Phase II trials in Ta, T1 bladder cancer. The marker tumour concept.
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Clinical Trials, Phase II as Topic↗
Biomedical subjects
K H Kurth
Publications and source records attributed to K H Kurth.
Does prostate-specific antigen density alter decision making on biopsy?
OBJECTIVE: The ability of prostate-specific antigen density (PSAD) to predict prostate cancer in biopsy specimens is evaluated in patients with benign digital rectal examination (DRE) and prostate-specific antigen (PSA) between 4.0 and 10.0 ng/ml. MATERIAL AND METHODS: 144 referred patients with a benign DRE and PSA > 4.0 ng/ml were additionally evaluated by transrectal ultrasonography and transrectal biopsies. PSAD values were calculated and statistical analysis was performed. RESULTS: The mean PSAD value was able to distinguish significantly between benign prostate conditions and prostate cancer in patients with PSA > 4.0 ng/ml. However, in 73 patients with 4.0 < PSA < or = 10.0 ng/ml no significant stratification was obtained. At a PSAD value of 0.15 the pretest probability of 18% for positive biopsy was lowered to a posttest probability of 8.1% and PSAD appeared to be of limited value regarding sensitivity and specificity at different cutoff values (ROC curve). Applying age-specific reference ranges would have reduced diagnostic procedures for men between 60 and 79 years old with 7.0% without missing prostate cancer. CONCLUSIONS: In this study PSAD was shown to have only a moderate additive value in decision making to omit biopsy for the individual patient with benign DRE and PSA between 4.0 and 10.0 ng/ml. Age-specific reference ranges of PSA can prevent unnecessary diagnostic procedures.
Adult↗
Urinary cytokines during intravesical bacillus Calmette-Guerin therapy for superficial bladder cancer: processing, stability and prognostic value.
PURPOSE: An accurate prognostic indicator to identify nonresponding patients with superficial transitional cell carcinoma of the bladder at an early stage of intravesical bacillus Calmette-Guerin (BCG) therapy is urgently needed. MATERIALS AND METHODS: The processing conditions and stability of several BCG induced urinary cytokines were analyzed, as was the possible correlation between these cytokines (indicating immune responsiveness to BCG) and bladder tumor recurrence. We studied 23 patients with superficial transitional cell carcinoma of the bladder. Monitoring was performed by serial collection of urine during the first 24 hours after each of the 6 consecutive weekly intravesical BCG instillations. Baseline pre-therapy cytokine levels were 3.9 +/- 4.7 pg./mumol creatinine for interleukin-6 and 0.1 +/- 0.2 pg./mumol creatinine for tumor necrosis factor-alpha (all measured by enzyme-linked immunosorbent assay). To investigate the correlation between interleukin-2 and bladder tumor recurrence, patients were stratified into 2 groups based on an early (6 months or less) or late (greater than 6 months) recurrent tumor. For each patient the highest cytokine value measured during the 6-week BCG treatment course was evaluated. RESULTS: The results were positive if the level in urine exceeded 0.34 units interleukin-2 per mumol. creatinine. A significant correlation between urinary interleukin-2 and tumor recurrence was found (p = 0.003, 23 patients). Of the studied cytokines obtained from BCG treated patients, interleukin-1 beta, 2 and 6 but not tumor necrosis factor-alpha were stable in urine at 4C and 20C. At 37C all cytokines were unstable. Interferon-gamma could only be detected in immediately dialyzed urine and its occurrence correlated most with that of interleukin-2. Processing of urine by centrifugation to remove leukocytes immediately after collection was not required for reliable measurements of interleukins-2 and 6. Based on these results interleukins-2 and 6 were preferred for extensive monitoring of the BCG induced immune reaction. CONCLUSIONS: Our study provides significant evidence for a correlation between urinary cytokine induction and clinical response following intravesical BCG therapy. Particularly, monitoring of interleukin-2 may have the potential for prognostic value provided that strict precautions regarding urine collection, such as maximal 2-hour sampling and immediate cooling, are taken.
