Nuclear overexpression of p53 protein in transitional cell bladder carcinoma: a marker for disease progression.

BACKGROUND: Approximately one third of the patients with superficially infiltrative transitional cell (T1-TNM pathological staging system) bladder carcinoma who are treated with transurethral resection alone have disease progression. Despite precise pathologic staging and grading, clinical outcome in these patients is not predictable. Recent reports reveal that mutations of the p53 tumor suppressor gene (also known as TP53) occur commonly in bladder cancers. PURPOSE: The aim of this study was to investigate the hypothesis that altered patterns of expression of the protein product(s) of the mutated p53 tumor suppressor gene are associated with tumor progression in patients with T1 bladder cancer. METHODS: We examined deparaffinized tumor tissue specimens from transurethral resection in 43 patients with T1 bladder cancer who had not received adjuvant therapy. Nuclear overexpression of p53 protein was detected by immunohistochemical analysis using the mouse monoclonal antibody PAb1801, which stains both wild-type and mutant p53 proteins. The data were then correlated with the following conventional prognostic variables: age, sex, histologic presence of associated carcinoma in situ, and vascular invasion of tumor. Disease progression rates per 100 person-years were calculated. RESULTS: Median follow-up was 119 months. None of the urothelial and stromal cells from normal bladder specimens showed nuclear overexpression of p53 protein, but patients with T1 bladder tumors could be stratified into two groups with different patterns of staining for p53 protein. Eighteen patients (42%) had no more than 20% tumor cells with positive nuclear staining (group A), while the remaining 25 patients (58%) had 20% or more tumor cells with nuclear immunoreactivity (group B). Patients in group B had a significantly lower progression-free interval (P < .001). Disease progression rates were 20.5% per year for group B and 2.5% for group A. CONCLUSION: These results suggest that T1 bladder cancers exhibiting nuclear overexpression of p53 protein have a higher probability of disease progression. This study also suggests that p53 overexpression is an important prognostic factor in these patients and may be useful in selecting appropriate therapy. IMPLICATIONS: Large prospective studies are needed to confirm these results and to evaluate nuclear overexpression of p53 protein as a prognostic marker in bladder cancer.

Decreased ability of blood leukocytes from patients with tumors of the urinary bladder to act as stimulator cells in mixed leukocyte culture.

Blood leukocytes from patients with active neoplasms of the urinary bladder were found to have a decreased ability to stimulate in one-way mixed leukocyte culture (MLC). The ability of the patients' leukocytes to act as stimulator cells in one-way MLC was assessed by simultaneous comparison to the ability of leukocytes from normal individuals to stimulate. In addition, the ability of the patients' leukocytes to act as responder cells in the one-way MLC was evaluated. Cells from 31 (56%) of 55 patients with active disease exhibited subnormal stimulatory activity in the MLC while 26 of these 31 patients (84%) had normal responsiveness. Cells from 9 of the 55 failed to respond normally. Poor stimulation occurred with both early and advanced disease, and the stimulatory activity increased after tumor removal in 12 of 15 patients who had previously shown subnormal stimulation. Six patients without active disease at the time of testing, in addition to the 55, exhibited normal levels of stimulation and responsiveness. This defective stimulatory activity is suggestive of an acquired, disease-related phenomenon and is not necessarily associated with decreased blood leukocyte responsiveness.

HLA antigens in patients with germ cell cancers of the testis.

The expression of HLA-A, -B, -C, and -DR antigens has been analyzed in 145 unrelated Caucasian patients with germ cell tumors of the testis. Eighteen of these patients had pure seminoma, while the remaining patients had nonseminomatous tumors with embryonal carcinoma, teratocarcinoma, choriocarcinoma, and/or yolk sac components, with or without seminoma. Increases were noted in the frequencies of Aw33, B5, DR5, and DRw6 among the patients with pure seminoma, A3 and B7 among the patients with embryonal carcinoma with or without seminoma, and Aw32 among the patients with yolk sac tumor components. A decrease in the frequency of HLA-DR3 was noted in all patients subgroups, although none of these differences were statistically significant after correction for the number of antigens tested. HLA typing results for three affected brothers of patients indicate that, in each family, the affected sibling pair share at least one HLA haplotype. The etiological and prognostic significance of this finding and of the increases in a few HLA antigen frequencies in particular patient groups and the overall decreases in DR3 remain to be determined.

