Benefits and risks of BCG maintenance therapy:

1
Benefits and risks ofBCG maintenance therapy
Which regimen for which patient?

• Don Lamm, M.D.
• Professor of Urology
• Mayo Clinic, Scottsdale
• Arizona, USA

2
Progress in Bladder Cancer

• Incidence up from 14.6 / 100,000 in 1973 to 16.5
  in 1997 (adjusted to 1970 population)
• Mortality down from 4.2 / 100,000 in 1973 to 3.2
  in 1997 5 yr survival 53 in 1950, 82 1997
• One of only 5 cancers (Testis - 5.1 Bladder -
  1.3 Breast - 0.3 Ovary - 0.5 Thyroid -1.1)
  with increased incidence and reduced mortality
• SEER, 2000

3
Thiotepa Controlled Studies
4
Summary of Controlled Chemotherapy Trials
5
Controlled BCG Trials
6
BCG vs. Doxorubicin Time to Treatment Failure
100 80 60 40 20 0
n 5-year RFS BCG CIS 64 45 BCG
Ta, T1 63 37 Doxorubicin Ta, T1 67
18 Doxorubicin CIS 68 17
Percentage of patients
0 12 24 36
48 60 72
Time after registration,
months
Lamm DL N Engl J Med. 1991 3251205
7
BCG vs. MMC Studies Bohle A., J Urol Jan 03
36.7 of 781 vs 53.8 of 771 (17) in
maintenance BCG studies. 6/6 maintenance BCG
studies significant vs 1/5 non-maint.
8
5 year Tumor Recurrence Curveswith Chemotherapy
vs Control
EORTC / MRC
100 90 80 70 60 50 40 30 20 10 0
Percent Tumor Free
Chemotherapy Control
0 1 2 3 4 5
Time (Years)
9
Improving BCG Immunotherapy

• Maintenance Therapy
• BCG plus vitamins
• Combination Immunotherapy BCG plus Interferon
  Alfa

10
3 Week Maintenance BCG
Survival
Worsening - free Survival
Recurrence - free Survival
p lt 0.0001
p 0.08
p 0.04
Lamm, D.L. et al., J Urol 163, 1124, 2000
11
Figure 1
100
90
80
M. Ta, T1
70
M. CIS
60
I. CIS
Percent Tumor Recurrence
50
I. Ta, T1
40
30
20
M I
Three Week Maintenance BCG Induction Only
10
0


Years
60055-11-N
12
SWOG BCG Arms
Papillary Patients Only
3 wk Maint
Monthly M
Percent Tumor Recurrence
Induction
Quarterly M
At Risk
Median In Months
Fail
BCG 8216 BCG 8507 BCG 8795 OBS 8507
63 129 191 126
41 30 77 63
23 Not Reached 46 37
p 0.001
Months After Registration
13
Repeated 6 week Maintenance BCG Palou J. J Urol.
165 1488, 2001

• 126 pts randomized to 6 wk induction v. 6 wk
  maintenance every 6 months for 2 years
• Mean follow-up 79 months
• 16/61 (26) recurrence in induction v. 10/65
• (15) with repeated 6 wk BCG
• 11/65 (34) completed maintenance
• No significant advantage observed

14
6 weekly 6 Month Maintenance
Palou, 2001
Global recurrence
126 pts. 6 week BCG every 6 months for 2 years,
PNS
Time in months
15
BCG Maintenance Not Created Equal
Figure 1
M BCG I BCG
Tumor Free
n 42 pts. 1q 3 mo.
M. Ta, T1
3
21
12
15
18
33
24
27
30
6
9
M. CIS
Months
I. CIS
M BCG I BCG
Percent Tumor Recurrence
I. Ta, T1
Disease Free
n 93 pts. 1q 1mo.
n 385, 3q 3-6 mo.
0
36
9
18
27
Months
M, Ta T1, 3wk maintenance BCG M,
CIS, 3wk maintenance BCG I, CIS, 6wk
induction BCG I, Ta T1, 6wk induction
BCG
Maintenance Group Control group
Global recurrence
n 126, 6q 6mo.


Years
0
12
24
36
48
60
72
Time in months
60055-15-N
16
Intravesical BCG Reduces the Risk of Progression
in superficial Bladder CancerA Meta-Analysis of
the Published Results of Randomized Clinical
Trials
J Urol 2002 Nov 168(5) 1964 -70

• 24 trials, 4863 patients eligible
• 22 induction BCG, 78 used maintenance 10 to
  30 instillations given for 18 weeks - 3 yrs
• 2.5 yr median follow (max. 15 years)
• 82 papillary, 18 CIS

17
Progression

• Treatment Progression
• No BCG 304 / 2205 (13.8)
• BCG 260 / 2658 ( 9.8)
• Difference 4.0
• Odds ratio (OR) 0.73
• Odds reduction 27 (95 CI 11 - 40)
• P Value 0.001

18
Progression Disease Type
Although their prognosis is different, the size
of the treatment effect was similar in papillary
tumors and CIS
19
Progression Maintenance BCG
Test for heterogeneity p 0.008 BCG was only
effective in trials with maintenance, where it
reduced the risk of progression by 37, p
0.00004.
20
Progression
All studies with maintenance
21
Survival
The reductions in the odds of death (11 all and
19) are not statistically significant, as would
be expected with a mean follow-up of 2.5 years
22
Conclusions

• Intravesical BCG reduces the risk of progression
  when maintenance is used
• The size of the treatment effect is similar in
  papillary tumors and CIS
• The benefit of maintenance BCG in intermediate
  and high risk papillary tumors and in CIS appears
  to outweigh the risks

23
Can BCG be Further Improved?
24
Kaplan Meier Estimate of 5 Year Tumor Free Rate
Lamm D.I., J Urol 151(1) 21-26, 1994
40,000u Vitamin A, 100mg B6, 2gm C, 400mg E
"Oncovite"
Percent Tumor Free
p 0.0014
Multi Vitamin (n 3) Mega Vitamin (n 35)
RDA Vitamins
Months After Registration
25
BCG Plus IFN-?2b Ongoing Randomized Trials

• Connaught strain
• ODonnell M.A., unpublished data, 1999.
• Esuvaranathan K., et al., J Urol.
  2000163(suppl)152. Abstract 675.

26
Conclusions

• BCG maintenance therapy significantly reduces
  recurrence and progression compared with
  chemotherapy or induction BCG alone.
• The 3 week maintenance schedule appears to be
  significantly better than other regimens
• Side effects of BCG can and should be reduced by
  reducing dose and delaying treatments in those
  with increasing side effects.
• Oncovite and Interferon Alfa appear to further
  improve results, but confirmatory studies are
  pending