A randomized prospective comparison of oral versus intravesical and percutaneous bacillus Calmette-Guerin for superficial bladder cancer

Reports of a dramatic decrease in tumor recurrence and regression of muscle invasive disease with oral bacillus Calmette-Guerin prompted us to conduct a randomized prospective comparison of oral bacillus Calmette-Guerin with the standard intravesical plus percutaneous therapy. Oral therapy consisted of 200 mg. Tice bacillus Calmette-Guerin 3 times each week. Intravesical and percutaneous Tice bacillus Calmette-Guerin at a dose of 50 mg. was given weekly for 6 weeks, at 8, 10 and 12 weeks, then at 6 months and every 6 months thereafter. Minimal side effects confirmed the safety of oral bacillus Calmette-Guerin. Tumor recurrence was documented in 21 of 33 oral bacillus Calmette-Guerin patients (64%) and 18 of 55 (33%) who received intravesical plus percutaneous therapy (p less than 0.002, chi-square test). We were unable to demonstrate any antitumor activity of oral bacillus Calmette-Guerin in this study.     

Principles of intravesical chemotherapy and immunotherapy.

By tailoring the use and selection of an intravesical agent to the individual patient, it should be possible to reduce toxicity and avoid overtreatment. Similarly, patients with more alarming disease processes can be treated sooner if the need for that more aggressive or toxic therapy is recognized early. Finally, it is important to recognize that patients who fail initial therapy with BCG have a good probability of responding to additional BCG and that there are promising investigational immunotherapies available for those who fail adequate courses of BCG.     

Comparative antitumor effects of hormonal ablation, estrogen agonist, estrogen cytotoxic derivative, and antiestrogen in the PAIII rat prostatic adenocarcinoma.

The effects of hormonal ablation, estrogen, estrogen-derived cytotoxic agent, and estrogen antagonist therapies used clinically were evaluated on in vitro colony formation, in vivo growth, and lymphatic and pulmonary metastasis of the PAIII tumor. Ventral prostatic and seminal vesicle weights were evaluated in the same animals to assess androgen-related responses. Estradiol, estramustine phosphate, and testosterone had no effects on PAIII colony formation in vitro. Castration, hypophysectomy, estradiol benzoate, and estramustine phosphate treatment of PAIII-bearing Lobund Wistar rats produced significant (P less than 0.05) regression of male accessory sex organs. Of these treatments, only hypophysectomy had significant (P less than 0.05) inhibitory effects on primary PAIII growth and lymphatic and pulmonary metastasis. LY117018 [6-hydroxy-2-(p-hydroxyphenyl)benzo(b)thien-3-yl-p-2-(l-pyrrolidin yl)ethoxy phenyl ketone] has antiestrogenic activity but produces no significant agonist responses. LY117018 had no effect upon PAIII colony formation in vitro. Following s.c. implantation of PAIII cells, LY117018 (2.0, 10.0, or 20.0 mg/kg s.c.) had no effect on primary tumor growth in the tail. In vitro LY117018 administration produced marked antimetastatic effects. In a dose-dependent manner, LY117018 inhibited PAIII metastasis to the gluteal (97%) and iliac lymph nodes (88%) (P less than 0.05 for both). LY117018 also maximally inhibited pulmonary metastasis by 86% (P less than 0.05). Maximal regression of 42% for ventral prostatic and 35% for seminal vesicle weights were also seen after LY117018 administration (P less than 0.05 for both). Co-administration of estradiol benzoate had no antagonistic effect upon the antitumor responses produced by LY117018. The mechanism of action of LY117018 is not known. The failure of estradiol benzoate to affect PAIII growth and metastasis supports the contention that the responses to LY117018 are not attributable to simple antagonism of estrogen action. LY117018 may be exerting its antitumor effects through autocrine, paracrine, or endocrine mechanisms. LY117018 represents a class of agents with potential utility in treating metastatic cancer of the prostate.     

The use of the BTA Test in the detection of persistent or recurrent transitional-cell cancer of the bladder

Summary The BTA Test is an adjunctive test for the diagnosis and management of bladder cancer. For estimation of its potential in the management of patients with transitional-cell cancer (TCC) a review of published results was undertaken. Three prospective studies were analyzed, in which a total of 699 patients with a history of TCC were enrolled. The BTA Test was performed on voided urine and compared with either voided-urine or bladder-wash cytologic analysis in a blinded fashion. In all three studies the sensitivity of the BTA Test was more than double that of cytology, irrespective of whether the cytologic analysis was performed on voided or bladder-wash samples. The third study also included an additional 225 patients undergoing evaluation for hematuria, and TCC was found in 67 cases. The BTA Test detected 70% of these tumors, whereas cytology detected only 25%. The BTA Test is a simple, rapid test that can diagnose a substantial percentage of patients having new or recurrent bladder TCC. Its complete role in the management of such patients remains to be defined.     

Fatal sepsis following intravesical bacillus Calmette-Guerin administration for bladder cancer

Intravesical administration of bacillus Calmette-Guerin has been shown to be highly effective treatment of superficial bladder cancer. Complications from bacillus Calmette-Guerin therapy are usually minor but serious and even fatal reactions can occur. Five recent cases illustrate the gravity of bacillus Calmette-Guerin sepsis. One man with severe debility and the organic brain syndrome died acutely with a fever of 40 C. Two men had frank sepsis that progressed to multiorgan failure and death. Sepsis progressed despite the use of isoniazid, rifampin and streptomycin. Two men who had equally progressive sepsis with intravesical bacillus Calmette-Guerin survived with the use of cycloserine for the first 72 hours of treatment. Triple antituberculous antibiotics, including cycloserine, may be lifesaving. Sepsis resulted from intravenous absorption through inflamed or disrupted urothelium. Bacillus Calmette-Guerin treatment should not be administered in the presence of severe cystitis or after grossly traumatic catheterization.     

