Dale R. Riggs

Apparent Failure of Current Intravesical Chemotherapy Prophylaxis to Influence the Long-Term Course of Superficial Transitional Cell Carcinoma of the Bladder

During the 4 decades since the first introduction of intravesical chemotherapy, 3,899 patients were enrolled in 22 randomized prospective controlled studies. Of these 22 studies 13 reported a statistically significant benefit of intravesical chemotherapy. With varying followup, the reported decrease in the incidence of patients with tumor recurrence averaged only 14% (range -3 to +43%). Unfortunately, long-term (5-year) studies show no decrease in the incidence of recurrent tumor. Maintenance chemotherapy has failed to improve these results and data suggest that a single early postoperative instillation may, in fact, be most effective. Among 10 studies that include progression data none showed decreased tumor progression, and overall among 2,011 randomized patients progression occurred in 7.5% of those receiving intravesical chemotherapy and 6.9% of those treated by surgery alone. Since intravesical chemotherapy has been demonstrated in animal models to be carcinogenic, these data raise the concern that intravesical chemotherapy might possibly be carcinogenic in humans. In the absence of demonstrated long-term benefit we question the advisability of routine prophylactic intravesical chemotherapy.

Megadose vitamins in bladder cancer : a double-blind clinical trial

Epidemiological and laboratory studies suggest that vitamin supplements may be helpful in the prevention of some cancers but clinical trials to date have failed to demonstrate protection with naturally occurring vitamins. Without substantiation of the highly touted benefits of vitamins, few physicians who care for cancer patients have recommended their use. A total of 65 patients with biopsy confirmed transitional cell carcinoma of the bladder enrolled in a randomized comparison of intravesical bacillus Calmette-Guerin (BCG) with or without percutaneous administration was also randomized by closed envelope to therapy with multiple vitamins in the recommended daily allowance (RDA) versus RDA multivitamins plus 40,000 units vitamin A, 100 mg. vitamin B6, 2,000 mg. vitamin C, 400 units vitamin E and 90 mg. zinc. The addition of percutaneous BCG did not significantly lessen tumor recurrence but recurrence after 10 months was markedly reduced in patients receiving megadose vitamins. The 5-year estimates of tumor recurrence are 91% in the RDA arm and 41% in the megadose arm (p = 0.0014, Mantel-Cox). Overall recurrence was 24 of 30 patients (80%) in the RDA arm and 14 of 35 (40%) in the high dose arm (p = 0.0011, 2-tailed Fishers exact test). Megadose vitamins A, B6, C and E plus zinc decrease bladder tumor recurrence in patients receiving BCG immunotherapy. Further research will be required to identify which ingredient(s) provide this protection.

Antibiotic And Steroid Therapy of Massive Systemic Bacillus Calmette-Guerin Toxicity

Intravesical bacillus Calmette-Guerin (BCG) is the most effective treatment of carcinoma in situ available today and is superior to chemotherapy in the prevention of bladder tumor recurrence. While therapy is generally well tolerated, serious and even life threatening toxicity can occur. Treatment options for serious infection include isoniazid, rifampin, ethambutol, and cycloserine, but shock may also be secondary to hypersensitivity and require the addition of corticosteroids. The morbidity and mortality of systemically BCG-infected mice treated with single and combined antimicrobial and/or corticosteroid therapies was evaluated. BCG immunized mice were unable to survive doses of BCG which were uniformly tolerated in naive mice. The addition of cycloserine increased survival in mice treated with isoniazid and rifampin, but optimal survival was achieved with isoniazid, rifampin, and prednisolone. These experimental results support the previously reported clinical success of isoniazid, rifampin and prednisolone in patients with septic BCG reactions.

Keyhole Limpet Hemocyanin Immunotherapy of Bladder Cancer: Laboratory and Clinical Studies

Background: Since the serendipitous observation by Olsson in 1974 that patients immunized with 5 mg of keyhole limpet hemocyanin (KLH) had a marked reduction in recurrence of superficial bladder cancer, multiple laboratory and clinical studies have confirmed the efficacy of KLH immunotherapy. Results: In 1981, we reported that KLH immunotherapy reduced tumor growth and prolonged survival in the MBT-2 murine model of transitional cell carcinoma (TCC), and in 1988, Jurincic and co-workers demonstrated that KLH was superior to mitomycin C chemotherapy in preventing bladder tumor recurrence. Subsequent studies using Immucothel (Biosyn), crude KLH, and endotoxin-free KLH confirmed the efficacy of KLH immunotherapy in the MBT-2 murine bladder cancer model (p < 0.05), and resulted in up to 100% survival. Conclusions: To evaluate the efficacy of KLH immunotherapy in patients, a multicenter clinical trial was performed. Sixty-four patients with CIS or residual stage Ta, T1 TCC, or both were enrolled in a phase I–II trial of escalating doses of weekly KLH given intravesically for 6 weeks. Patients were followed with cystoscopic examination, urine cytology, and bladder biopsy. Complete response was seen in 50% of patients with CIS, 20% of patients with residual Ta, T1 TCC, and 33% of patients with both CIS and residual Ta, T1 TCC. Responses occurred at all doses tested: 0.4, 2, 10 and 50 mg. No significant difference in response according to dose was noted, but optimal overall complete response was seen with a dose of only 2 mg. The toxicity of KLH is minimal. KLH appears to be a safe and highly effective immunotherapy for superficial bladder cancer.

