SLIDES & TRANSCRIPTS
Friday, December 13, 2002

BCG Failure or Iatrogenic Immunosuppression: Definitions, Pitfalls, and Pearls

Donald Lamm, M.D.

I'm going to review for you that too much BCG suppresses the immune response, and that can happen when you repeat BCG six-week courses, that complete eradication of carcinoma in situ in particular does take time, and may not be complete by the third month.
We know that our staging has great limitations. We know that BCG wanes with time, and further treatment is necessary. And we hope to show ways to improve treatment, so that it is only BCG that has failed.

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The simple definition of BCG failure would be tumor recurrence at three months, or tumor progression at any time, but that leaves a lot of questions. What about the patient that has pre-existing invasion, or pre-existing metastases? We have limitations in our staging.
What about the patient that has a marked reduction in grade stage, number of tumors, but eventually does have a low-grade recurrence? Some of our patients are already on third base. They don't necessarily need a home run. A single would suffice for many of these patients.

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The treatment options need to be divided into patients who fail with low-grade disease, and those who fail with high grade disease. With a low-grade failure, certainly all of the chemotherapy options are available. Mike O'Donnell is going to talk about interferon. KLH is approved in Europe and in Asia, and can be highly effective.

One option is oncovite, high doses of vitamins of A, B6, C, and E.

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And in BCG treated patients, our randomized, double blind study found a 40 percent reduction in tumor recurrence with the administration of just vitamins.

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With high-grade disease, T1 or carcinoma in situ, the primary option for those patients is cystectomy, but again, Michael O'Donnell will present some very good data looking at BCG plus interferon. And there are some new chemotherapies and new techniques of delivery of chemotherapy, including hyperthermia that can be very effective.

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Well, what about the three-month recurrence? That is a problem. We all know that if you recur at three months, it greatly increases your risk of further recurrence and disease progression. But it may also be under-staging the disease. And in many patients it may be premature to assess the response of BCG at three months.

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Here are some typical clinical data, patients undergoing cystectomy for stage T1 disease, only 47 percent of patients actually had T1 disease; 19 percent had no tumor in the bladder, and were potentially over-treated. But over 30 percent of patients had muscle invasion or more advanced disease. Many would say then, if the invasion is that high, why not go ahead and go to cystectomy early?

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But if you look at the increasing experience of using BCG in grade 3 T1 disease 16 series, only 12 percent of patients went on to muscle invasion or metastasis when followed for 22 to 78 months.

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Also, in many patients, three months may be too early to pull the plug. In the Southwest Oncology Group, with 230 randomized patients, evaluable patients, at six weeks the complete response was 58 percent of those in the induction group, and 55 percent of those in the maintenance group without any further BCG.

By six months the complete response rate was up to 69 percent in the induction group, and with three weekly installations, up to 84 percent in the maintenance group. So 26 percent of CIS failures at three months will go on to complete response by six months without further treatment; 64 percent if you give three additional BCG treatments.

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What about the schedule, and the treatment technique? To get the optimal response, BCG must come in close proximity with the tumor. We must minimize the tumor burden. And we need to use an appropriate dose and schedule of BCG. Again, excess BCG or repeated six-week installations can actually impair the immune response.

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And here is the data looking at survival in the mouse model of bladder cancer. And the optimal response with various preparations occurs with 10 to the 7th organisms. If you give too little or too much BCG, you impair the immune response.

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So this does have clinical applicability, as shown here in Pagano's study. There is a 40 percent reduction in tumor recurrence by reducing the very potent Pasteur strain of BCG by 50 percent.

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We owe the Washington University investigators a debt for showing to us that six weekly induction BCG was suboptimal. They found increase in response percent disease-free from 37 percent with a single six-week induction, to 64 percent with a repeated six-week induction. But the rest of the story is that six plus six is also suboptimal.

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And it in fact, no better in other studies compared with induction alone, monthly maintenance, or quarterly maintenance. And immunological studies show with the initial course, that immune stimulation peaks at six weeks. And with subsequent courses, it peaks at three weeks, and can actually be suppressed with the fourth, fifth, and sixth installation.

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And looking at the 64 percent disease-free at two years, you see that it is not different from induction alone or monthly maintenance, but three weekly installations is clearly superior.

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With six repeated six-week installations, an excellent study from Spain, with patients followed for 79 months found no significant advantage of repeated six-week installations. The results are excellent.

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The patients had to be disease-free at six months to go on this study, but again, repeated six week installations was no better than induction alone.

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So repeated six-week installations, monthly maintenance, and quarterly single installations do not provide optimal maintenance therapy. Three weekly installations, as seen here in patients with papillary tumor versus induction alone is dramatically superior.

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Patients will eventually fail if given just an induction course, as shown at Memorial Sloan-Kettering, sixty-nine percent of patients relapsed or progressed by 10 years, and prostatic and upper tract disease was highly fatal.

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Looking at the role of maintenance therapy and the 24 randomized studies in the meta-analysis,

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there was a reduction in disease progression from 13.8 percent in studies where BCG was compared with control, surgery alone, various chemotherapies, or immunotherapies to 9.8 percent, a 27 percent reduction in disease progression.

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But this occurred only when maintenance BCG was used. With maintenance, there was a 37 percent reduction in disease progression.

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The forest plot is illustrated here. And notice that six-weekly maintenance did not reduce disease progression.

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In conclusion then, we need improved methods to stage high grade T1 transitional cell carcinoma. And assessment at three months in patients with carcinoma in situ may be too early. Twenty-six percent of patients will go on complete response with additional BCG, 64 percent if you give three weekly installations.

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We know that six-week induction is suboptimal, as is monthly maintenance, and quarterly maintenance, and repeated six-week installations. Simply put, too much BCG does reduce the immune response and increase toxicity.

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The risk of progression in patients with high-grade disease, particularly T1 is long-term, and it's longer than the effect of BCG. With maintenance BCG, we can significantly reduce progression, but only with maintenance.

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Again, with T1 disease, patients with suboptimal BCG had only a 12 percent incidence of subsequent progression.

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We can dramatically improve that with the three-week maintenance.

Thank you very much.

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