PURPOSE:The standard approach to treatment for patients with high risk Ta, Tis, or T1 bladder cancer that persists or recurs after bacillus Calmette-Guerin is radical cystectomy in medically fit patients. Maintenance bacillus Calmette-Guerin has been shown in both SWOG (Southwest Oncology Group) and EORTC (European Organization for Research and Treatment of Cancer) studies to reduce the probability of disease worsening events. As new drugs come on line and experience with maintenance and combination immunotherapy increases, there may be a tendency to delay definitive local therapy and thereby expose patients to a higher risk of progression to invasive and potentially metastatic disease. We explored a large prospective data set from the SWOG 8507 randomized trial of maintenance bacillus Calmette-Guerin to better understand this risk and specifically to assess the impact of timing of recurrence on survival. MATERIALS AND METHODS:The database includes 501 evaluable patients who were treated with induction bacillus Calmette-Guerin and then were randomized to maintenance bacillus Calmette-Guerin or observation. Recurrence patterns were defined as early (less than 12 months following randomization) or late (12 or more months after randomization). Patients were identified who underwent cystectomy at any time after induction bacillus Calmette-Guerin. All patients were followed for life for determination of vital status. Outcome measure of overall survival was assessed using Kaplan-Meier analysis and adjustment for covariates was done with proportional hazards models. Survival was defined from date of randomization to death from any cause. RESULTS:A total of 501 patients were randomized after induction bacillus Calmette-Guerin, of whom 251 had recurrence and 229 died. Of the patients who died 59% had recurrence following randomization. Early recurrence was not associated with a higher risk of death compared to late recurrence (p=0.68). There was no evidence that bacillus Calmette-Guerin affected the relationship of timing of relapse and survival. There was no difference in progression to T2 or greater between early and late recurrence (38 of 117, 32% vs 34 of 134, 25%; p=0.21). Cystectomy was performed infrequently as 56 of 251 patients who had recurrence underwent the operation. Patients who had early recurrence had a slightly higher cystectomy rate than those with late recurrence (32 of 117, 27% vs 24 of 134, 18%; p=0.07). Among 394 patients with no evidence of disease at randomization those who underwent cystectomy for T2 or greater disease had a higher risk of death compared to patients who underwent cystectomy for Tis or T1 disease (HR 1.76; 95% CI 0.77, 4.00; p=0.18). CONCLUSIONS:There was no association of the timing of recurrence after induction bacillus Calmette-Guerin on long-term survival probability. When patients had early recurrence there was a slightly higher probability of cystectomy but not progression to muscle invasive cancer. When cystectomy was performed the 5-year postoperative survival probability was lower than that reported in contemporary series.

Cancer is a major cause of mortality and morbidity throughout the world and is projected to become the leading cause of death in the United States and other developed countries in the next few years. There is a large body of evidence linking diet and nutrition with the development of urologic cancers. This is an area where intervention and education can have a major preventive effect on the occurrence of cancer on a worldwide basis. With bladder cancer, a significant protective effect is conferred by a combination of high doses of vitamins A, B6, C and E plus zinc. For prostate cancer, reduced fat intake has a protective effect. A lesser benefit is also suggested with intake of vitamins D and C. Evidence for chemoprevention against renal cell cancer is supported mainly by epidemiologic studies with animal studies indicating possible benefit of vitamin D supplementation. Further research is needed before vitamins and other nutritional supplements can be advocated as standard therapy. Current data support increased intake of vitamins A, B6, C, D and E, reduction of animal fat and increased intake of fruits and vegetables.

Article Tools EDITORIALS Article Tools OPTIONS & TOOLS Export Citation Track Citation Add To Favorites Rights & Permissions COMPANION ARTICLES No companion articles ARTICLE CITATION DOI: 10.1200/JCO.2003.08.099 Journal of Clinical Oncology - published online before print November 1, 2016 PMID: 14581444 Intravesical Therapy for Superficial Bladder Cancer: Slow but Steady Progress Donald L. LammxDonald L. LammSearch for articles by this author Show More Deparment of Urology, Mayo Clinic in Scottsdale, Scottsdale, AZ https://doi.org/10.1200/JCO.2003.08.099 Full Text PDF Figures and Tables "Intravesical Therapy for Superficial Bladder Cancer: Slow but Steady Progress." Journal of Clinical Oncology, 21(23), pp. 4259–4260© 2003 by American Society of Clinical Oncology

Many people do not realize that smoking tobacco is the single most important known risk factor for bladder cancer. Smoking is estimated to contribute to 50% of bladder tumors. Current smokers are at higher risk than former smokers. Second-hand smoke can also increase the risk for the development of bladder cancer. While many people think “vaping” is safer than smoking, recent research suggests that both e-cigarettes and traditional cigarettes contribute to an increased risk for bladder cancer.

