment. The instillation was repeated once a week for six consecutive weeks and thereafter once every 2 weeks, six times more. In total, every patient should have received 12 instillations and the treatment completed within 5 months from the intervention. If there was a superficial recurrence or persistence of Tis before finishing the treatment, TURBT (or biopsy of Tis) was followed by the necessary instillations to complete the schedule.

The patients were withdrawn from the study at the first recurrence after completing treatment or, for Tis, when positive cytology persisted or reappeared after the 12 instillations. Subsequent treatment was at the discretion of the researcher but the patients were followed until the end of the study or death, and the treatments (cystectomy included) reported.

For papillary tumours the disease-free interval was defined as that between the initial endoscopic treatment and the date of the first positive biopsy. For Tis it was the interval between negative cytology or biopsies and the reappearance of positive cytology or biopsies. The time to progression was defined as the interval between the initial endoscopic treatment and the pathological confirmation of muscle invasion or, for Tis, extravesical extension; in those with no vesical recurrence, it was the interval to the appearance of regional or distant metastases. If a patient died before recurrence or progression it was not counted as an event, but if a patient recurred during treatment it was.

Quantitative data are described by the mean (sd) or median (range), and qualitative data as percentages. For quantitative data differences between the arms were tested using Student's t-test for unrelated samples and the qualitative data by the chi-square test. The disease-free interval (time to first recurrence), time to progression and overall survival were estimated by the Kaplan-Meier method, with the log-rank test used to compare arms. The log-rank test was stratified for the presence or absence of Tis and G3 to adjust for the imbalance in the frequency of Tis and G3 tumours between the arms. Stepwise multivariate Cox regression models were used to assess the independent effect of treatment adjusted by several variables. Two-sided tests were used and P < 0.05 considered to indicate statistical significance.

Results

  1. Top of page
  2. Abstract
  3. Introduction
  4. Patients and methods
  5. Results
  6. Discussion

Of the 500 patients enrolled in the study, 252 were allocated to the standard arm and 248 to the RD arm, but one of the patients in the latter arm was found to be ineligible. Recruitment began in February 1991 and was completed in June 1992. The mean (sd) number of instillations received by patients in the standard and RD arms was 11.14 (2.27) and 11.5 (1.75), respectively (P=0.0417); 431 patients (86.2%) received the 12 scheduled instillations (209 standard, 222 RD), with 46 (9.2%) receiving 6–11 (27 standard, 19 RD) and 22 receiving < 6 instillations (16 standard, six RD). As of April 2000 the median follow-up for the entire population was 69 months (maximum 109).

Altogether, recurrences were seen in 147 (29.4%) patients, i.e. 71 (28.1%) in the standard and 76 (30.7%) in the RD arm. The median time to recurrence has not yet been attained but the mean (sd) percentage of recurrence-free patients at 5 years was 70.53 (3.12) and 70.4 (3.1) for the standard and RD arms, respectively (Fig. 1a).

image

Figure 1. Kaplan-Meier curves for a, overall disease-free interval; b, overall time to progression and c, overall time to death (all causes) for the standard BCG dose (green dashed line) and the reduced dose (red solid line).

Download figure to PowerPoint

Overall, for the time to first recurrence, there was no significant difference in hazard ratio (HR) for patients in the RD arm (Table 2). To adjust for the imbalance in grade (G3) a second analysis, retrospectively stratified by G and Tis (Table 2) also showed no significant differences.

Table 2.  Time to event comparisons
End pointEvents/ patientsUnstratified HR (95% CI)PStratified for grade HR (95% CI)PStratified for Tis HR (95% CI)P
  1. HR, hazard ratio (RD relative to standard).

First recurrence
 Standard71/2521.09 1.11 1.09
 RD76/247(0.79–1.51)0.5864(0.80–1.54)0.5265(0.79–1.51)0.5810
Progression
 Standard29/2521.17 1.47 1.24
 RD33/247(0.71–1.93)0.5219(0.88–2.45)0.1326(0.75–2.06)0.3928
Death
 Standard51/2521.08 1.21 1.09
 RD55/247(0.74–1.58)0.6913(0.82–1.78)0.3329(0.75–1.61)0.6267

Subgroup analyses by age, disease status, size, grade and T category showed no differences; only when there were three or more existing tumours were there significantly fewer recurrences (P=0.03).