Adjuvants, Immunologic↗
A combined analysis of EORTC/MRC randomized clinical trials for the prophylactic treatment of TaT1 bladder cancer. Eortc Genito-Urinary Tract Cancer Cooperative Group and the Medical Research Council Working Party on Superficial Bladder Cancer.
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Administration, Intravesical↗
Intravesical chemotherapy for superficial bladder tumors category Ta/T1: who should be treated and how?
Superficial bladder cancer is the presenting feature in 75% to 80% of patients with newly diagnosed bladder carcinoma. Treatment goals are (1) to eradicate existing disease, (2) to provide prophylaxis against recurrence, and (3) to prohibit muscular invasion and metastases to lymph nodes. First-line treatment for stages Ta and T1 disease is transurethral resection (TUR). Recurrence rates with surgery alone, however, range from 40% to 80%. Study results show a statistically significant benefit in treatment results over those observed with TUR alone when adjuvant intravesical instillation of cytotoxic agents or immunomodulators is added. Patient characteristics are important factors in determining which patients might benefit from adjuvant treatment. Based on several trials reported by the European Organization for the Research and Treatment of Cancer Genitourinary Group, the following conclusions can be drawn: (1) patients with < 1 recurrence/year or with a primary solitary bladder tumor category Ta G2-3 or T1 G1-3 may benefit from a single, early instillation of a cytotoxic agent, (2) solitary Ta G1 lesions may be treated with TUR alone, (3) adjuvant therapy with cytotoxic agents should be instituted as soon as possible after TUR (this is not feasible with immunotherapy), (4) for patients treated within 6 hours after or on the day of TUR, a 6-month course of therapy is sufficient, whereas a 12-month course provides better results for patients in whom such early intravesical instillation is not feasible.
Administration, Intravesical↗
A combined analysis of European Organization for Research and Treatment of Cancer, and Medical Research Council randomized clinical trials for the prophylactic treatment of stage TaT1 bladder cancer. European Organization for Research and Treatment of Cancer Genitourinary Tract Cancer Cooperative Group and the Medical Research Council Working Party on Superficial Bladder Cancer.
PURPOSE: The use of prophylactic agents after primary resection can decrease the incidence of tumor recurrence in patients with stage TaT1 bladder cancer. However, the long-term impact on progression to muscle invasive disease as well as on duration of survival is unknown. A combined analysis of individual patient data from previously performed European Organization for Research and Treatment of Cancer (EORTC) and Medical Research Council (MRC) randomized clinical trials was done in an attempt to answer these crucial questions. We compared immediate versus no adjuvant prophylactic treatment after transurethral resection with respect to disease-free interval, time to progression to muscle invasive disease, time to appearance of distant metastases, duration of survival and progression-free survival. MATERIALS AND METHODS: All EORTC and MRC prophylactic, randomized phase III trials with primary or recurrent, stage TaT1 transitional cell bladder cancer that compared transurethral resection alone or with adjuvant prophylactic treatment were included in the study. Four EORTC and 2 MRC trials using intravesical chemotherapy or oral agents and including a total of 2,535 patients were studied. RESULTS: A statistically significant effect of adjuvant treatment over no adjuvant treatment was found in terms of the duration of the disease-free interval (p < 0.01). No clear advantage of adjuvant treatment was shown with respect to progression to invasive disease, time to appearance of distant metastases or duration of survival and progression-free survival. Median survival followup was 7.8 years. CONCLUSIONS: Despite prologation of the disease-free-interval adjuvant treatment has no apparent long-term impact on the evolution of stage TaTi bladder cancer.
Adolescent↗
Hyperbaric oxygen treatment for haemorrhagic radiation cystitis.
