Bagley Regimen

The Management of “Advanced” Prostate Cancer
by: Stephen B. Strum, MD – 1998

The Nature of the Problem

Patients who have progressive disease after primary hormone blockade and secondary measures are no longer effective, represent a significant problem area in the management of prostate cancer. In such settings, the present-day approaches to eradicate active disease are most often characterized by remissions of short duration ranging from 3-12 months. Essentially these approaches involve different chemotherapy or chemo-hormonal drug combinations intended to eradicate significant tumor burdens associated with androgen insensitive disease (hormone refractory prostate cancer). Patients treated with the above approaches usually have had prior therapies that are known to alter the cell populations resulting in resistant tumor clones. How can we expect to make a major impact in such a setting? How can we eradicate prostate cancer if we don’t achieve complete remissions of durable duration?

The Need for Combined Chemo-hormonal Therapy

Animal models of prostate cancer suggest that we must treat with chemotherapy and androgen ablation simultaneously to eradicate the heterogeneous tumor cell populations occurring within individual patients. (Isaacs and Coffey 1981, Ellis and Isaacs 1985, Redding and Schally 1985, Kung et al. 1988, and Isaacs 1984 and 1989). “… effective chemotherapy, specifically targeted against the androgen-independent cancer cell, must be simultaneously combined with androgen ablation to affect the androgen-dependent cells. This approach should be initiated early in the course of the disease using regimens that take into account the relative long cell-cycle times that characterize prostate cancer growth. Such regimens could use infusion therapies to destroy cell populations that are slow in going through their DNA cycling. Alternatively, they could employ a prolonged oral regimen to accomplish the same goal. In addition, the use of two non-cross resistant regimens would likely achieve better results.

Has This Approach Ever Been Used Before?

Studies conducted by Charles Bagley M.D. et al1 at the Northwest Institute in Seattle have involved such an approach to patients with high-risk PC. These patients had many of the “high-risk” parameters, including one or more of the following:

• High baseline serum PSA
• Elevated prostatic acid phosphatase (PAP)
• Gleason score > 6
• Bulky localized PC (e.g., CS T2c, T3a-c)
• Metastatic disease (e.g., CS D1, D2)

The types of patients treated by Bagley et al are summarized in the table below.

Patients were treated with chemotherapy for 6 cycles with each course of treatment being given over 3 weeks. The regimen consisted of Velban, Adriamycin and Mitomycin. The treatment cycle is 21 days with details shown below.

Dose intensity evaluation of the chemotherapy revealed that 93% of the intended chemotherapy was given. Bone marrow suppression was limited to the white blood cells, with the median lowest neutrophil count being 200 (range 0-1500). No marrow growth factors such as Neupogen or Procrit were used in this study. Nausea and vomiting were minimal. Mitomycin-induced pneumonitis (lung inflammation) occurred in 2 patients.

In the treated group, there have been 4 relapses for a 5-year relapse-free survival of 85%. Of the 10 patients offered this approach who had refused, 8 of 10 have relapsed with a median relapse-free survival of 27 months. Of the 27 treated patients, 22 patients have non-detectable PSA levels. 3 others have PSA levels less than 2 and two patients have PSA levels of 33 and 13.

Editor’s note: In 2002, a follow-up study2 reported – “At 10 years the cumulative relapse free rate determined by continuously undetectable PSA levels was 73%, and the cumulative cancer specific survival was 81%. Of node-positive patients, 82% were relapse-free at 10 years.”

We believe that such an approach is reasonable. In addition, we would infuse the Adriamycin over 48-96 hours to decrease the chance of cardiac toxicity from Adriamycin or use Novantrone as an alternative agent. We would use growth factors such as Neupogen and Epogen to diminish chemotherapy toxicity. We would also give the patient the option to use combination hormone blockade instead of orchiectomy. We also would consider the use of Brachytherapy for local treatment and question the use of pelvic node irradiation. We hope to plan a cooperative trial with other medical oncologists interested in pursuing this approach.

What Other Approaches Could Be Used in a Clinical Trial Setting?

The Bagley regimen has some drawbacks in the toxicity pattern of Mitomycin C and also in the potential damage to the myocardium (heart wall) as a result of Adriamycin or Novantrone. Other drug combinations could be employed. Examples of one such regimen could utilize the known efficacy of Cyclophosphamide along with 5FU as one regimen. This could be administered as a 120-hour infusion via an ambulatory infusion pump. The latter approach diminishes toxicity to the patient while exposing the cell population to a prolonged time period. In addition, dexamethasone added to the infusion pump not only serves as an anti-tumor drug but also as an antiemetic. This approach is given as an outpatient every 3 weeks. 4 cycles of this high-dose Cytoxan regimen with 5FU and Dexamethasone is therefore given over 3 months. This is followed by a non-cross resistant regimen such as Emcyt plus Taxotere with the latter given as a weekly regimen. Coumadin is given to prevent any venous embolic complications known to occur with estrogenic agents such as Emcyt. The latter regimen is continued for an additional three months. The total treatment time is approximately 6 months, similar to what is used in high-risk breast cancer patients.

References

1. Bagley C, Lane R, Grimm P, et al: Adjuvant chemotherapy and hormonal therapy of high-risk prostate cancer. Proc Amer Soc Clin Oncol. 14:230, 1995.

2. Bagley CM Jr, Lane RF, Blasko JC, Grimm PD, Ragde H, Cobb OE, Rowbotham RK. Adjuvant chemohormonal therapy of high risk prostate carcinoma. Ten year results. Cancer. 2002 May 15;94(10):2728-32.