Jpn J Clin Oncol 2003;33(8)382–390
A Clinical Study of PMCJ-9 (Bacillus Calmette–Guérin Connaught
Strain) Treatment of Superficial Bladder Cancer and Carcinoma In
Situ of the Bladder
Hideyuki Akaza1, Kenkichi Koiso1,2, Seiichiro Ozono3, Masao Kuroda4, Shuji Kameyama5, Eigoro Okajima3,
Toshihiko Kotake4, Tadao Kakizoe6, Kazuki Kawabe7 and the PMCJ-9 Study Group in Japan
1Department
of Urology, Institute of Clinical Medicine, University of Tsukuba, Tsukuba, Ibaraki, 2Senpo Tokyo
Takanawa Hospital, Tokyo, 3Department of Urology, Nara Medical University, School of Medicine, Kashihara, Nara,
4Department of Urology, Osaka Medical Center for Cancer and Cardiovascular Diseases, Osaka, 5Department of
Urology, Kanto Medical Center, NTT EC, Tokyo, 6Department of Urology, National Cancer Center Hospital, Tokyo
and 7Department of Urology, Faculty of Medicine, University of Tokyo, Tokyo, Japan
Received January 28, 2003; accepted July 18, 2003
Background: Intravesical Bacillus Calmette–Guérin (BCG) is now a standard treatment for Ta,
T1 carcinoma and carcinoma in situ (CIS) of the urinary bladder. In Japan, however, only BCG
Tokyo 172 strain is commercially available. We therefore designed a clinical study of PMCJ-9
(BCG Connaught strain) for obtaining approval from Japanese Ministry of Health, Labor and
Welfare.
Methods: In the phase I–II study, PMCJ-9 40.5, 81 (standard dose overseas) or 121.5 mg in
saline was instilled into the bladder of patients with Ta, T1 or CIS once weekly for 8 weeks. The
recommended dose was decided and similarly administered in the late phase II study.
Results: In the phase I–II study, 49 patients were evaluable for efficacy. The complete
response (CR) rates were 60.0% (9/15), 68.2% (15/22) and 75.0% (9/12) in the 40.5, 81 and
121.5 mg groups. The incidence of adverse drug reactions (ADRs) was similar in all groups, but
four 121.5 mg group patients developed severe ADRs. Thus, 81 mg was the recommended
dose for the late phase II study. In that study, 39 patients were evaluable, showing CR rates of
71.8% (28/39) overall and 61.5% (16/26) and 92.3% (12/13) for the Ta, T1 and CIS cases. The
safety was assessed in 42 patients and three (7.1%) were discontinued owing to ADRs.
Conclusion: The recommended dose for the BCG Connaught strain was decided as 81 mg.
PMCJ-9 administration at this dose level weekly for 8 weeks showed a clear antitumor effect
and good safety profile against Ta, T1 and CIS transitional cell carcinoma of the bladder.
Key words: BCG – Ta, T1 – CIS – bladder cancer – immunotherapy – intravesical therapy
INTRODUCTION
PMCJ-9 is the Bacillus Calmette–Guérin (BCG) Connaught
strain, which is used in the treatment of bladder cancer. Intravesical instillation of BCG is considered to be the most effective immunotherapy now available for Ta, T1 and carcinoma in
situ (CIS) transitional cell carcinoma of the bladder (1–3). In
the USA, the Southwest Oncology Group (SWOG) carried out
a randomized comparative study of doxorubicin hydrochloride
intravesical instillation, a standard therapy and the BCG Connaught strain in high-risk Ta, T1 and CIS bladder cancer
patients (4). The results of that study showed that BCG intra-
For reprints and all correspondence: Hideyuki Akaza, Department of Urology,
Institute of Clinical Medicine, University of Tsukuba, 1-1-1 Tennoudai,
Tsukuba, Ibaraki 305-0006, Japan. E-mail: [email protected]
vesical instillation was superior in terms of the recurrence-free
survival after transurethral bladder resection (TUR-Bt) of Ta,
T1 disease and the antitumor effect and the recurrence-free survival in CIS cases. BCG Connaught strain has been approved
in Europe and the USA on the basis of those clinical study
results.