Radiation-induced severe haemorrhagic cystitis is difficult to treat. Conventional treatments may decrease haematuria but do not affect the radiocystitis itself. Hyperbaric oxygen treatment has been reported to do both. We report the results of a prospective study of hyperbaric oxygen (20 sessions of 100% oxygen inhalation at 3 bar for 90 min in a multiplace hyperbaric chamber) to 40 patients with biopsy-proven radiation cystitis and severe haematuria. Haematuria disappeared completely or improved in 37 patients after treatment. Mean follow-up was 23.1 months (range 1-74); and the recurrence rate was 0.12/year. There were no adverse effects. Hyperbaric oxygen treatment should be considered for patients with severe radiation-induced haematuria.
Aged↗
Kinetics of prostate-specific antigen after manipulation of the prostate.
Kinetics of prostate-specific antigen (PSA) were investigated after manipulation of the prostate in two groups of patients: those treated with digital rectal examination (DRE), and those with needle biopsy. 8 patients had serial PSA measurements to study the effect of DRE (group 1). 7 of 8 patients had PSA baseline values < 10 ng/ml. Blood samples were taken at 1 min, 30 min, 1, 3, 6, 12 and 24 h after DRE. Some patients were further monitored for 5 days with one blood sample taken at the same time each day. Statistically significant increased PSA levels were found after DRE (P < 0.001). Maximal increase was 70%. In most patients, peak levels were found between 30 and 60 min after DRE. Based on the results, it is concluded that after DRE it is prudent to wait 3 days before PSA is determined. 7 patients had serial PSA measurements after transrectal prostate needle biopsy (group 2). PSA sampling was similar as in the previous group. All patients had increased PSA levels after biopsy (range 1.3-9.5-fold). After 5 days, only 2 of 7 patients had returned to baseline levels. We conclude that biopsies of the prostate induce an important and long-lasting PSA elevation.
Adenocarcinoma↗
Factors affecting recurrence and progression in superficial bladder tumours.
Prognostic factors in superficial bladder tumours are highly correlated with each other. In this study, their relative importance is examined and grouping of patients in three different prognostic groups suggested. 576 patients (from EORTC protocols 30790 and 30782) were analysed. They have been followed from 3 months to 8.6 years with a median of 4 years. 76 patients developed an invasive tumour (> or = T2); the shortest time to invasion was 12 weeks, the longest was 6.6 years. Time from invasion to death ranged from 3 weeks to 4.4 years with a median of 2 years. Prognostic factors contributing to recurrence, invasion and survival were investigated: age, sex, size of largest tumour, number of tumours, T-category, G-grade, time from diagnosis (years), prior recurrence rate/year, site of involvement. The relative importance of these factors was measured by performing a multivariate analysis based on Cox's proportional hazards regression model. Based on the most important prognostic factors and their association with invasion and death, an index was computed reflecting the risk of both invasion and death due to malignant disease, respectively. The index was used to assign patients to one of three prognostic groups. Three main factors determined patient's prognosis: tumour size, G-grade and prior recurrence rate/year. The model coefficients for invasion were 0.51 (recurrence rate < 1/year, 1-3/year, > 3/year), 84 (grade 1, 2, 3), 0.48 (size < 1.5, 1.5-3, > 3 cm) and for death due to malignant disease 0.89 (recurrence rate), 0.73 (grade) and 0.44 (size), respectively. Risk groups are suggested based on the index. Additional treatment in patients with superficial transitional cell carcinoma of the bladder may be decided depending on the risk group to which the patient belongs.
Adolescent↗
Placebo controlled double-blind study to test the efficacy of the aromatase inhibitor atamestane in patients with benign prostatic hyperplasia not requiring operation. The Schering 90.062 Study Group.
PURPOSE: We tested the theoretical concept that a selective decrease in estrogens has a beneficial therapeutic effect on established benign prostatic hyperplasia. MATERIALS AND METHODS: In a double-blind study 160 patients from 14 centers were randomized between 2 groups to receive either placebo or the aromatase inhibitor atamestane (1-methyl-androsin-1,4 diene-3 17-dione, 400 mg. daily for 48 weeks). RESULTS: The aromatase inhibitor decreased the mean estradiol level by approximately 40% and estrone by 60%. The testosterone concentration increased by more than 40% and dihydrotestosterone increased to 30%. Analysis of clinical parameters showed no difference between placebo and atamestane. CONCLUSIONS: The counter regulatory increase in androgens may counterbalance any positive effect of the decrease in estrogens to preserve intraprostatic homeostasis.