The disease-free interval was nearly significantly better for patients with G3 tumours in the standard arm (P=0.060) and there was a trend to longer disease-free survival in patients with T1G3 tumours and Tis in the standard arm.

Among the 367 patients (190 from the standard and 177 from the RD arm) considered at high-risk for recurrence and/or progression, because their tumour was either T1G3 or Tis, or relapsing often (geqslant R: gt-or-equal, slanted two previous relapses, independent of time) or multifocal (geqslant R: gt-or-equal, slanted 3) or large (geqslant R: gt-or-equal, slanted 3 cm), 56 (29.5%) of those treated with standard courses recurred, in contrast to 65 (36.7%) of those treated with RD, but the difference was not significant (P=0.14).

Progression

In 62 (12.4%) patients the tumour progressed, 29 (11.5%) in the standard and 33 (13.3%) in the RD arm. Progression to muscle-invasive disease alone occurred in 14 (5.5%) and 21 (8.5%) patients, respectively; distant metastases alone developed in seven (2.7%) and in four (1.6%) patients, respectively, and progression to both occurred in seven in each arm. In six of the patients who progressed to distant metastases the bladder remained free of recurrence (four standard and two RD). One patient in each arm with Tis had local extension into the prostatic ducts.

The median time to progression has not yet been attained, but the percentage of progression-free patients at 5 years was 88.8 (2.23) and 86.9 (2.31) for the standard and RD arms, respectively (Fig. 1b); the difference was not significant (P=0.52). Table 2 also summarizes the time-to-event comparisons for progression and death. There were no significant differences between the arms, but the respective HR was always higher for patients in the RD arm even when the results were stratified by G and Tis.

In all, 27 cystectomies (one partial) were undertaken, respectively 12 (5%) and 15 (6%) in the standard and RD arms. Five patients died after surgery (three and two, respectively); 12 (44%) are alive (four standard and eight RD) and eight (30%) progressed to death (four in each arm; one further patients in the standard arm died from cardiovascular illness but disease-free, and one RD patient was lost to follow-up).

Of the 62 progressing patients 13 (21.6%) are currently alive (one with disease), 33 (53.2%) died from their urothelial cancer, five (8%) died after surgery, three (5%) died from a new primary tumour, four (6.6%) from intercurrent illness and four (6.6%) were lost to follow-up. There were no statistically significant differences between the treatment arms for any of these factors.

Subgroup analyses by age, status of the tumour, size, T category and G category showed no generally significant differences in progression; only patients with three or more tumours fared significantly better in the standard than in the RD arm (P=0.043).

The differences in time to first progression of Tis were not significant but the HR was higher for RD patients (2.66, 95% CI 0.805–10.212). The HR for death was also higher for this group, and nearly significant (P=0.0513; 3.4, 0.99–11.65).

In the group of high-risk tumours (190 standard, 177 RD), the rate of progression to > T1 was similar for both arms, with 28 (14.7%) and 29 (16.4%) in the respective arms (P=0.663).

Survival analysis

The percentage of surviving patients (any cause) at 5 years was 84.25 (2.5) in the standard and 80.57 (2.67) in the RD arms; cause-specific survival at 5 years was 94.03 (1.62) and 93.01, respectively. There were no differences between the arms either in any-cause mortality (Fig. 1c) or in cause-specific mortality. Currently, 106 (21.2%) patients have died, 70 (14%) are lost to follow-up and 323 (64.6%) are still being followed. Table 3 summarizes the cause of death; overall, 38 (7.6%) patients died from their bladder cancer. Specifically, 20 (4%) deaths were caused by a second new tumour (12 standard and eight RD). The most frequent new primaries were lung cancer (seven) bronchogenic cancer (three) and gastric cancer (three).

Table 3.  Causes of death
Cause of death, n (%)StandardRDTotal
No. of patients252247499
Disease specific20 (7.9)18 (7.3)38 (7.6)
Cardiovascular11 (4.4)22 (8.9)33 (6.6)
Infection1 (0.4)01 (0.2)
Comorbidity2 (0.8)6 (2.4)8 (1.6)
New tumour12 (4.7)8 (3.2)20 (4)
Other5 (2)1 (0.4)6 (1.2)
Total51 (20.2)55 (22.3)106 (21.2)

Age (leqslant R: less-than-or-eq, slant 65 years or  > 65 years) had no influence on the survival time, nor did other variables except multifocality. In the subgroup of patients who had three or more tumours there was a trend towards better cause-specific survival in those in the standard arm (P=0.196), but in general neither the number of previous recurrences, the size, T category or grade had any influence on the efficacy of both doses in terms of duration of survival. The number of instillations influenced the rate of cause-specific deaths, with a statistically significant difference in favour of patients receiving the complete treatment (P=0.018). The same significant benefit occurred for to disease-free interval and progression (P=0.02).