There have not been many reports on the direct effect of
BCG intravesical instillation in reducing the size of tumors in
the case of Ta, T1 bladder carcinoma. A clinical study carried
out by the present authors using the Tokyo 172 strain represents the largest study reported so far (5). In addition, even
outside Japan, there has been no study on the direct tumorshrinking effect of the BCG Connaught strain on Ta, T1
bladder carcinoma. Moreover, no phase I clinical studies or
dose-finding studies have been carried out on PMCJ-9. With
this background, a multi-institutional phase I–II study and a
© 2003 Foundation for Promotion of Cancer Research
Jpn J Clin Oncol 2003;33(8)
383
PATIENT ENROLMENT
formed once per week, for a total of eight instillations. PMCJ9 administration was started at least 1 week after biopsy or
TUR-Bt. When gross hematuria was present, the PMCJ-9
administration was postponed until it had resolved.
The lowest dose of PMCJ-9, i.e., 40.5 mg, was selected on
the basis of its being half the standard dose used in Europe and
the USA. After the safety of the starting dose (40.5 mg) had
been confirmed, patients were enrolled in higher dosage
groups. For Ta, T1 patients, the target number of patients was
10 for each of the 40.5–121.5 mg dosage groups. CIS patients
are even less common than Ta, T1 patients and for this reason
no targets were defined for the number of CIS patients in each
dosage group. The decision regarding dose escalation was
carried out after receiving a review from the Efficacy and
Safety Evaluation Committee.
PHASE I–II STUDY
LATE PHASE II STUDY
The patients enrolled in the phase I–II clinical study had histologically confirmed recurrent or multiple transitional cell
carcinoma (Ta, T1) or primary or recurrent carcinoma in situ
(CIS) of the bladder. For the Ta, T1 cases, it was necessary for
there to be at least one measurable or evaluable lesion as
revealed by cystoscopy, with the largest tumor diameter being
£2 cm. For the CIS cases, it was necessary for the urinary
cytology to be positive and for biopsy to confirm CIS. In addition, the patients satisfied the following inclusion criteria: (1)
age between 20 and 74 years, (2) no previous BCG intravesical
therapy and no carry-over effects of previous anticancer drug
chemotherapy, etc., (3) sufficient function of the major organs
(i.e. bone marrow, liver, kidneys, heart and lungs) (WBC count,
4000–8000/mm3; platelet count, ³10 ´ 104/mm3; hemoglobin,
³9.5 g/dl; GOT, GPT: <two-fold the upper limit of normal;
serum total bilirubin, £2 mg/dl; BUN, £25 mg/dl; and serum
creatinine, £1.5 mg/dl) and (4) performance status (PS) of 0–2.
The exclusion criteria were as follows: (1) primary and single
Ta, T1, (2) T2 or more advanced invasive carcinoma or a history thereof, (3) presence of a complication of a malignant
tumor of the upper urinary tract or urethra or a history thereof
(however, patients with CIS of the prostatic urethra were not
excluded), (4) presence of lymph node metastasis or metastasis
in other organs, (5) current history of other neoplasms, (6) a
history of serious hypersensitivity, (7) a history of having
undergone therapy having an immunosuppressive effect, such
as chemotherapy or radiotherapy, within the most recent 4
weeks, (8) presence of active tuberculosis, currently undergoing anti-tuberculosis therapy, (9) extremely small bladder volume, (10) pregnancy, lactation or the possibility of pregnancy
and (11) any other serious complications.
The investigators registered each patient who satisfied all of
the above inclusion and exclusion criteria with a central registration center. The designated amount of 40.5, 81 or 121.5 mg
was suspended in 40 ml of physiological saline and then
instilled into the bladder through a urethral catheter. This BCG
suspension was to be retained in the bladder for 2 hours whenever possible and then voided. This administration was per-
The inclusion criteria for this late phase II study were the same
as for the phase I–II study, except that the upper age limit for
inclusion was increased to 79 years and the acceptable baseline
WBC count range was changed to 3300–10 000/mm3. In addition, a history of drug allergy and a strongly positive tuberculin
reaction were added to the exclusion criteria. The PMCJ-9
dose was 81 mg, which was intravesically instilled once per
week, to a total of eight instillations.
late phase II study were conducted in Japan from October 1994
to March 2000 with the objectives of investigating the direct
tumor-shrinking effect and safety of the BCG Connaught strain
in Ta, T1 bladder carcinoma and CIS.
PATIENTS AND METHODS
The study protocols for these clinical studies were approved by
the institutional review board of each participating institution.