Aged↗
Current methods of assessing and treating carcinoma in situ of the bladder with or without involvement of the prostatic urethra.
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Carcinoma in Situ↗
Results and review of EORTC prospective randomized trials for the treatment of prostatic carcinoma.
Since its formation in the 1976, the European Organization for Research and Treatment of Cancer Genitourinary group has completed six phase III trails and six phase II trials in prostate cancer. Although these studies did not have a very strong influence on the management of prostate cancer worldwide or even in Europe, they did help investigators to design better studies and to gain some insight into the natural disease of the tumor.
Journal Article↗
Progression in untreated carcinoma of the prostate metastatic to regional lymph nodes (stage t0 to 4,N1 to 3.M0,D1). European Organization for Research and Treatment of Cancer Genitourinary Group.
PURPOSE: We attempt to contribute to the understanding of the natural history of prostate cancer metastatic to lymph nodes. MATERIALS AND METHODS: A total of 61 patients with node-positive prostate cancer was prospectively followed without adjuvant treatment for an average of 41 months. The impact of T and P categories, grade, tumor volume and prostate specific antigen change on interval to progression was studied in a univariate and multivariate analysis. RESULTS: Median interval to progression was 18 months, and correlated with grade and prostate specific antigen doubling time. Changes in prostatic volume with time were not predictive. CONCLUSIONS: Our study provides insight into the natural history of node-positive disease and identifies relevant prognostic factors that may be used for treatment decisions.
Aged↗
Intravesical adjuvant chemotherapy for superficial transitional cell bladder carcinoma: results of 2 European Organization for Research and Treatment of Cancer randomized trials with mitomycin C and doxorubicin comparing early versus delayed instillations and short-term versus long-term treatment. European Organization for Research and Treatment of Cancer Genitourinary Group.
The European Organization for Research and Treatment of Cancer genitourinary group has completed 2 parallel prospective randomized studies, one with 30 mg. mitomycin C and the other with 50 mg. doxorubicin as adjuvant intravesical treatment after transurethral resection of superficial transitional cell bladder carcinoma. These studies were designed to compare early (the day of resection) versus delayed (between 7 and 15 days after resection) instillations and short-term (6 months) versus long-term (12 months) treatment. The results indicate that in regard to recurrence rate patients having a delayed and short-term treatment do worse than those having early instillations (for 6 or 12 months) or those having prolonged treatment (either immediate or delayed). With an average followup of 4 years survival, progression beyond T1 disease, development of distant metastases and appearance of a second primary were not influenced by the therapeutic regimen. A multivariate analysis of prognostic factors is presented, which indicates that after adjustment for these factors, patients in the delay, no maintenance arm have a significantly higher recurrence rate than the other patients.
Administration, Intravesical↗
Hypercalcemia and cosecretion of interleukin-6 and parathyroid hormone related peptide by a human renal cell carcinoma implanted into nude mice.
Humoral hypercalcemia of malignancy is a paraneoplastic syndrome believed to be due to production by the tumor of substances that stimulate osteoclastic bone resorption primarily. The human renal cell carcinoma cell line RC-8, grown in nude mice, was investigated for factors involved in renal cancer-induced hypercalcemia. At a tumor load of 200 to 400 mm.3 the mice developed hypercalcemia and hypophosphatemia associated with a rise in serum 1,25-dihydroxyvitamin D concentration and cachexia. The tumor released 1) significant amounts of human interleukin-6 (IL-6) and 2) parathyroid hormone-related peptide (PTHrP) into the circulation. Cancer cells further expressed mRNA for both human IL-6 and PTHrP. No secretion of human tumor necrosis factor-alpha or interleukin-1 beta could be demonstrated in the circulation of the host. Antibodies to IL-6 caused a significant (p = 0.043) inhibition of tumor growth and decreased serum calcium concentrations compared with control animals. Our data suggest that IL-6 is involved, either directly or indirectly, in the development of hypercalcemia in renal cell carcinoma.