Characterization of bladder papilloma by two-parameter DNA-RNA flow cytometry.

Two-parameter flow cytometry (FCM) studies of 0.9% NaCl solution bladder irrigation specimens were performed on 48 patients with histologically orderly or atypical papilloma of the urinary bladder in order to assess the value of RNA as a possible second parameter, along with DNA, in the detection of bladder tumors. DNA, RNA, and nuclear diameter measurements were obtained for each of 5000 cells/sample, and analyses were based on the distributions of those values. With the use of DNA content alone, 22 cases (46%) were classified positive by FCM. With RNA content as an additional parameter, 40 cases (83%) were positive. Two cases were suspicious, and 6 cases were normal by both parameters. Of 28 patients with papillomas showing histological atypia, 16 patients had positive DNA histograms, including 3 patients with aneuploid stemlines, but 24 of the 28 patients had positive RNA histograms. Of 20 patients with orderly papillomas, 6 patients had positive DNA histograms, including 3 patients with aneuploid DNA stem cell lines, but 16 of the 20 patients had positive RNA histograms. Thus, the probability of positive DNA histograms is higher in atypical papillomas (57%) than in orderly papillomas (30%), whereas elevated (positive) RNA is more characteristic of all papillomas without distinction between those that are histologically atypical (86% positive) or orderly (80% positive). For patients at risk of developing papillary bladder tumors, two-parameter DNA-RNA FCM appears to offer greater diagnostic sensitivity than does FCM based on DNA content alone.

Anticarcinoma activity of rhodamine 123 against a murine renal adenocarcinoma.

The mitochondria of carcinoma cells retain the permeant cationic compound rhodamine 123 longer than the mitochondria of normal epithelial cells. The possibility of exploiting this difference in the chemotherapy of a murine renal adenocarcinoma was investigated. Rhodamine 123 exhibited anticarcinoma activity in mice and this activity was potentiated by 2-deoxyglucose and methylglyoxal bis(guanylhydrazone), a chemotherapeutic agent that is toxic to mitochondria. Prolonged retention of rhodamine 123 by renal tumor cells compared with normal renal epithelial cells was demonstrated by flow cytometry, perhaps explaining its antitumor activity. A combination of both mitochondrial toxins, rhodamine 123 and methylglyoxal bis(guanylhydrazone) produced the longest survival and had the greatest antitumor effect.

Effects of alpha-difluoromethylornithine and methylglyoxal bis(guanylhydrazone) on the growth of experimental renal adenocarcinoma in mice.

alpha-Difluoromethylornithine (DFMO) and methylglyoxal bis-(guanylhydrazone) (MGBG) were tested against a murine renal adenocarcinoma, because polyamines are necessary for neoplastic cell growth and because human renal adenocarcinomas contain higher levels of spermidine than do normal renal cells; MGBG inhibits spermidine synthesis and has some activity against human renal tumors; DFMO irreversibly inhibits ornithine decarboxylase, the first rate-limiting enzyme controlling polyamine biosynthesis; and DFMO promotes intracellular accumulation of MGBG in experimental tumor models and human leukemia. DFMO (2%) in drinking water, MGBG (15 mg/kg i.p.), or a combination of DFMO and MGBG was administered daily to BALB/c mice (n = 80) with intrarenal transplants of renal adenocarcinoma cells. At 28 days, renal carcinomas weighed 64 and 73% less, respectively, in DFMO- and DFMO-MGBG-treated mice than in control animals (p less than 0.01). MGBG alone had no antigrowth effect. DFMO-MGBG reduced the total metastatic index (total number of metastases/total number of animals) to 1.2 versus 3.6 in control animals (p less than 0.01) and increased survival by 12.3 +/- 1.5 (S.E.) days, from 30.8 to 42.5 days (p less than 0.05). Compared with control, DFMO-, or MGBG-treated animals, DFMO-MGBG exposure reduced tumor growth and the number of metastases, prevented metastases in some animals (47%), and increased survival of mice bearing renal adenocarcinomas. DFMO also appeared to selectively increase the uptake of [14C]MGBG by tumor tissue, which may help to explain the enhanced synergistic antigrowth effect of DFMO and MGBG against this murine renal adenocarcinoma.

Effect of intravesical Bacillus Calmette-Guérin on detection of a urothelial differentiation antigen in exfoliated cells of carcinoma in situ of the human urinary bladder.