In addition, for each patient, the study procedures were initiated
after written informed consent had been obtained and the study
was conducted in compliance with Japanese Good Clinical
Practice (GCP) (6,7).
ANTITUMOR EFFECTS
In both the phase I–II study and the late phase II study, the
primary efficacy assessment endpoints were the complete
response (CR) rate and the response rate (CR + PR rate). Antitumor effects were judged in accordance with the Japanese
Urological Association’s General Rules for Clinical and Pathological Studies on Bladder Cancer (2nd edition) (8). Patients
who received at least four PMCJ-9 intravesical instillations
were included in the efficacy analysis and the evaluation of the
antitumor effects was performed 4 weeks after the final instillation. Ta, T1: CR = complete disappearance of tumors; PR= at
least 50% reduction in the size of tumors or at least 60%
reduction in the number of multiple tumors having a long
diameter of £1 cm; NC = <50% reduction or <25% increase in
size of tumors; PD = progressive disease, as evidenced by at
least a 25% increase in size of tumors or development of new
lesions. CIS: CR = the urinary cytological diagnosis becomes
negative and biopsy finds no cancer (even in the case of not
performing a biopsy, CR is diagnosed if the urinary cytology is
negative in three consecutive inspections); NC = the urinary
cytological diagnosis is positive or false-positive or biopsy
finds cancer; PD = cystoscopy reveals tumor formation or
biopsy finds invasive cancer.
SAFETY EVALUATION
In the phase I–II study, evaluation of adverse drug reactions
(ADRs) was performed in accordance with the Japan Society
for Cancer Therapy’s Criteria for the Evaluation of the Clinical
384
Clinical study of PMCJ-9
Table 1. Patients’ characteristics in phase I–II study
Characteristic
No. of patients
Total
40.5 mg group
81 mg group
121.5 mg group
Entered
51
15
22
14
Eligible
51
15
22
14
Evaluable
49
15
22
12
Ta
13
6
5
2
T1
13
4
5
4
CIS
23
5
12
6
Male
40
13
16
11
Female
9
2
6
1
Tumor stage:
Gender:
Age (years): median (range)
62 (38–75)
65 (50–75)
62.5 (38–74)
60.5 (44–74)
Weight (kg): median (range)
60.8 (42.2–93.0)
59.0 (42.2–72.2)
59.9 (43.6–93.0)
64.4 (51.0–73.0)
0
45
14
19
12
1
4
1
3
Performance status:
Prior therapy:
None
13
5
5
3
Done
36
10
17
9
TUR
19
7
7
5
Chemotherapy
1
TUR + chemotherapy
16
1
3
10
3
Primary or recurrent
Primary
20
6
8
6
Recurrent
29
9
14
6
1
2
Tuberculin reaction (before treatment):
–
3
±
10
3
5
2
+
28
7
14
7
++
6
4
2
+++
1
Unknown
1
1
G1
7
3
3
1
G2
26
8
13
5
G3
15
4
5
6
GX
1
1
Tumor grade:
1
Maximum tumor length (cm):
<1
11
4
4
3
1–2
15
6
6
3
1–4
16
7
4
5
5–10
4
2
2
³11
6
1
4
Number of tumors:
1
Jpn J Clin Oncol 2003;33(8)
385
Table 2. Tumor response in phase I–II study
Dosage group (mg)
Stage
Evaluated cases
CR
PR
NC
PD
CR rate (95% CI, %)
³PR rate (%) (95% CI, %)
40.5
Ta,T1
10
7
3
0
0
70.0 (34.8–93.3)
100.0 (69.2–100)
81
121.5
Overall
CIS
5
2
–
3
0
40.0 (5.3–85.3)
40.0 (5.3–85.3)
Sub-total
15
9
3
3
0
60.0 (32.3–83.7)
80.0 (51.9–95.7)
Ta,T1
10
5
2
2
1
50.0 (18.7–81.3)
70.0 (34.8–93.3)
CIS
12
10
–
1
1
83.3 (51.6–97.9)
83.3 (51.6–97.9)
Sub-total
22
15
2
3
2
68.2 (45.1–86.1)
77.3 (54.6–92.2)
Ta,T1
6
5
0
0
1
83.3 (35.9–99.6)
83.3 (35.9–99.6)
CIS
6
4
–
1
1
66.7 (22.3–95.7)
66.7 (22.3–95.7)
Sub-total
12
9
0
1
2
75.0 (42.8–94.5)
75.0 (42.8–94.5)
Ta,T1
26
17
5
2