THE POTENTIAL APPLICATION OF ALLIUM SATIVUM (GARLIC) FOR THE TREATMENT OF BLADDER CANCER

Additional studies are needed to identify the active ingredients in Allium Sativum (garlic) that are responsible for the observed antitumor activity and immune stimulation. Garlic seems to detoxify chemical carcinogens and prevent carcinogenesis and can also directly inhibit the growth of cancer cells. Current data suggest that low molecular weight sulfur compounds and protein F4 have immune-stimulation properties. Garlic is reported to stimulate immunity, including macrophage activity, natural killer and killer cells, and LAK cells, and to increase the production of IL-2, TNF, and interferon-gamma. These cytokines are associated with the beneficial Th1 antitumor response, which is characteristic of effective cancer immunotherapies. As is true of BCG, garlic stimulates the proliferation of macrophages and lymphocytes and protects against the suppression of immunity by chemotherapy and ultraviolet radiation. Garlic is clearly not a panacea for cancer, but its broad range of beneficial effects are worthy of serious consideration in clinical trials for the prevention and treatment of cancer.

Allium sativum (garlic) treatment for murine transitional cell carcinoma.

Currently, immunotherapy with Bacillus Calmette‐Guérin (BCG) is the most effective treatment for superficial bladder carcinoma, but treatment‐related toxicity may limit its use in some patients. Alternative treatments are needed for patients who fail to respond to BCG immunotherapy. Allium sativum (AS), or garlic, is known to have a broad range of biologic activities, including immune stimulation and reported antitumor activity. For these reasons, the authors conducted a series of experiments designed to explore the possible therapeutic effects of AS in the MBT2 murine bladder carcinoma model.

Drug therapy of bacillus Calmette-Guérin sepsis.

Intravesical bacillus Calmette-Guérin (BCG) is widely used for the treatment of transitional cell carcinoma of the bladder. Although it is usually well tolerated, sepsis can occur, which has resulted in at least eight deaths [3]. The survival of Connaught BCG-infected mice treated with single and combination antibiotic and steroid therapy was evaluated. Triple-drug therapy with isoniazid, rifampin, and prednisolone resulted in 53% survival compared with 25% survival in the control group (P=0.0209). A survival of only 10.5% was observed with treatment using prednisolone alone. This survival was worse than that of the control group (25%), and approached statistical significance (P`0.0669). Our data suggest that BCG sepsis probably has components of both a hypersensitivity reaction and bacterial sepsis; they support the current use of combination antibiotic and steroid therapy for treatment of BCG sepsis in humans, but argue against treatment with steroids alone.

Immunotherapy of Murine Transitional Cell Carcinoma of the Bladder Using Alpha and Gamma Interferon in Combination with Other Forms of Immunotherapy

BCG immunotherapy is very effective in the treatment of superficial transitional cell carcinoma of the bladder, but its significant toxicity may limit its use in some patients. In an effort to find less toxic and potentially more effective treatments we investigated the possible immunotherapeutic potential of combinations of Alpha Interferon (1000 IU) and Gamma Interferon (500 IU) with bacillus Calmette Guerin (BCG) (10(7) cfu), Interleukin-2 (4000 IU), and Keyhole Limpet Hemocyanin (50 micrograms.) in the MBT2 murine bladder cancer model. Significant reductions (p less than 0.05) in tumor incidence relative to the saline control, 83%, Day 35) was observed in groups receiving alpha interferon (42%), Keyhole limpet hemocyanin (42%), interleukin-2 (25%), alpha interferon + Keyhole limpet hemocyanin (17%), alpha interferon + interleukin-2 (33%), gamma interferon + BCG (42%), and gamma interferon + interleukin-2 (17%). All treatment groups with the exception of the group receiving gamma interferon had significantly reduced tumor volume (p less than 0.05) relative to the saline control. Combination treatment groups were significantly more effective than single agent treatments (p = 0.0057). The exhibited anti-tumor effect of these immunotherapeutic agents alone and in combination suggest that they may prove to be effective forms of immunotherapy for transitional cell carcinoma of the bladder.

Immunotherapy of murine bladder cancer with keyhole limpet hemocyanin (KLH)

Keyhole limpet hemocyanin (KLH) is a potent immunogen that is being evaluated as an immunotherapeutic alternative to BCG in the treatment of bladder cancer. In the mouse bladder tumor model (MBT2) intralesional KLH significantly reduced tumor incidence, growth rate, and mortality and exhibited antitumor activity similar to that achievable with BCG. Endotoxin contamination of KLH was not responsible for the antitumor activity, although endotoxin alone was shown to have anti-tumor activity in this animal model. Keyhole limpet hemocyanin is both safe and effective in the MBT2 model, and is an immunomodulator to consider for clinical trials.

Keyhole limpet hemocyanin immunotherapy of murine bladder cancer

SummaryThe current treatment of choice for superficial bladder cancer, bacillus Calmette-Guérin, has significant adverse side effects. We have compared two alternative immunotherapies—crude keyhole limpet hemocyanin (KLH) and Immucothel, a KLH modified for clinical use (Biosyn)-in an intralesional mouse model of bladder cancer (MBT2). Crude KLH required either immunization before tumor transplant or frequent intralesional therapy after transplantation to be effective. In addition, Immucothel required pre-immunization to be effective, and increasing the frequency and dosage of post-transplant immunization was not effective without pre-immunization. Preliminary investigations into the KLH-induced anti-tumor mechanism(s) suggest that natural killer cell activity may be involved. Both crude KLH and Immucothel appear to be effective immunotherapies of use in the treatment of transitional cell carcinoma.