Flow cytometry was used to detect and quantify expression of a urothelial differentiation antigen (Om5) and nuclear DNA in exfoliated epithelial cells of the urinary bladder from 15 patients with nonpapillary carcinoma in situ during and after intravesical therapy with Bacillus Calmette-Guérin (BCG). Before BCG treatment exfoliated cells reacting with the mouse monoclonal antibody Om5 were found in 13 cases. Following treatment Om5 positive cells were still present in 9 cases but 4 patients who had had Om5 positive cells prior to BCG therapy no longer had detectable antigen-positive cells after therapy. Thus intravesical BCG therapy can alter detection of a urothelial differentiation antigen in exfoliated bladder epithelial cells. It is not certain whether this antigen or other differentiation antigens measured by flow cytometry will advance our present techniques for assessing effects of therapy on carcinoma in situ and other bladder tumors. However, five of nine patients showing persistence of Om5 positive cells after therapy were found to have recurrent tumor by biopsy and two others had positive cytology (median follow-up, 13 months). None of the four without detectable antigen-positive cells after therapy had clinical evidence of tumor by cystoscopy, biopsy, or cytology (median follow-up, 12 months). It now appears feasible and desirable to initiate clinical investigations of this and other differentiation antigens in combination with DNA by flow cytometry of bladder irrigation specimens.

Effects of intermittent diethylstilbestrol diphosphate administration on the R3327 rat prostatic carcinoma.

Clinical trials have utilized intermittent diethylstilbestrol diphosphate (DES) therapy in advanced symptomatic prostatic carcinoma to diminish the morbidity of standard endocrine therapy. To determine the effect of intermittent DES administration on the Dunning R3327 rat prostatic adenocarcinoma 60 days following tumor implant, 6 groups were randomly assigned: control (N = 8), castrate (N = 10), high dose DES (N = 8, 1.6 micrograms/ml DES continuously in drinking water), low dose DES (N = 10, 0.4 microgram/ml continuously in drinking water), intermittent high dose DES (N = 10, 1.6 micrograms/ml DES in drinking water for 1 week, then off for 3 weeks), and intermittent low dose DES (N = 10, 0.4 microgram/ml DES for 1 week, then off for 3 weeks). Results indicate that low or high dose DES, and intermittent low or intermittent high dose DES during the week of administration were able to reduce serum testosterone to castrate levels (0.1 ng/ml). After withdrawal of intermittent DES, serum testosterone returned toward control levels (1.0 ng/ml). Initial mean tumor burden between control and treatment groups was not significantly different. All DES exposed rats had a tumor volume at death (range, 15.6-18.3 cm3) smaller than control (mean, 25.4 cm3) or castrate (mean, 40.8 cm3) rats. Despite this significant survival advantage from the time of randomization was achieved only in castrate (median survival, 331 days) or high dose DES (median survival, 359 days) groups compared to control (median survival, 225 days). Similarly, significant prolongation in tumor doubling time was achieved only by rats receiving castration or high dose DES. Intermittent DES administration controls tumor volume but does not provide a survival advantage. In this respect, intermittent DES is inferior to castration.

Transurethral resection of muscle-invasive bladder cancer: 10-year outcome.

PURPOSE: To determine the 10-year outcome of patients with muscle-invasive bladder cancer treated by transurethral resection (TUR) alone. PATIENTS AND METHODS: Of 432 newly evaluated patients with muscle-invasive bladder cancer, 151 were treated by standard radical cystectomy or by definitive TUR, if restaging TUR of the primary tumor site showed no (T0) or only non-muscle-invasive (T1) residual tumor. Patients were followed-up every 3 to 6 months thereafter for a minimum of 10 years and up to 20 years. Primary end points of the study were disease-specific survival, survival with a bladder, frequency of recurrent invasive tumors in the bladder, and survival after salvage cystectomy. RESULTS: The 10-year disease-specific survival was 76% of 99 patients who received TUR as definitive therapy (57% with bladder preserved) compared with 71% of 52 patients who had immediate cystectomy (P: = .3). Of the 99 patients treated with TUR, 82% of 73 who had T0 on restaging TUR survived versus 57% of the 26 patients who had residual T1 tumor on restaging TUR (P: = .003). Thirty-four patients (34%) relapsed in the bladder with a new muscle-invasive tumor, 18 (53%) were successfully treated with salvage therapy via cystectomy, and 16 patients (16%) died of disease. CONCLUSION: Radical TUR for muscle-invasive bladder cancer is a successful bladder-sparing therapeutic strategy in selected patients who have no residual tumor on a repeat vigorous resection of the primary tumor site.