2
65.4 (44.3–82.8)
84.6 (65.1–95.6)
CIS
23
16
–
5
2
69.6 (47.1–86.8)
69.6 (47.1–86.8)
Total
49
33
5
7
4
67.3 (52.5–80.1)
77.6 (63.4–88.2)
Table 3. Adverse drug reactions in phase I–II study
Event
Evaluated
cases
No. of
patients
Urinary frequency
51
Pain on urination
Difficulty in urination
³Grade 1 incidence: No. (%)
³Grade 3 incidence: No. (%)
40.5 mg group
(n = 15)
81 mg group
(n = 22)
121.5 mg group
(n = 14)
40.5 mg
(n = 15)
81 mg
(n = 22)
121.5 mg
(n = 14)
44
13 (86.7)
19 (86.4)
12 (85.7)
2 (13.3)
0
2 (14.3)
51
42
13 (86.7)
17 (77.3)
12 (85.7)
1 (6.7)
0
2 (14.3)
51
14
3 (20.0)
5 (22.7)
6 (42.9)
0
1 (4.5)
2 (14.3)
0
0
2 (14.3)
Gross hematuria
51
39
11 (73.3)
17 (77.3)
11 (78.6)
Fever (³37°C)
51
33
13 (86.7)
9 (40.9)
11 (78.6)
Malaise
51
17
6 (40.0)
5 (22.7)
6 (42.9)
Anorexia
51
7
3 (20.0)
2 (9.1)
2 (14.3)
Arthritis
51
1
0
0
1 (7.1)
0
0
1 (7.1)
Interstitial pneumonia
51
1
0
0
1 (7.1)
0
0
1 (7.1)
0
0
1 (7.1)
Hypoxemia
51
1
0
0
1 (7.1)
GOT elevation
51
4
0
2 (9.1)
2 (14.3)
GPT elevation
51
6
1 (6.7)
3 (13.6)
2 (14.3)
ALP elevation
51
4
1 (6.7)
1 (4.5)
2 (14.3)
0
0
1 (7.1)
2 (13.3)
4 (18.2)
2 (14.3)
Urinary protein positive
51
16
4 (26.7)
8 (36.4)
4 (28.6)
Microscopic hematuria*
51
31
9 (60.0)
13 (59.1)
9 (64.3)
Urinary RBC increase*
51
30
10 (66.7)
12 (54.5)
8 (57.1)
Urinary WBC increase*
51
43
11 (73.3)
20 (90.9)
12 (85.7)
*Not graded.
Effects of Solid Cancer Chemotherapy (9). In the late phase II
study, evaluation of ADRs was performed in accordance with
the Society’s Toxicity Grading Criteria (10).
STATISTICAL ANALYSIS
For the phase I–II study, the CR rate, response rate and 95%
confidence interval were calculated for each of the three
dosage groups. The differences among the three groups in relation to the CR rate and the ADR rate were tested for statistical
significance by application of the chi-squared test. In addition,
exploratory analysis was carried out for the existence of a
dose–response by applying the Cochran–Armitage test to the
CR rate for the combined Ta, T1 and CIS cases.
For the late phase II study, first, consideration was given to
the feasibility of setting the target number of cases. Assuming
that CR would be achieved by 26 of 40 patients (i.e. a CR rate
of 65%), it would be possible to guarantee that the CR rate at
the lower limit of the confidence interval would be at least
50%. On this basis, a target of 40 patients was set. In addition,
386
Clinical study of PMCJ-9
the CR rate, response rate and 95% confidence interval were
calculated from the generated results of the therapy.
RESULTS
PHASE I–II STUDY
A total of 51 patients were enrolled in the phase I–II study and
all were judged to be eligible. One patient was excluded from
the efficacy analysis owing to discontinuation of the therapy
after only three courses because of the manifestation of interstitial pneumonia and one other patient was excluded because
of the great delay in the time of evaluation of the efficacy compared with the time stipulated in the protocol owing to complications, etc. Accordingly, 49 patients were included in the
efficacy analysis. Table 1 presents the data on the background
characteristics of the total of 51 patients and the patients allocated to each of the dosage groups. No statistically significant
biases were found in the distribution of the background characteristics among the three groups.