Univariate and multivariate analysis

Although not an endpoint of the study, a stepwise Cox proportional hazards regression univariate and multivariate analysis was conducted to evaluate the relative importance of individual factors for response (Table 4). In the univariate analysis the risk of recurrence was significantly greater for patients with frequently recurrent tumours (P < 0.001) or with multifocal tumours (P=0.0045), or with a high-risk tumour (P=0.007). For progression, the significant factors were T stage (P=0.0491), grade (P < 0.001) and tumour in the high-risk group (P=0.0017).

Table 4.  Recurrence-free interval and time to progression (Cox models) by univariate and multivariate analyses
VariablesRecurrence-free intervalTime to progression
Univariate (unadjusted) HR (95% CI) [P]Multivariate (adjusted) HR (95% CI) [P]Univariate (unadjusted) HR (95% CI) [P]Multivariate (adjusted) HR (95% CI) [P]
  1. HR, hazard ratio; NS, not significant.

Age[0.642]NSNS
leqslant R: less-than-or-eq, slant 651 1
> 651.36 (0.98–1.88) 1.61 (0.27–2.67)
No. recurrences[< 0.001][< 0.001]NS[0.0187]
< 21111
geqslant R: gt-or-equal, slanted 22.4 (1.69–3.04)2.26 (1.58–3.22)1.57 (0.89–2.77)2 (1.12–3.59)
No. tumours[0.0045][0.034]NS
< 3111
geqslant R: gt-or-equal, slanted 31.7 (1.18–2.47)1.5 (1.03–2.18)0.85 (0.43–1.08)
SizeNSNSNS
< 31 1
geqslant R: gt-or-equal, slanted 30.91 (0.65–1.26) 1.23 (0.75–2.04)
T categoryNSNS[0.0491]
Ta1 1
T10.94 (0.65–1.35) 2.34 (1.15–4.79)
Tis only0.77 (0.28–2.16) 3.13 (0.34–11.59)
G categoryNSNS[< 0.001][< 0.001]
G11 11
G21.02 (0.65–1.58) 1.31 (0.54–3.18)1.44 (0.59–3.52)
G31.26 (0.75–2.11) 4.96 (2.05–11.95)5.82 (2.38–14.22)
TisNSNS[0.0053]
No1 1
Yes1.21 (0.68–2.14) 2.62 (1.33–5.16)
High-risk tumour[0.0072]NS[0.0017]
No1 1
Yes1.78 (1.17–2.73) 4.31 (1.73–10.77)
BCG dosesNSNSNS
Standard1 1
RD1.09 (0.79–1.51) 1.18 (0.71–1.94)

In the multivariate analysis the most important factor for disease recurrence was frequently recurrent tumour, independent of the period (P < 0.001) and multifocality (P=0.034), while the variables affecting progression were also two or more previous occurrences (P=0.0187), and grade of malignancy (P < 0.001).

Side-effects

Toxicity data were available for all the patients (252 standard and 247 RD) all of whom had received 1–12 instillations. The proportion of patients with no toxicity, either local or systemic, was significantly higher in the RD than in the standard arm; similarly the number of patients withdrawn from the study for excessive toxicity and the number of instillations postponed for the same reason was lower in the RD arm (Table 5). Local toxicity grades 1–2 (light-mild), needing none or only anti-inflammatory therapy, was similar in both arms (Table 5); conversely, local toxicity grade 3–4 was significantly more frequent in the standard arm (P < 0.001). (Grade 3 toxicity was severe cystitis requiring therapy with isoniazid, NSAIDs, anticholinergics and postponement of the next instillation or dose reduction; grade 4 was repeated grade 3 side-effects despite therapy, requiring withdrawal from the study). When each local side-effect was analysed separately, severe toxicity grades were significantly more frequent in the standard arm, except for loss of bladder capacity. Bladder retraction occurred in four patients (0.8%), three standard and one RD, and slightly reduced bladder capacity in five (1%) additional cases (two standard and three RD). Urethral strictures were detected in five (1%) patients, all in the standard arm; most likely, repeat TURBTs (in one patient, 10) and repeat urethral injury by catheters were at least as important as BCG in the development of the strictures.