Extravesical tumor relapse in patients with superficial bladder tumors.

PURPOSE: To define the incidence of extravesical urothelial tumors among patients with high-risk superficial bladder tumors. PATIENTS AND METHODS: Three hundred seven patients with multiple recurrent papillary and in situ carcinomas of the bladder were treated with transurethral resection and intravesical bacillus Calmette Guérin (BCG) therapy and monitored for a median of 12 years (range, 10 to 18). Extravesical tumors were detected during investigation of a positive urine cytology after no tumor was found in the bladder. RESULTS: Among 307 patients, 78 (25%) developed tumors in the upper urinary tract (UTT). Of 251 men, 61 (24%) had tumors detected in the prostatic urethra or ducts (T4p). The median times to detection of an UTT or prostatic epithelial tumor were 56 months and 11 months, respectively, and 32% of the UTT and 44% of the T4p relapses were lethal. CONCLUSION: Patients with high-risk superficial bladder tumors who are treated successfully by a bladder-sparing strategy are at increased risk for tumor relapse that involves extravesical mucosa.

Neoadjuvant chemotherapy and partial cystectomy for invasive bladder cancer.

PURPOSE: This clinical trial evaluated a bladder-sparing strategy using a combined modality approach of neoadjuvant methotrexate, vinblastine, doxorubicin, and cisplatin (M-VAC) chemotherapy followed by a partial cystectomy for patients with invasive (T2-4N0M0) bladder cancer. PATIENTS AND METHODS: One hundred eleven surgical candidates received a median of four cycles of neoadjuvant M-VAC. Following treatment, of those with a favorable response to chemotherapy based on cystoscopic examination, 26 underwent a partial cystectomy. RESULTS: Of 26 patients, 17 (65%) are alive beyond 5 years (median, 6.9 years; range, 4 to 8), including 14 (54%) with an intact, functioning bladder. Twelve patients (46%) developed bladder recurrences, which were invasive in five (18%) and superficial in seven (26%). Patients with no (P0) or noninvasive (Pis) tumor in their surgical specimens had a 5-year survival rate of 87% (14 of 16), compared with 30% (three of 10) among patients with residual invasive cancer. The majority of deaths was attributed to preexisting metastases. CONCLUSION: Neoadjuvant M-VAC chemotherapy permitted bladder-sparing surgery in selected responding patients with invasive bladder neoplasms. The bladder remained at risk for new tumor development, but local recurrences were treated successfully by local therapy or salvage cystectomy.

Upper-tract tumors after an initial diagnosis of bladder cancer: argument for long-term surveillance.

PURPOSE: To determine the relative risk (RR) of upper-tract tumors (UTT) after bladder cancer, stratified by bladder tumor characteristics, demographic factors, and follow-up duration, in order to develop an improved risk-based surveillance strategy. PATIENTS AND METHODS: The 1973 to 1996 Surveillance, Epidemiology, and End Results (SEER) database was used to determine the observed and expected number of UTT after bladder cancer. The RR with 95% confidence intervals (CI) were calculated, stratifying by race, sex, stage, grade, histology, and follow-up duration. The tumor characteristics and clinical outcome were compared in patients with UTT after bladder cancer and those with de novo UTT. RESULTS: A total of 94,591 patients had a first diagnosis of bladder cancer, of whom 91,245 had follow-up (median, 4.1 years), with no antecedent or synchronous UTT. UTT developed subsequently in 657 of 91,245 (0.7%), with 12.80 expected cases (RR = 51.3; 95% CI, 47.5 to 55.4). The respective RRs for UTT for white men and women were 64.2 (95% CI, 55.1 to 74.3) and 75.4 (95% CI, 57.7 to 96.9) at less than 2 years, 44.3 (95% CI, 36.7 to 53.0) and 40.5 (95% CI, 27.9 to 56.8) at 2 to 5 years, 50.8 (95% CI, 42.2 to 60.7) and 42.1 (95% CI, 28.8 to 59.4) at 5 to 10 years, and 43.2 (95% CI, 32.6 to 56.1) and 22.2 (95% CI, 10.1 to 42.2) at >or= 10 years. Similar RRs were seen among different strata of race, stage, grade, and histology. Patients with UTT after bladder cancer had lower stage and improved disease-specific survival compared with those with de novo UTT. CONCLUSION: The incidence of UTT is stable on long-term follow-up, with no significant risk factors identified. These findings suggest that upper-tract surveillance remain rigorous on extended follow-up of bladder cancer patients.