Table 2 compiles the data for the tumor response of the 49
analyzed patients in the phase I–II study as a function of each
dosage group. The CR rates for the Ta, T1 patients were 70.0%
in the 40.5 mg group, 50.0% in the 81 mg group and 83.3% in
the 121.5 mg group. Thus, the CR rate was at least 50% in each
dosage group. For the CIS patients, the CR rates were 40.0,
83.3 and 66.7% in the 40.5, 81 and 121.5 mg groups, respectively. The differences in the CR rates among the three dosage
groups were not statistically significant for either the Ta, T1
patients or the CIS patients (Ta, T1: chi-squared test, P = 0.369;
CIS: P = 0.206). When the data for the Ta, T1 patients and the
CIS patients were combined, the CR rates were 60.0, 68.2 and
75.0% in the 40.5, 81 and 121.5 mg groups, respectively.
Hence the CR rate increased as the dosage of PMCJ-9 was
increased, but exploratory analysis of the dose–response using
the Cochran–Armitage test did not find the differences among
the dosages to be statistically significant (P = 0.203).
All 51 patients were analyzed for the safety of the PMCJ-9
intravesical instillation at three dosages. All patients developed
some sort of ADR. Table 3 compiles, for each dosage group,
the data on ADRs that occurred at an incidence of at least 10%
or were rated as grade 3 or worse. The incidence of fever in the
81 mg group was significantly (chi-squared test, P = 0.007)
lower than in the other two dosage groups, but otherwise there
were no other significant differences in the incidences of
ADRs among the groups. In the 121.5 mg group, two patients
developed severe local symptoms of the bladder (difficulty in
urination accompanied by hematuria) and two other patients
manifested severe systemic ADRs (arthritis in one patient and
interstitial pneumonia in the other). In both the 40.5 and 81 mg
dosage groups there were no cases of severe ADRs which
represented a problem and the ADRs in the 81 mg dosage
group were not increased in incidence or severity compared
with the 40.5 mg dosage group. The full eight courses of instillation therapy could not be completed by seven patients
(13.7%), consisting of two of 15 patients (13.3%) in the 40.5
Table 4. Patients’ characteristics in late phase II study
Characteristic
No. of patients
Entered
43
Eligible
41
Evaluable
39
Tumor stage:
Ta
14
T1
12
CIS
13
Gender:
Male
30
Female
9
Age (years): median (range)
71 (30–78)
Weight (kg): median (range)
56.4 (38.7–93.0)
Performance status:
0
37
1
2
Prior therapy:
None
13
Done
26
TUR
13
TUR + chemotherapy
13
Primary or recurrent
Primary
21
Recurrent
18
Tuberculin reaction (before treatment):
–
10
+
19
++
10
Tumor grade:
G1
5
G2
21
G3
13
Maximum tumor length (cm):
<1
12
1–2
14
Number of tumors:
1–4
20
5–10
2
³11
4
mg group, two of 22 patients (9.1%) in the 81 mg group and
three of 14 patients (21.4%) in the 121.5 mg group.
LATE PHASE II STUDY
A total of 43 patients were enrolled in the late phase II study,
including 29 Ta, T1 patients and 14 CIS patients. Two of those
patients (one Ta and one CIS patient) were determined as in-
Jpn J Clin Oncol 2003;33(8)
387
Table 5. Tumor response in late phase II study
Dose (mg)
Stage
Evaluable cases CR
PR
NC
PD
CR rate (%) (90% CI, %) ³PR rate (%) (90% CI, %)
81
Ta,T1
26
6
3
1
61.5 (43.6–77.4)
16
84.6 (68.2–94.6)
CIS
13
12
–
1
0
92.3 (68.4–99.6)
92.3 (68.4–99.6)
Total
39
28
6
4
1
71.8 (57.7–83.3)
87.2 (74.9–94.8)
Table 6. Adverse drug reactions in late phase II study
Event
Evaluated cases
Grade
1
2
3
No. of patients
%
³Grade 3 (%)
4
Urinary frequency
42
15
10
6
31
73.80
14.30
Pain on urination
42
14
13
4
31
73.80
9.50
Difficulty in urination
42
7
5
12
28.60
Gross hematuria
42
–
13
20
47.60
Fever (³37°C)
42
14
11
25
59.50
Malaise
42
10
4
14
33.30
Anorexia
42
5
5
11.90
Leukocytosis*
41
6
14.60
Eosinophilia*
40
4
10.00
Urinary protein positive
42
22
52.40
Microscopic hematuria*
41
24
58.50
Urinary RBC increase*
42
26
61.90
Urinary WBC increase*
42
35
83.30
9
12
7
1
16.70
2.40
*Not graded.