In Vivo Antitumor Activity of Bropirimine Against PAIII and Dunning Mat-Lylu Rodent Prostate Cancers

Purpose

To evaluate bropirimine for in vivo activity in rodent prostate cancer.

Materials and Methods

Subcutaneously injected PAIII and Dunning MAT-LyLu rodent prostate cancer cells caused solid tumors and death in controls. Bropirimine was given on varying schedules at 250 mg./kg. by gavage, and tumor volume and survival were recorded.

Results

Bropirimine prevented growth when given on the day of tumor injection and caused 95 percent of advanced tumors to regress completely in the PAIII model. Bropirimine caused significant growth inhibition and prolongation of survival in the MAT-LyLu model.

Conclusions

Bropirimine has statistically significant in vivo activity against both of these rodent prostate cancer cell lines.     

Organization and expression of human telomere repeat binding factor genes

The ends of mammalian chromosomes terminate in structures called telomeres. Recently a human telomere repeat binding factor (TRF1) that binds the vertebrate TTAGGG telomeric repeat in situ was isolated by Chong et al. (1). TRF1 regulates telomere length (2), which is often altered in cancer cells. To understand their genetic organization, TRF1 genes were localized to human chromosomes 13 cen, 21cen, and Xq13 by analysis of human monochromosomal hybrids, and by fluorescent in situ hybridization. We also confirmed the recent localization of a human TRF1 gene to chromosome 8, and provide evidence that this locus is alternatively spliced. In contrast to the TRF1 genes on chromosomes 8 and X, the chromosomes 13 and 21 TRF1 genes contained a 60 bp deletion in the coding region. The results suggest that two distinct forms of TRF1 are expressed and that the TRF1 gene family includes at least three pseudogenes whose dispersal in the human genome may have occurred via cDNA intermediates.     

Urinary Nuclear Matrix Protein as a Marker for Transitional Cell Carcinoma of the Urinary Tract

Purpose

The purpose of this trial was to evaluate an immunoassay for urinary nuclear matrix protein, NMP22,^* as an indicator for transitional cell carcinoma of the urinary tract.

Materials and Methods

Three groups of subjects participated in this trial of NMP22: 1--175 with transitional cell carcinoma, 2--117 with benign urinary tract conditions and 3--375 healthy volunteers. Each subject provided a single (3 voids) urine sample for analysis at the time of study entry. Each sample was assayed for the level of NMP22.

Results

In normal healthy volunteers and in subjects with benign conditions median NMP22 levels were 2.9 and 3.3 units per ml., respectively. Median urinary NMP22 levels in patients with transitional cell carcinoma were significantly greater than in comparison subjects. Patients with active transitional cell carcinoma had significantly greater median urinary NMP22 levels than those with no evidence of disease (6.04 versus 4.11 units per ml., p = 0.027, 1-tailed Mann-Whitney U test). We noted no effect of tumor grade, extent of disease or exposure to intravesical therapy on urinary NMP22 levels.

Conclusions

NMP22 is a promising urinary tumor marker for monitoring transitional cell carcinoma. Nuclear matrix proteins are a new class of tumor markers that represent the basis for the development of assays with increased efficacy for the detection and treatment of cancer.     

Urinary and rectal complications of contemporary permanent transperineal brachytherapy for prostate carcinoma with or without external beam radiation therapy

BACKGROUND: Prostate brachytherapy is increasingly used to treat prostate carcinoma, alone or combined (combination therapy) with external beam radiation therapy (EBRT). This report cites the frequency and nature of urinary and rectal complications requiring unplanned interventions after contemporary brachytherapy with or without EBRT. METHODS: A total of 177 consecutive patients underwent either brachytherapy (100 patients [56.5%]) or combination therapy (77 patients [43.5%]) for clinical T1-2 prostate carcinoma between July 1998 and July 2000. All the patients were analyzed with regard to disease characteristics, treatment details, and complications requiring unplanned interventions in up to 48 months of follow-up. RESULTS: Catheter drainage for urinary retention was required for a median of 55 days (range, 3-330 days) in 36 patients (20%), including 24% after brachytherapy and 16% after combination therapy. Transurethral resection of the prostate (TURP) was performed at a median of 12 months (range, 8-18 months) after implantation in 5% of patients after brachytherapy and 14.5% of patients after combination therapy (P = 0.029). Colonoscopy with or without fulguration for rectal bleeding was performed in 37 of 158 patients (97 in the brachytherapy group and 61 in the combination therapy group) (23.4%) at a median of 17 months (range, 4-45 months), including 15 patients (15.5%) after brachytherapy and 22 patients (36%) after combination therapy (P = 0.002). Combination therapy resulted in fecal diversion in 6.6% of patients (P = 0.021), urinary diversion in 3.2% of patients (P = 0.148), and clean intermittent self-catheterization for recurrent stricture after multiple TURPs in 4.9% of patients (P = 0.055), none of which occurred after brachytherapy. Overall, 20.6% of patients underwent TURP or colonoscopy after brachytherapy, whereas 44.2% underwent those or more extensive unplanned procedures after combination therapy (P = 0.001). CONCLUSIONS: Complications requiring unplanned procedures may occur after brachytherapy, and may be increased significantly after brachytherapy combined with EBRT. These data reinforce the concept that quality assurance and technique are important in prostate brachytherapy, but, even when these are in place, complications can occur, especially when EBRT is added to brachytherapy.