The goals of this study were to determine the expression of metallothionein isoform 1 and 2 proteins (MT-1 and MT-2) in bladder cancer and then to determine which MT isoform-specific genes promoted the expression of these proteins. Immunohistochemical analysis disclosed no immunoreactivity for MT-1 and MT-2 (designated as MT-1/2 to reflect the nonspecificity of the antibody for the two isoforms) in cells comprising the normal bladder or in nonmalignant bladder disorders, such as cystitis and interstitial cystitis. Immunohistochemical analysis demonstrated that MT-1/2 was overexpressed in all samples of carcinoma in situ and in high-grade bladder cancer, with variable overexpression in low-grade bladder cancer and dysplastic lesions. The intensity and frequency of MT-1/2 staining correlated with the grade of the tumor. The MT-1 and MT-2 proteins are encoded by a family of eight genes (MT-1A, MT-1B, MT-1E, MT-1F, MT-1G, MT-IH, MT-1X, and MT-2A), and reverse transcriptase-polymerase chain reaction was used to determine which genes were expressed in the normal bladder and in bladder cancer. This analysis demonstrated that both normal and cancerous bladder tissue expressed mRNA for the MT-2A and MT-1X genes. The expression of MT-1E mRNA was variable in both normal bladder and bladder cancer specimens. Comparison of expression relative to that of beta-actin demonstrated that the level of MT-1X mRNA was overexpressed greatly in bladder cancer as compared to the level in normal bladder tissue. In contrast, the level of MT-2A mRNA was similar in both the normal and the bladder cancer specimens. The level of MT-1X expression did not vary with tumor grade. These studies suggest that the overexpression of MT-1/2 protein in bladder cancer is a result of the overexpression of the MT-1X gene.

Of the many beneficial actions of garlic, inhibition of the growth of cancer is perhaps the most remarkable. Our previous animal studies demonstrated that aged garlic extract was highly effective, and unlike the approved immunotherapy for human bladder cancer, bacillus Calmette--Guérin (BCG), garlic was effective when added to the diet. To elucidate the mechanism of this antitumor effect, the literature describing antitumor and immune-enhancing effects of garlic is reviewed. Garlic can detoxify carcinogens by stimulation of cytochrome P(450) enzymes, antioxidant activity or sulfur compound binding. Studies demonstrate a direct toxic effect of garlic to sarcoma and gastric, colon, bladder and prostate cancer cells in tissue culture, but these effects cannot explain the inhibition of growth of transplanted cancer in animal models. The most likely explanation of this effect is immune stimulation. Comparison of the effects of garlic to BCG immunotherapy reveals many similarities. Both stimulate proliferation of lymphocytes and macrophage phagocytosis, induce the infiltration of macrophages and lymphocytes in transplanted tumors, induce splenic hypertrophy, stimulate release of interleukin-2, tumor necrosis factor-alpha and interferon-gamma, enhance natural killer cell, killer cell and lymphokine-activated killer cell activity. These activities represent effective stimulation of the immune response. Studies suggest that garlic may be useful in preventing the suppression of immune response that is associated with increased risk of malignancy. Data suggest that maintenance of immune stimulation can significantly reduce the risk of cancer. Clinical trials should be initiated to test the hypothesis that the immune stimulation and other beneficial effects of garlic are able to reduce the incidence of cancer.

In the United States, bladder cancer is the fourth most common human malignancy. In the past decade, the incidence of bladder cancer has increased by 36%. However, mortality has declined by 8%. Intravesical chemotherapy was considered to be partially responsible for this improvement in survival, but a recent review of clinical studies shows no reduction in disease progression with intravesical chemotherapy. Fortunately, the results of immunotherapy with bacille Calmette-Guérin (BCG) are quite different, and it is expected that patients treated with optimal BCG treatment regimens will have a long-term reduction in tumor recurrence, tumor progression, and cancer mortality.

Objective: This study was undertaken to identify the expected first- and second-year clinical costs associated with intravesical valrubicin therapy, using a decision analytic model, for patients with Bacilli Calmette-Guerin (BCG)-refractory carcinoma in situ (CIS) of the urinary bladder.Background: Cancer of the urinary bladder is the fourth most common malignancy in men and the sixth most common noncutaneous carcinoma overall. One histopathologic stage of bladder cancer is CIS, for which BCG intravesical immunotherapy is the first-line therapy. Radical cystectomy has been recommended for patients with CIS who do not respond to or become refractory to therapy with BCG. Surgery, however, may not be appropriate for all patients, especially those who are ineligible for the lengthy procedure because of advanced age or comorbidities and those who prefer alternative nonsurgical management. For these groups, intravesical valrubicin therapy is a plausible alternative.Methods: Models were developed and populated with data from 1 open-label study of 90 patients, information from the medical literature, and input from clinical experts. The analysis was conducted from the payor perspective for direct costs only.Results: Our data indicate that first- and second-year expected costs for valrubicin therapy are $19,912 and $23,496, respectively. Expected cost for radical cystectomy was also evaluated, since some patients may have no other option if drug therapy fails.Conclusion: Our cost-consequence analysis and clinical data provide decision-makers with tools to aid in global budgetary projections of fractional and total expected health care costs associated with the management of BCG-refractory CIS of the urinary bladder.