eligible because of confirmation of a complication of upper
urinary tract tumors. In addition, the treatment was discontinued for one patient (Ta) after three PMCJ-9 instillations, and
for another patient (T1) it was discontinued after one drug
instillation because of the retraction of informed consent. As
a result of exclusion of these four patients, 39 patients (Ta,
T1 26 patients, CIS 13 patients) were included in the efficacy
analysis. Tables 4 and 5 present the data on the patients’ background characteristics and antitumor response, respectively.
The CR rates for the patients evaluated for the efficacy of the
treatments were 61.5% for the Ta, T1 patients and 92.3% for
the CIS patients.
The efficacy evaluation was carried out for 42 patients, after
exclusion of the one patient who had retracted informed consent. Table 6 presents the data on the ADRs (which occurred at
an incidence of at least 10% or were rated as grade 3 or worse)
that manifested in the 42 patients.
Some sort of ADR developed in 40 of the 42 patients. The
principal ADRs were frequency of urination in 73.8%, pain on
urination in 73.8%, difficulty in urination in 28.6%, hematuria
in 47.6% and fever in 59.5%. Grade 3 or worse ADRs consisted of frequency of urination in 14.3%, pain on urination in
9.5%, hematuria in 16.7%, etc. These ADRs included a case of
serious acute cystitis in one patient, but this resolved after
the patient was hospitalized for treatment. In addition, three
patients (7.1%) were unable to complete the full eight instillations of PMCJ-9 because of the manifestation of ADRs.
COMBINED RESULTS OF PHASE I–II AND LATE PHASE II
STUDIES
As a result of the combination of the data from the phase I–II
and late phase II studies, a total of 88 patients were analyzed
for the efficacy of the treatments and Table 7 presents the
results for the antitumor effect. Table 8 compiles the combined
data on the ADRs in the total of 93 patients included in the
safety analysis.
Disappearance of the tumors was confirmed in 61 of the
88 patients in the efficacy analysis, representing a CR rate of
69.3%. The CR rates for the Ta, T1 patients and the CIS
patients were 63.5% and 77.8%, respectively. Some sort of
ADRs were recorded in 91 of the 93 patients in the safety
analysis. Ten patients (10.8%) were unable to complete the
full eight instillations of PMCJ-9 because of ADRs. Analysis
was performed of the incidence of ADRs as a function of the
patient background factors for the 93 patients. The background
factors selected were (1) gender, (2) age ³65 or <64 years, (3)
PS, (4) history of prior therapy, (5) primary or recurrent, (6)
tuberculin reaction positive or negative, (7) tumor grade and
(8) stage. Correlation of the above factors with the five major
symptoms (frequency of urination, pain on urination, difficulty
388
Clinical study of PMCJ-9
Table 7. Combined results of phase I–II and late phase II studies: tumor responses in all patients
Dosage group
(mg)
40.5
81
121.5
Overall
³PR rate (%)
(95% CI, %)
Stage
Evaluated
cases
CR
PR
NC
PD
CR rate (%)
(95% CI, %)
Ta,T1
10
7
3
0
0
70.0 (34.8–93.3)
100.0 (69.2–100)
CIS
5
2
–
3
0
40.0 (5.3–85.3)
40.0 (5.3–85.3)
Sub-total
15
9
3
3
0
60.0 (32.3–83.7)
80.0 (51.9–95.7)
Ta,T1
36
21
8
5
2
58.3 (40.8–74.5)
80.6 (64.0–91.8)
CIS
25
22
–
2
1
88.0 (68.8–97.5)
88.0 (68.8–97.5)
Sub-total
61
43
8
7
3
70.5 (57.4–81.5)
83.6 (71.9–91.8)
Ta,T1
6
5
0
0
1
83.3 (35.9–99.6)
83.3 (35.9–99.6)
CIS
6
4
–
1
1
66.7 (22.3–95.7)
66.7 (22.3–95.7)
Sub-total
12
9
0
1
2
75.0 (42.8–94.5)
75.0 (42.8–94.5)
Ta,T1
52
33
11
5
3
63.5 (49.0–76.4)
84.6 (71.9–93.1)
CIS
36
28
–
6
2
77.8 (60.8–89.9)
77.8 (60.8–89.9)
Total
88
61
11
11
5
69.3 (58.6–78.7)
81.8 (72.2–89.2)
Table 8. Adverse drug reactions in all patients
Event
Evaluated cases
Urinary frequency
93
Grade
1
2
3
37
28