Table 5.  Side-effects categorized as local or systemic toxicity
Patients, n (%)StandardRD
Local SystemicLocal Systemic
  1. P value, linear trend (no toxicity, toxicity grades 1–2, toxicity grades 3–4), local <0.001, systemic 0.001

With no toxicity84 (33.3) 172 (68.3)112 (45.3) 209 (84.6)
With toxicity
 Grades 1–2124 (49.2) 71 (28.2)119 (48.2) 27 (10.9)
 Grades 3–444 (17.5) 9 (3.6)16 (6.5) 11 (4.4)
Withdrawn from study 23 (9.1)  10 (4)
Instillations delayed 37 (16.8)  22 (8.8)

The differences in severe systemic toxicity were not significant; indeed 4.4% of the patients in the RD arm had severe systemic side-effects, similar to the 3.6% in the standard arm. High fever (> 39 °C) and severe malaise appeared with similar frequency in both arms, but pulmonary ‘BCGitis’ was slightly more frequent in the standard arm (six, four severe) than the one in the RD arm, but not significantly so (P=0.06). Neither life-threatening episodes nor sepsis were reported for either arm. One patient in the RD arm had a necrotizing granulomatous epididymitis and simultaneous polyneuropathy with axonal demyelinization, not previously reported, but whether it was caused by BCG is unclear.

Discussion

  1. Top of page
  2. Abstract
  3. Introduction
  4. Patients and methods
  5. Results
  6. Discussion

The main finding of the present study is the similar efficacy of both BCG doses in preventing recurrences and/or progression. The overall proportion of patients with a recurrence for the standard and RD arms was 28.1% and 30.7%, respectively. The percentage of progressions was, respectively, 11.1% and 12.9%, and there were no differences in time to progression or in the overall survival.

Subgroup analyses suggested that the standard dose was significantly more effective against recurrences and progression in patients with multifocal (geqslant R: gt-or-equal, slanted 3) tumours, but we are cautious about the significance of this finding, because if enough subgroups are analysed then eventually at least one will be found where the difference is significant by chance. Moreover, the power to detect differences in any one subgroup is low, because there are then few patients [6].

Poorly differentiated tumours also recurred less when treated with the standard dose, but the benefit was marginal (P=0.060) and retrospective stratification by grade to adjust for the imbalance in the two treatment groups did not reveal significant differences in either time to progression or in overall survival. Nevertheless, an insignificant difference does not imply that the two treatments have equivalent efficacy; the CIs provide the best indication of the sizes of treatment differences. Thus, Table 2 shows that the risk of progression is 17% higher for RD (HR 1.17) and the 95% CI (0.71–1.93) is consistent with the risk of progression being as much as 93% higher with the RD.

The present results do not agree with those of other studies assessing low BCG doses. Bassi et al.[7] reported the definitive results of the only phase III study conducted so far. The trial showed similar or improved responses for disease-free survival and progression for each T stage in the low-dose arm (75 mg) and significantly less toxicity than the standard dose (150 mg). The present study had similar findings for toxicity and overall efficacy, but not in the subgroup analysis for diverse variables; there was a trend to better efficacy for the standard dose in multifocal tumours and in frequently recurrent, poorly differentiated and T1 tumours. These trials, which include populations with different characteristics, different schedules and dosage, and different BCG strains, are difficult to compare. Pasteur BCG was (it is no longer manufactured) a highly potent fresh preparation containing 5×108 viable bacilli in the 75 mg dose, which cannot be considered a low dose, as it is equivalent to the standard Tice dose of 50 mg. It is also likely that the 2-year maintenance programme of Bassi et al. may have influenced their results, in view of the recent data from another trial [8]. The report by Bassi et al.[7] lacks important details, e.g. the number of tumours by T category and the grade of malignancy. In addition, there were 210 evaluable patients, considered too few (by current standards) to detect differences in progression.

