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Tice

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Tice

CLINICAL PHARMACOLOGY

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 carcinoma in 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
n = 54
1987/CRNC
n = 36
1987 Response
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

  N = 117 N = 134 N = 136
Estimated Disease-Free Survival at 2 years 95% Confidence Interval (CI) 53% (44%, 64%) 62% (53%, 72%) 64% (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 reviewed on RxList: 8/18/2014
This monograph has been modified to include the generic and brand name in many instances.

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