10
No. of patients
%
³Grade 3 (%)
75
80.60
10.80
4
Pain on urination
93
38
28
7
73
78.50
7.50
Difficulty in urination
93
14
9
3
26
28.00
3.20
9
59
63.40
9.70
58
62.40
Gross hematuria
93
–
50
Fever (³37°C)
93
30
28
Malaise
93
19
12
31
33.30
Anorexia
93
11
1
12
12.90
Arthritis/arthralgia
93
1
1
1
3
3.20
1.10
Interstitial pneumonia
93
1
1
1.10
1.10
Hypoxemia
93
1
1
1.10
1.10
Leukocytosis*
92
10
10.90
GPT elevation
92
8
2
ALP elevation
91
5
1
1
Urinary protein positive
93
14
15
9
Microscopic hematuria*
92
10
10.90
7
7.70
1.10
38
40.90
9.70
55
59.80
Urinary RBC increase*
93
56
60.20
Urinary WBC increase*
93
78
83.90
*Not graded.
in urination, gross hematuria and fever) was analyzed. No
particularly clear causative factors were identified. However,
patients who were positive for the tuberculin reaction prior to
the start of this study showed a significantly higher incidence
(86.6%) of frequency of urination (chi-squared test, P = 0.04)
compared with the patients who were negative (68.0%), thus
indicating a correlation.
DISCUSSION
The combined results of these phase I–II and late phase II
studies showed CR rates of 63.5% (33/52 patients) for Ta, T1
bladder cancer patients and 77.8% (28/36) for CIS bladder
cancer patients. Although direct comparison is impossible, it is
observed that the CR rate reported for Ta, T1 patients treated
with the Tokyo 172 strain was 66.4% (5), which is almost the
same as our present result. In addition, the range of CR rates
reported from outside Japan for CIS patients treated with
Jpn J Clin Oncol 2003;33(8)
Connaught strain was 70–83% (4,11,12), which is also similar
to our present result. These results lead us to surmise that the
antitumor effect of PMCJ-9 is real.
With regard to the safety of PMCJ-9, there were no large differences in the ADRs that were recorded in the phase I–II study
and the late phase II study. ADRs which occurred at high frequency were symptoms of bladder irritation, such as frequency
of urination and pain on urination, hematuria, fever, etc.
Inflammatory symptoms of the bladder may occur because
BCG that has been instilled into the bladder attaches to and
then is taken up by tumor cells (13,14) and bladder submucosal
cells (15), thereby causing local acute and subacute inflammation accompanied by macrophage or lymphocyte infiltration
(16). In addition, this inflammatory response is considered to
be an essential factor in the expression of the immunological
effects of BCG (17–19). These inflammatory symptoms were
transient in nature and most were able to be controlled without
any treatment or by the use of conventional anti-inflammatory
analgesics, etc. They usually resolved on the day of BCG
instillation or within a day or two thereafter.
As for serious systemic ADRs, interstitial pneumonia and
arthritis occurred in one patient each in the group administered
121.5 mg of PMCJ-9 in the phase I–II study. The study was
discontinued for the patient who developed interstitial pneumonia after the third BCG instillation because of the manifestation of persistent fever and elevated values of liver enzymes.
BCG was not detected in the sputum or bronchial lavage of this
patient and interstitial pneumonia was diagnosed on the basis
of chest X-rays, CT image diagnosis, the histopathological
picture of a bronchial biopsy, etc. The patient responded to
treatment with steroids (including pulse therapy) and antituberculosis drug administered concomitantly. Lamm et al.
(17) reported that analysis of 2602 patients showed a 0.7%
incidence of pneumonia or hepatitis due to BCG. Israel-Biet et
al. (20) reported that, rather than actual tuberculosis, bilateral
interstitial pneumonia was the more common pulmonary complication of BCG intravesical therapy, which they considered
to be a hypersensitivity reaction to BCG.