A unrandomized study by Morales et al.[9] indicated that large doses are necessary if a short course of treatment is considered; 97 patients were sequentially assigned to receive either 60 mg or 120 mg BCG (Armand Frapier strain) intravesically for 6 weeks. The overall results at a mean of 21 months suggested that high doses are necessary to eradicate carcinoma in situ, but there were too few patients to draw a firm conclusion.

In another unrandomized study, Takashi et al.[10] used the Tokyo 72 strain at 80 mg (4.8 × 109 c.f.u.) and 40 mg. Very few of the tumours were poorly differentiated (eight), with most being G2. The recurrence-free Kaplan-Meier curves suggested a significantly shorter interval for recurrent tumours when treated with 40 mg (P=0.03). The degree of toxicity was significantly lower with the 40 mg dose.

Also conflicting are the results of six unrandomized phase II studies with low-dose BCG in high-risk tumours. Three used short courses of six weekly instillations [11–13], whilst the other three added a 12-month maintenance therapy [14–16]. The former yielded recurrence rates of 26–47% and progression rates of 9–25%; the latter studies, using maintenance therapy, gave recurrence rates of 16–23% and progression rates of 0–13.7%. Thus maintenance seems to be crucial in obtaining a benefit from low doses and the number of instillations is an important factor. However, the only study to date to confirm the value of maintenance BCG is that of the South-west Oncology Group [8], which used an entirely different schedule, with three weekly standard dose instillations at 3, 6, 12, 18, 24, 30 and 36 months. The discrepancy between the present results and the Italian trial [7] might be a consequence of the 2-year monthly maintenance therapy used in the latter. In the present study the efficacy was better when all 12 instillations (six weekly plus six fortnightly) were completed. It might be argued that although there is a correlation between the number of instillations and the treatment outcome, a cause and effect cannot be confirmed, i.e. patients receiving the full treatment survive longer. To confirm that complete treatment influences outcome the results were analysed after omitting the 16 patients who died before the end of 12 instillations (all deaths being not specific); there was then a significant difference (P < 0.001).

Interesting results were reported from Chile using only 1 mg BCG (16×106 c.f.u.); Rivera et al.[17] published results from 67 patients followed up for a median of 51.3 months. Most (67%) had T1G2 tumours and only 15 (22%) were T1G3. Seventeen (25%) patients developed recurrences, and in two (3%) the tumour progressed and one (1.5%) died after refusing radical surgery. During the study, the population of T lymphocytes and lymphokines was assessed in blood samples, showing a significant increase in the CD3 and CD4/CD8 subpopulations, and an increase in the interleukin-2 levels, but no variations in interleukin-6 and -8, or γ-interferon and TNF [18].

The Chilean experience with 1 mg intravesical BCG highlights the ignorance about the optimal dose per instillation; their results do not agree with those in the present study and from other low-dose trials [7,9]. However, the series was not randomized, and comprised relatively few patients and poorly defined groups, but the data are intriguing. For the results of Rivera et al.[17] the explanation may be the high sensitivity of the Chilean population to BCG; every neonate is vaccinated with BCG, receives a second dose at 10 years old and there is chronic contact with the bacillus because of the high incidence of pulmonary tuberculosis in Chile (28.9 per 100 000 inhabitants).

As such low-dose therapy was felt to warrant a randomized study, the CUETO Group began another trial in 1995 (95011) to compare low- and intermediate-risk tumours treated with 13.5 mg BCG (Connaught strain), 27 mg BCG or mitomycin C (30 mg); the interim analysis at 20 months medium follow-up [19] showed better efficacy for both BCG doses against recurrences (P=0.055) and a longer disease-free interval in patients treated with BCG (P=0.046). Local and systemic toxicity was significantly higher in both BCG groups than with mitomycin C but there were no differences between the BCG arms. Although provisional, the results seem to agree with those of Rivera et al.[17] for the efficacy of very low-dose BCG in the short term. In addition, de Boer et al.[20] showed in an animal model of superficial TCC that although many BCG bacilli are instilled into the bladder, the immune response seems to require very few bacteria; after an instillation into the Guinea pig bladder there were < 40 BCG bacteria/bladder but which nevertheless induced a local immune response.