Neoadjuvant chemotherapy and bladder-sparing surgery for invasive bladder cancer: ten-year outcome.

PURPOSE: To evaluate the 10-year outcome of patients with invasive (T2-3N0M0, staged according to the tumor, node, metastasis system) bladder cancer who responded completely to a combination of methotrexate, vinblastine, adriamycin, and cisplatin (MVAC) chemotherapy followed by bladder-sparing surgery. PATIENTS AND METHODS: Of 111 surgical candidates who received neoadjuvant MVAC, 60 (54%) achieved a complete clinical response (T0) on transurethral resection (TUR) of the primary tumor site. Of these, 28 requested follow-up with TUR alone, 15 had a partial cystectomy, and 17 elected a radical cystectomy. The patients were followed up for a median of 10 years (range, 8 to 13 years). RESULTS: Of 43 patients who had bladder-sparing surgery, 32 (74%) are alive, which includes 25 (58%) with an intact functioning bladder. Twenty-four patients (56%) developed bladder tumor recurrences from 5 to 96 months, which were invasive in 13 (30%) and superficial in 11 (26%). Thirteen patients required a salvage cystectomy, of whom 6 died, which includes 4 (9%) from a new invasive neoplasm. Of the 17 patients who had radical cystectomy, 11 (65%) are alive. CONCLUSION: The majority of patients with invasive bladder tumors who achieve T0 status after neoadjuvant MVAC chemotherapy preserve their bladders for up to 10 years with bladder-sparing surgery. The bladder remains at risk for new invasive tumors. Cystectomy salvages the majority, but not all, of relapsing patients.

Paternity in men with stage I testis tumors on surveillance.

PURPOSE: We report long-term paternity in men with stage I testis tumors who were managed initially by surveillance. PATIENTS AND METHODS: One hundred five patients with clinical stage I nonseminomatous germ cell tumors of the testis were entered on a surveillance protocol and followed up for more than 10 years. Actual fertility potential was assessed by pregnancy. RESULTS: Of the 105 patients, 41 (39%) have fathered children, which includes 36 of 78 (46%) patients while on active surveillance and five of 27 (19%) patients after treatment for relapse. Of 63 couples who attempted a pregnancy on surveillance or were presumed capable of impregnation (whether they tried or not), 41 (65%) were successful. CONCLUSION: These results show that the majority of men with stage I testis tumor who are on surveillance after orchiectomy, have a suitable partner, and attempt impregnation achieve a successful pregnancy. Pregnancy rates appear to be less than reported in men who have a nerve-sparing retroperitoneal lymph node dissection (RPLND) because more patients on surveillance require treatment for relapse, which reduces their chances for pregnancy.

Prognostic value of p53 nuclear overexpression in patients with invasive bladder cancer treated with neoadjuvant MVAC.

PURPOSE: This study sought to examine the prognostic role of p53 nuclear overexpression in muscle-invasive bladder cancer because of its correlation with progression of superficial bladder cancer. PATIENTS AND METHODS: Ninety of 111 patients treated with neoadjuvant methotrexate, vinblastine, doxorubicin, and cisplatin (MVAC) with a median follow-up duration of 5.8 years were evaluated. p53 nuclear overexpression was determined by immunohistochemistry on deparaffinized tissue sections. Patients were stratified into two groups according to the percent of tumor cells with positive nuclear reactivity. Overexpression was defined as tumors with > or = 20% cells with positive nuclear reactivity and nonoverexpression as tumors with less than 20% reactivity. RESULTS: Nuclear overexpression was observed in 47 patients and nonoverexpression in 43 patients. Patients whose tumors had p53 overexpression had a significantly higher proportion of cancer deaths. A multivariate analysis that evaluated the pretreatment variables p53 nuclear overexpression, age, sex, palpable mass, prechemotherapy tumor stage, performance status, ureteral obstruction, tumor size, multifocality, and grade showed that p53 overexpression had independent significance for survival (P = .001; relative risk ratio, 3.1). The impact of p53 overexpression on survival was predominantly in T2 and T3a tumors. Long-term survival was evident in seven of 17 patients (41%) with p53 overexpression versus 20 of 26 (77%) in whom p53 was not overexpressed (P = .007). CONCLUSION: p53 nuclear overexpression has independent prognostic value for survival in patients with invasive bladder cancer treated with neoadjuvant chemotherapy.