The patient in the present study who developed arthritis
exhibited a severe degree of arthritis of the right knee accompanied by edema. The patient recovered in response to the
administration of anti-inflammatory analgesics, isoniazid and
an antibacterial agent. Bacterial tests performed on the synovial fluid were negative. Arthritis is also thought to be an
allergic reaction to BCG (17,21) and it was concluded that
the present case was an example of reactive arthritis caused
by a strong immunological response.
Definitive factors related to the manifestation of ADRs to
BCG remain unclear (22). In our evaluation, patients who were
positive for the tuberculin reaction prior to the start of study
showed a significantly higher incidence of frequency of urination (chi-squared test, P = 0.04) in comparison with the patients
who were negative. Four patients who were enrolled in the
studies had had a history of tuberculosis, and developed ADRs
that persisted, although not severe, for a long period of time
(frequency of urination, pain on urination and hematuria).
389
There is a possibility that these patients showed stronger
immunological responses to BCG, hence in such patients BCG
preparations should be used with caution.
In the present study, intravesical instillation of PMCJ-9 at a
dose of 81 mg once per week for 8 weeks showed clear antitumor effects in patients with Ta, T1 or CIS bladder cancer. In
terms of the safety of this therapy, although there were some
serious ADRs, they occurred at a low frequency. Moreover,
most of the ADRs were transient in nature and controllable.
Accordingly, it was confirmed that this BCG regimen of
81 mg weekly for 8 weeks was well tolerated by the patients.
At present in Europe and the USA, intravesical therapy with
BCG for superficial bladder carcinoma is widely employed to
treat and prevent recurrence of CIS and to achieve prophylaxis
of recurrence after TUR-Bt in patients with Ta, T1 carcinoma.
In Japan, owing to the limitations of the protocols of clinical
studies carried out for the approval of application of PMCJ-9,
the officially approved indications for Ta, T1 and CIS that are
covered by the national health insurance system are only for
the treatment of those diseases, and not for prevention of tumor
recurrence. However, considering the biological characteristics
of superficial bladder carcinoma, it is expected that intravesical
BCG therapy would have great significance in the prevention
of recurrence. PMCJ-9 should be quickly approved for use in
the prophylaxis of recurrence of superficial bladder carcinoma.
In addition, on the basis of the results of the clinical study
presented here, it is necessary to carry out further clinical
studies aimed at alleviating the strong local bladder symptoms
and the systemic adverse effects caused by the BCG intravesical therapy.
Acknowledgments
These studies received a research grant from the Drug Organization in Japan.
The participating institutions and their representative investigators and the members* of the Efficacy and Safety Evaluation
Committee are as follows: Department of Urology, Sapporo
Medical School of Medicine (Taiji Tsukamoto), Department
of Urology, Hirosaki University, School of Medicine (Tadashi
Suzuki), Department of Urology, The Central Hospital and
Cancer Center of Ibaraki Prefecture (Mikinobu Ohtani),
Department of Urology, School of Medicine, Chiba University
(Haruo Ito, Jun Shimazaki), Department of Urology, School of
Medicine, Keio University (Masaru Murai), Department of
Urology, National Cancer Center Hospital (Kenichi Tobisu),
Department of Urology, Faculty of Medicine, the University of
Tokyo (Tadaichi Kitamura), Department of Urology, Toranomon Hospital (Masao Yokoyama), Department of Urology,
The Jikei University School of Medicine (Yukihiko Ohishi),
Department of Urology, Yokohama City University, School of
Medicine (Masahiko Hosaka, Yoshinobu Kubota), Department
of Urology, School of Medicine, Kanazawa University (Mikio
Namiki), Department of Urology, Japanese Red Cross Nagoya
First Hospital (Tatsuro Murase), Department of Urology,
Nagoya Daini Red Cross Hospital (Kouji Obata), Department
390
Clinical study of PMCJ-9
of Urology, Kyoto Prefectural University of Medicine (Tsuneharu Miki), Department of Urology, Nara Prefectural Nara
Hospital (Shoji Sanma), Department of Urology, Nara Medical
University (Yoshihiko Hirao), Department of Urology, Nagasaki University, School of Medicine (Yutaka Saito, Hiroshi
Kanetake), Senpo Tokyo Takanawa Hospital (*Tadao Niijima),
Tsurumi University (*Hiroshi Hujita), Kanagawa Cardiovascular and Respiratory Center (*Shigeki Odagiri).
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