BCG immunotherapy provides a superior reduction in tumour recurrence compared with chemotherapy. Unlike chemotherapy, however, it also appears to reduce disease progression. The benefit of BCG is long-term, but protection from disease progression without maintenance therapy is lost when comparisons are made after 15 years. Data suggest that optimal maintenance therapy with BCG provides even better protection from tumour recurrence, reduces disease progression and improves survival. Maintenance BCG schedules using single instillations at 1–3 month intervals have not been proved to be better than induction alone. However, a Southwest Oncology Group (SWOG) study using three, weekly instillations of Connaught BCG, found this regimen to be markedly superior. Before the introduction of BCG, carcinoma in situ (CIS) would progress to muscle invasion in 52% of patients. In the SWOG study, the additional instillations increased the complete response rate in CIS from the expected 68% to 84%. With maintenance BCG, long-term (7 years) tumour recurrence in high-risk patients reduced from the expected 52% with a single 6-week course to only 25% (p < 0.000001). Worsening-free survival, defined as the absence of evidence of disease progression, including pathologic stage T2 or greater disease, or the need for systemic chemotherapy, radiation therapy or cystectomy, significantly increased (p < 0.049, log rank test). In 391 randomized patients, the already excellent 86% survival at 4 years observed with induction therapy improved to 92% in patients receiving maintenance BCG (p < 0.04). There is thus increasingly good evidence that BCG maintenance therapy, at the optimal treatment schedule, provides superior protection from tumour progression and recurrence, and improves long-term survival.

The purpose of this study was to examine the effect of moderate treadmill exercise on the development of prostate cancer. in rats. A secondary objective was to find out if animals were homogeneous in their response to a given exercise intensity. Forty male Lobund-Wistar rats were randomly assigned to treadmill exercise (TE; n = 20) or control (C; n = 20) groups. Treadmill exercise consisted of running on a motor-driven treadmill at 20 m.min(-1) (73.4 +/- 13.1% (V)over dotO(2)max), 15 min daily 3 times weekly for 6 weeks. Following the 6-week period, all animals were inoculated with 1 x 10(6) transplantable rat prostate cancer (PA-m) cells, subcutaneously on the back above the sacral region (Day 0). The TE group exercised two more weeks post-inoculation. Maximum (V)over dotO(2) did not change in either group during the initial 6-week training period, nor was it different between groups at either time, mean values ranging from 64.4 +/- 4.6 to 66.0 +/- 4.4 ml.min(-1).kg(-1). The numbers of rats displaying tumour on Day 30, were in groups TE and C alike (20 and 18: respectively). The total tumour volumes and numbers of lung metastatic lesions, determined on Days 30 and 45 (n = 10 each) did not differ between groups. In the TE group, the post-training maximum treadmill time and body mass was negatively correlated (r = -0.687; P < 0.05) while training intensity and the number of lung metastatic lesions - positively (r = 0.691; P < 0.05). The treadmill exercise protocol was not sufficient to elicit a training response and had no significant effect on the incidence or growth of prostate cancer in rats although animals which exercised at the highest intensity had the greatest number of lung metastatic lesions. It appears that rodents may not be homogeneous in their response to a given load.

INTRODUCTION AND OBJECTIVE Photodynamic therapy (PDT) combines a photosensitizer such as Photofrin with red laser light (630 nm) to destroy cancer cells. Investigators have reported effectiveness of PDT in the management of patients with recurrent superficial bladder cancer. We retrospectively reviewed our experience in 58 patients to assess the long-term role of PDT in the management of resistant superficial transitional cell carcinoma (TCC) including Ta, T1, and refractory carcinoma in situ (CIS) of the urinary bladder. MATERIALS AND METHODS All 58 patients had failed at least one course of standard intravesical therapy or had contraindication for intravesical chemo- or immunotherapy. Patients with malignancy present (Ta-T1/Grade I-III, CIS) were accepted for ablative PDT. Patients undergoing prophylactic PDT after complete resection were confirmed to be tumor-free by cystoscopy and bladder was cytology before PDT. Post-PDT evaluations included weekly telephone contact to assess acute adverse reactions and assessment of efficacy and bladder toxicity at three months and quarterly thereafter. RESULTS These 58 patients underwent a single PDT treatment with 2.0 or 1.5 mg/kg of Photofrin and 10-60 J/cm2 light (630 nm). At three months, complete response rates were 84% and 75% for residual resistant papillary TCC and refractory CIS respectively; and 90% of patients treated prophylactically had not had recurrences. At a median followup of 50 months (range 9-110), 59% (34/58) of the responders are alive, with 31/34 still disease-free. CONCLUSION PDT using 1.5 mg/kg of Photofrin and 15 J/cm2 of light (630 nm) should be considered a safe and effective treatment for refractory CIS or recurrent papillary TCC.

The most obvious improvements in the care of patients with bladder cancer over the past 20 years are bacille Calmette-Guérin immunotherapy for superficial bladder cancer and cisplatin and methotrexate-based combination chemotherapy for advanced disease. The challenges that remain are prevention, early detection, and improved treatment of both superficial and advanced disease. Meeting these challenges requires research, financial investment, and public education.