Intravesical bacillus Calmette-Guérin therapy prevents tumor progression and death from superficial bladder cancer: ten-year follow-up of a prospective randomized trial.

PURPOSE: Superficial bladder tumors (stage Ta, T1, and Tis) may progress to invade the bladder muscle and cause death from metastatic cancer. Transurethral tumor resection (TURB) is the standard therapy for such tumors, but surgery alone may not prevent tumor progression. Intravesical therapy is widely used as an adjunct to TURB. Bacillus Calmette-Guérin (BCG) is the most active intravesical agent, but whether BCG prevents tumor progression and death from bladder cancer is unknown. PATIENTS AND METHODS: Between 1978 and 1981, 86 high-risk patients with superficial bladder cancer were randomly assigned to receive either TURB (n = 43) or TURB plus BCG (n = 43). Adverse tumor features for progression were equally distributed between the two groups. BCG was administered weekly for 6 weeks. Patients were evaluated every 3 to 6 months thereafter for progression to muscle invasion or metastasis. Control (TURB) patients with recurrent superficial tumors were eligible for crossover to the BCG arm. All patients have been monitored until event or for a minimum of 10 years (range, 10 to 14). RESULTS: The 10-year progression-free rate was 61.9% (95% confidence interval [CI], 47.2% to 76.7%) for patients treated with BCG and 37% (95% CI, 22.9% to 53.1%) for control patients. The median progression-free interval was not reached for the BCG group and was 46 months for the control group (P = .0063). Of 18 control patients crossed over to BCG (median, 29 months), 15 did not show tumor progression. TURB plus BCG resulted in a 10-year disease-specific survival rate of 75%, compared with 55% with TURB alone (P = .03). CONCLUSION: This study shows that intravesical therapy with BCG delays tumor progression and death from tumor in patients who present with superficial bladder cancer.

Neoadjuvant chemotherapy for invasive bladder cancer: prognostic factors for survival of patients treated with M-VAC with 5-year follow-up.

PURPOSE: To determine survival in patients with muscle-invasive bladder cancer treated with neoadjuvant chemotherapy and to analyze prechemotherapy and postchemotherapy factors for prognostic significance. PATIENTS AND METHODS: The survival of 111 patients with T2-4N0M0 bladder cancer treated with neoadjuvant methotrexate, vinblastine, doxorubicin, and cisplatin (M-VAC) was assessed. Prechemotherapy and postchemotherapy factors were analyzed for correlation with survival. Factors found to be significant on univariate analysis were subjected to multivariate analysis using Cox's proportional hazards model. RESULTS: The median follow-up duration was 5.3 years. Initial tumor (T) stage (P = .0001), presence of ureteral obstruction (P = .0074), and presence of a palpable mass (P = .0039) were the only pretreatment factors found to be significant on univariate analysis. Postchemotherapy surgery was performed in 81 patients. In these cases, postchemotherapy clinical stage and pathologic stage were significant factors on univariate analysis. In the multivariate analysis, the initial prechemotherapy T stage and the postchemotherapy pathologic stage (pT stage) were the only two factors to demonstrate independent significance. An association between downstaging postchemotherapy and survival was observed for patients with extravesical disease (T < or = 3B) at the start of treatment. In this subset, the 5-year survival rate was 54% for patients with downstaging versus 12% for those without downstaging. This association was not observed for patients with bladder-confined disease (T < or = 3A) at presentation. CONCLUSION: The stage of bladder cancer at presentation and at postchemotherapy pathologic staging are independent prognostic factors for long-term survival in patients treated with neoadjuvant chemotherapy. Downstaging after neoadjuvant chemotherapy was associated with improved survival in patients with muscle-invasive bladder cancers, but only for those with extravesical disease (T > or = 3B) pretreatment. Randomized comparisons will be required to assess the impact of chemotherapy on overall survival.

