TICE® BCG induces a granulomatous reaction at the local site of administration.
Intravesical TICE® BCG has been used as a therapy for, and prophylaxis against,
recurrent tumors in patients with carcinomain situ (CIS) of the urinary
bladder, and to prevent recurrence of Stage TaT1 papillary tumors of the bladder
at high risk of recurrence. The precise mechanism of action is unknown.
Clinical Studies
To evaluate the efficacy of intravesical administration of TICE® BCG in
the treatment of carcinoma in situ, patients were identified who had
been treated with TICE® BCG under six different Investigational New Drug
(IND) applications in which the most important shared aspect was the use of
an induction plus maintenance schedule. Patients received TICE® BCG (50
mg; 1 to 8 x 108 CFU) intravesically, once weekly for at least 6
weeks and once monthly thereafter for up to 12 months. A longer maintenance
was given in some cases. The study population consisted of 153 patients, 132
males, 19 females, and 2 unidentified as to gender. Thirty patients lacking
baseline documentation of CIS and four patients lost to follow-up were not evaluable
for treatment response. Therefore, 119 patients were available for efficacy
evaluation. The mean age was 69 years (range: 38–97 years). There were two categories
of clinical response: (1) Complete Histological Response (CR), defined as complete
resolution of carcinoma in situ documented by cystoscopy and cytology,
with or without biopsy; and (2) Complete Clinical Response Without Cytology
(CRNC), defined as an apparent complete disappearance of tumor upon cystoscopy.
The results of a 1987 analysis of the evaluable patients are shown in Table
I.
TABLE I: THE RESPONSE OF PATIENTS WITH CIS BLADDER CANCER
IN SIX IND STUDIES
| |
Entered |
Evaluable |
CR |
CRNC |
Overall Response |
| No. (%) Of Patients |
153 |
119 (78%) |
54 (46%) |
36 (30%) |
90 (76%) |
A 1989 update of these data is presented in Table II. The median duration of
follow-up was 47 months.
TABLE II: FOLLOW-UP RESPONSE OF PATIENTS WITH CIS BLADDER
CANCER IN SIX IND STUDIES
| Response |
1989 Status of 90 Responders (CR or CRNC) |
| 1987/CR |
1987/CRNC |
1987 Response |
|
| n = 54 |
n = 36 |
n = 90 |
Percent |
| CR |
30 |
15 |
45 |
50 |
| CRNC |
0 |
0 |
0 |
0 |
| Unrelated Deaths |
6 |
6 |
12 |
13 |
| Failure |
18 |
15 |
33 |
37 |
There was no significant difference in response rates between patients with
or without prior intravesical chemotherapy. The median duration of response,
calculated from the Kaplan-Meier curve as median time to recurrence, is estimated
at 4 years or greater. The incidence of cystectomy for 90 patients who achieved
a complete response (CR or CRNC) was 11%. The median time to cystectomy in patients
who achieved a complete response (CR or CRNC) exceeded 74 months.
The efficacy of intravesical TICE® BCG in preventing the recurrence of
a TaT1 bladder cancer after complete transurethral resection of all papillary
tumors was evaluated in two open-label randomized phase III clinical trials.
Initial diagnosis of patients included in the studies was determined by cystoscopic
biopsies. One was conducted by the Southwestern Oncology Group (SWOG) in patients
at high risk of recurrence. High risk was defined as two occurrences of tumor
within 56 weeks, any stage T1 tumor, or three or more tumors presenting simultaneously.
The second study was conducted at the Nijmegen University Hospital; Nijmegen,
The Netherlands. In this study patients were not selected for high risk of recurrence.
In both studies treatment was initiated between 1 and 2 weeks after TUR.
In the SWOG trial (study 8795) patients were randomized to TICE® BCG or
mitomycin C (MMC). Both drugs were given intravesically weekly for 6 weeks,
at 8 and 12 weeks, and then monthly for a total treatment duration of 1 year.
Cystoscopy and urinary cytology were performed every 3 months for 2 years. Patients
with progressive disease or residual or recurrent disease at or after the 6
month follow-up were removed from the study and were classified as treatment
failures.
A total of 469 patients was entered into the study: 237 to the TICE® BCG
arm and 232 to the MMC arm. Twenty-two patients were subsequently found to be
ineligible, and 66 patients had concurrent CIS, and were analyzed separately.
Four patients were lost to follow-up, leaving 191 evaluable patients in the
TICE® BCG arm and 186 in the MMC arm. Of the patients, 84% were male and
16% were female. The average age of these patients was 65 years old.
The Kaplan-Meier estimates of 2 year disease-free survival are shown in Table
III. The difference in disease-free survival time between the two groups was
statistically significant by the log rank test (p=0.03). The 95% confidence
interval of the difference in 2 year disease-free survival was 12% ±
10%. No statistically significant differences between the groups were noted
in time to tumor progression, tumor invasion, or overall survival.
TABLE III: RESULTS OF SWOG STUDY 8795
| |
TICE® BCG Arm
N = 191 |
MMC Arm
N = 186 |
| Estimated Disease-Free Survival at 2 years |
57% |
45% |
| 95% Confidence Interval (CI) |
(50%, 65%) |
(38%, 53%) |
In the Nijmegen study, the efficacy of three treatments was compared: TICE
substrain BCG, Rijksinstituut voor Volksgezondheid en Milieuhygiene substrain
BCG (BCG-RIVM), and MMC.
TICE® BCG and BCG-RIVM were given intravesically weekly for 6 weeks. In
contrast to the SWOG study, maintenance BCG was not given. Mitomycin C was given
intravesically weekly for 4 weeks and then monthly for a total duration of treatment
of 6 months. Cystoscopy and urinary cytology were performed every 3 months until
recurrence.
A total of 469 patients was enrolled and randomized. Thirty-two patients were
not evaluable, 17 were ineligible, 15 were withdrawn before treatment, and 50
had concurrent CIS and were analyzed separately, leaving 387 evaluable patients:
117 in the TICE® BCG arm, 134 in the BCG-RIVM arm, and 136 in the MMC arm.
Twenty-eight patients (24%) in the TICE® BCG arm, 32 patients (24%) in the
BCG-RIVM arm and 24 patients (18%) in the MMC arm had TaG1 tumors. The median
duration of follow-up was 22 months (range 3–54 months).
The Kaplan-Meier estimates of 2 year disease-free survival are shown in Table
IV. The differences in disease-free survival among the three arms were not statistically
significant by the log-rank test (p=0.08).
TABLE IV: RESULTS OF NIJMEGEN STUDY
| |
TICE® BCG Arm
N = 117 |
BCG-RIVM Arm
N = 134 |
MMC Arm
N = 136 |
| Estimated Disease-Free Survival at 2 years |
53% |
62% |
64% |
| 95% Confidence Interval (CI) |
(44%, 64%) |
(53%, 72%) |
(55%, 74%) |
In both the SWOG 8795 study and the Nijmegen study, acute toxicity was more
common, and usually more severe, with TICE® BCG than with MMC (see ADVERSE
REACTIONS).
Last updated on RxList: 11/17/2008