However, numerous animal studies assessing the inhibitory effect of BCG on tumours in rats, mice, hamsters and Guinea pigs have established that doses of 106–108 c.f.u. are needed for antitumour activity [21] and Böhle et al.[22] reported that an optimal dose/response to generate BCG-activated killer cells in vitro was 3.5×105 c.f.u. of BCG/105 effector cells. Thus not only does the exact mode of the antitumour action of BCG remain to be defined, but the optimal dosage and schedule of BCG therapy remains unclear, despite more than 20 years of use.

The most prevalent side-effect of intravesical BCG is irritative voiding symptoms, which occur in up to 85% of patients, associated with ‘flu-like symptoms, which include low-grade fever (< 38 °C) and malaise. These symptoms usually last for 24–48 h and are relieved with (if necessary) NSAIDs or antipyretics. More serious local side-effects may occur in up to a third of patients and include urgency, pain, cramping, haematuria and passing of debris in the urine. Long-term local adverse outcomes include bladder contracture, which occurs in ≈3% of patients.

Severe systemic symptoms are more threatening, including high fever, chills, arthralgia, hepatic dysfunction, myelosuppression and infectious complications, e.g. pneumonitis, hepatitis, epididymitis, prostatitis, urethritis and sepsis. The estimated probability of treatment complications after standard-dose instillations, reported by the AUA Bladder Cancer Clinical Guidelines Panel [23], is higher than that reported from series using low-dose instillations.

In the present study there were significantly more patients with no toxicity, either local or systemic, in the RD arm, and they had significantly fewer side-effects. Also, fewer patients from RD arm were withdrawn from the trial for excessive toxicity (4% vs 9%, P=0.027). The probability estimate (95% CI) of treatment interruption reported previously [23] is 7 (5–11)%, and higher than the present 4% in the RD group. The incidence of bladder retraction in the RD arm was 0.4%; the previous probability estimate [23] was 5 (2–5)%. Also, the present rate of overall systemic side-effects in the RD arm was lower than that reported previously [23], at 15.4% and 23 (19–27)%, respectively. Nevertheless, there is no consensus about a direct relationship between dosage and toxicity, but some contend that the schedule and number of instillations are the most important [24]. Analysing those patients discontinuing the study for excessive toxicity, 63% in each arm were withdrawn when fewer than five instillations had been administered, which means that adverse reactions occur more often and more severely within the first weekly induction courses than within fortnightly courses, and that the interval between each instillation is important for toxicity. Bassi et al.[25], testing a modified induction course with a standard dose, but with an instillation interval of 2 weeks, showed a reduction in the proportion of side-effects and no delay or interruption of scheduled treatment because of toxicity. Another approach would be to have fewer induction instillations; for > 20 years the induction schedule included six weekly instillations, and the rationale for this regimen (proposed empirically by Morales) was that the BCG was then manufactured in six ampoules per package! Zlotta et al.[26] showed that in most patients the maximal peripheral immune response is already apparent after four weekly instillations (and returns to pre-BCG values at 6 months of follow-up) but patients not previously immunised against mycobacterial antigen require six instillations to achieve the maximum stimulation. Böhle et al.[22] also found in a recent clinical cooperative project that the maximum BCG-activated killer activity was apparent after the fourth instillation. Determining prospectively whether six weekly BCG-instillations are really necessary in patients previously immune against the mycobacteria would be of interest; a 3- or 4-week initial BCG regimen might reduce the side-effects without reducing (or even increasing) its efficacy.

In conclusion, a three-fold reduction in the standard BCG dose per instillation is as effective as the standard dose. Although subgroup analysis showed a trend towards better efficacy of the standard dose against recurrence of multifocal tumours and high-grade and -stage (T1,Tis) tumours, the relatively scarcity and imbalance in G3 tumours between the treatment arms diminishes the significance of this finding. There was a greater proportion of progression only when the patients received an incomplete treatment (< 12 instillations). Side-effects were significantly less frequent or severe when the RD was used but toxicity remained a concern. The ideal dose of BCG has not yet been determined but it may require modification depending on the factors that predict potential biological aggressiveness and according to individual tolerance. Currently, we propose using the standard dose for inducing all high-risk tumours and the RD for intermediate-risk tumours and all maintenance schedules.

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Abbreviations
CUETO

Club Urológico Espan˜ol de Tratamiento Oncológico

RD

reduced dose

HR

hazard ratio.

J.A. Martı´nez-Pin˜eiro, Avenida San Luis 95, 28033 Madrid, Spain. e-mail: mpineiro@pulso.com or mpineiro@telefonica.net