Overexpression of p53 protein in a high-risk population of patients with superficial bladder cancer before and after bacillus Calmette-Guérin therapy: correlation to clinical outcome.

PURPOSE: We have previously demonstrated that p53 overexpression is predictive of disease progression and survival in Ta, Tis, and T1 tumors. Instillation of Bacillus Calmette-Guérin (BCG) is now accepted to be the most efficient adjuvant therapy for superficial bladder carcinoma. The aim of this study was to determine if p53 status, assessed before and after intravesical BCG therapy, can predict clinical outcome in a high-risk population of patients with superficial bladder carcinoma. MATERIALS AND METHODS: We examined 196 tissue specimens from 98 patients, obtained immediately before and after intravesical BCG therapy. The pretherapy population was composed of 22 Ta, 57 Tis, and 19 T1 tumors. After BCG, 66 specimens were TO and 32 had residual tumors. Nuclear p53 overexpression was analyzed in relation to time to disease progression and disease-specific survival. RESULTS: The median follow-up duration was 44 months. The detection of nuclear p53 overexpression before BCG therapy did not predict response to BCG therapy. Pre-BCG p53 protein overexpression, response to BCG therapy, and pre-BCG stage were all independent markers of disease progression. In patients with residual disease after BCG therapy (nonresponders), multivariate analysis confirmed that posttherapy p53 overexpression was the only independent marker of disease progression. CONCLUSION: In this high-risk population of patients with superficial bladder tumors, patients who have p53 nuclear overexpression in the tumor and stage T1 disease before BCG therapy are at high risk of disease progression. Furthermore, in the group of patients with residual disease after BCG therapy, p53 status is a better predictor of disease progression than post-BCG stage.

A prospective randomized trial of maintenance versus nonmaintenance intravesical bacillus Calmette-Guérin therapy of superficial bladder cancer.

Between August 1981 and July 1984, 93 patients with polychronotopic superficial papillary carcinoma (Ta and/or T1), flat carcinoma in situ (Tis), or concomitant superficial papillary and in situ bladder carcinoma were entered into a prospective randomized trial of maintenance v nonmaintenance intravesical bacillus Calmette-Guérin (BCG) therapy. Forty-six patients who received BCG weekly for 6 weeks were compared with 47 patients receiving the six-weekly doses of BCG plus monthly BCG for 2 years. Both groups were evaluated every 3 months by cytology, cystoscopy, and biopsy. A significant reduction in the number of recurrent tumors per patient-month was demonstrated for both groups (P less than .0001); however, the difference in reduction of tumors between the two groups was not significant. Additionally, patients receiving maintenance and nonmaintenance therapy had similar tumor recurrence and progression rates. These results indicate that monthly maintenance BCG does not prevent, delay, or reduce tumor recurrence or progression observed with the 6-week regimen. Maintenance BCG was associated with increased local toxicity, primarily dysuria, frequency, and urgency. Dosage reduction was required in 22 of 47 patients (46.8%). When the data were subjected to multivariate analysis, the presence or absence of tumor following induction BCG and PPD skin test results were found to be significant variables. Controlling for either the presence or absence of tumor following induction BCG, tumor recurrence and progression rates were not significantly different for the two treatment groups. However, the absence of tumor after induction BCG was associated with a longer disease-free duration (P = .00001) and time to progression (P = .095). Patients with a reactive tuberculin skin test before and after induction BCG had significantly less tumor recurrences than patients with different PPD skin tests results (P = .02). Tumor progression was not related to tuberculin skin testing.

Bacillus Calmette-Guérin therapy alters the progression of superficial bladder cancer.

The effectiveness of BCG in preventing disease progression in patients with superficial bladder cancer is evaluated. Long-term follow-up of high-risk patients treated in a previously reported randomized control trial of intravesical plus percutaneous BCG shows that progression occurred in 41/43 (95%) of control and 23/43 (53%) of BCG-treated patients. Muscle invasive and/or metastatic disease occurred with equal frequency in the two groups, but was significantly delayed by BCG treatment (P = .012). Cystectomies were required in 18/43 (42%) control and 11/43 (26%) BCG-treated patients. Median time to cystectomy was 8 months for control v 24 months for BCG-treated patients. Based on initial treatment, survival was improved by BCG therapy (P = .032) (median follow-up 6 years). These results suggest that in high-risk patients intravesical BCG can delay disease progression, prolong the period of bladder preservation, and increase overall survival.