Animals↗
Tumor growth delay by laser-generated shock waves.
The antiproliferative effect of laser-generated shock waves (L-SW) was investigated on a human renal cell carcinoma, RC-8, grown subcutaneously in the nu/nu mouse. The RC-8 is characterized by the syndrome of humoral hypercalcemia of malignancy (HHM) associated with profound cachexia, increase of serum Ca level, hypophosphatemia, and an enhancement of serum parathyroid-like peptides. In this model system, the effects on cachexia and tumor growth were studied after a series of pulses (3-200) generated by a Candela LFDL/3 equipped pulsed-dye laser with optical fiber guided through a hypodermic needle with a 45 degrees angle bended tip, stuck through the skin of the mouse, and positioned directly below the tumor. The antitumor effect, expressed as a delay of tumor growth, was found to be dependent on number of pulses applied, tumor size, and growth rate (alpha). Treatment of RC-8 with alpha = 0.21 was effective only after 200 pulses combined with a tumor volume smaller than 100 mm3. Under these conditions a growth delay of approximately 8 days was observed, paralleled by delay of animal weight loss (cachexia). Under conditions of a decreased growth rate of RC-8 (alpha = 0.13), the susceptibility toward L-SW was found to be increased, expressed by a suppression of tumor growth after 100 pulses. However, no L-SW-associated delay of cachexia was observed under these latter conditions.
Animals↗
Glycosaminoglycans and proteoglycans in the urinary tract.
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Animals↗
Interaction between bacteria and the lumenal bladder surface: modulation by pentosan polysulfate, an experimental and theoretical approach with clinical implication.
An attempt was made to interpret bacterial adsorption to the lumenal surface of the urinary bladder wall under normal and pathological conditions according to the DLVO theory of lyophobic colloid stability, which describes the interaction between a bacterium and the bladder-wall surfaces as a balance of attraction and repulsion forces. Computer modeling suggested that a decrease in the surface potential of the bladder wall may well explain an increased bacterial adsorption, possibly associated with bacterial cystitis. With the intent of preventing bacterial adsorption, treatment of bacterial cystitis by intravesical instillation of pentosan polysulfate (PPS) was evaluated. PPS is a polysaccharide with high affinity (4 +/- 2 mg/bladder) to the bladder. The attachment of PPS strongly depends on the intrinsic properties of the bacterial surface. Theoretical considerations indicate that either complete coverage of the bacterium with PPS or an absence of PPS affinity is a prerequisite for obtaining steric interaction or prevention of bacterial sorption. Experimentally, an absence of PPS affinity (0-0.7 microgram/mg bacteria) was found for bacteria commonly found during cystitis. Immunological treatment of superficial bladder cancer by bacillus Calmette-Guérin (BCG) depends on the interaction of BCG with the bladder wall. Improvement of the treatment may be obtained by increasing BCG adsorption. In this respect, the phenomenon of bridging in which PPS binds simultaneously to both BCG and the bladder-wall surface was investigated. Theoretical considerations and experimental results appeared to be in good agreement. It was found that BCG binds a considerable amount of PPS (3.4 +/- 0.3 microgram/mg BCG). In a guinea pig model the theoretical considerations, indicating the occurrence of bridging at a low and narrow range of PPS concentrations, seemed to be confirmed. In contrast to a high PPS concentration of 10 mg/ml, at a low (0.1 mg/ml) PPS concentration a significant stimulation of the BCG-associated immune reaction(s) was observed. The results suggest that to obtain PPS-induced bridging between BCG and the bladder wall and to prevent steric interaction, PPS should be instilled prior to BCG, separated by extensive washout of free PPS.
Administration, Intravesical↗