Phase II trials in Ta, T1 bladder cancer. The marker tumour concept.
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Clinical Trials, Phase II as Topic↗
Biomedical subjects
R Sylvester
Publications and source records attributed to R Sylvester.
Chemoresection in Ta-T1 bladder cancer. Members of the EORTC Genito-Urinary Group.
OBJECTIVES: The authors present the results of two parallel phase II trials, instituted by the EORTC Genito-Urinary Group in 1986, whose aims were to assess the tolerability and ablative capacity of mitomycin C (study 30864) and epirubicin (study 30869) in patients with multiple primary or recurrent Ta-T1 bladder cancer. METHODS: A well-defined tumour (marker lesion) was left in the bladder after transurethral resection (TUR). All patients received 8 weekly instillations, after which cystoscopy with bladder biopsies +/- TUR was performed. Responses were rated as follows: (1) complete-no visible or microscopic bladder cancer; (2) no change-persistence of the marker lesion; (3) progression-increased marker lesion size, new tumour(s) or presence of muscle-invasive disease at any site. RESULTS: Ninety-six evaluable patients were treated with mitomycin and 36 with epirubicin. The overall bladder response in the former group was complete in 50%, no change in 30% and progression in 20% of patients, while the marker lesion response was complete in 57%, no change in 39% and progression in 4%. In the epirubicin group, 56% of the patients achieved a complete overall response, while there was no change in 22% and progression in 22%. The marker lesion response in this group was complete in 67%, no change in 31% and progression in 3%. Only 2 cases of progression were due to the presence of muscle-invasive disease. Both of these were in the mitomycin group; 1 was at the marker lesion site, and 1 was at a remote site. CONCLUSIONS: The present studies confirm the feasibility and safety of the marker lesion model for the objective evaluation of the antitumoural activity of intravesically administered drugs.
Administration, Intravesical↗
Marker tumour responses to the sequential combination of intravesical therapy with mitomycin-C and BCG-RIVM in multiple superficial bladder tumours. Report from the European Organisation for Research and Treatment on Cancer-Genitourinary Group (EORTC 30897).
OBJECTIVES: To study the ablative activity of intravesical mitomycin C followed by intravesical bacillus Calmette-Guérin (BCG) on a papillary marker tumour and to determine the incidence of side effects. METHODS: Thirty-five patients with multiple pTa or pT1 bladder tumours were treated with 4 instillations of mitomycin C at weekly intervals followed by 6 instillations at weekly intervals of BCG-RIVM. All visible tumours were resected before starting intravesical instillations except one marker tumour. Response was determined 2 weeks after the last instillation. RESULTS: The incidence of adverse effects was similar to previously reported toxicity of either mitomycin C or BCG alone. Complete response, histologically proven, was observed in 16 of 35 patients and in 3 patients without histological confirmation. One patient showed progression. CONCLUSION: The sequential combination of mitomycin C and BCG is an efficacious treatment. The measurement of response to a marker tumour is a safe and efficient method to test new drugs or combinations of drugs.
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↗
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↗
Cisplatin, vincristine and ifosphamide combination chemotherapy of metastatic seminoma: results of EORTC trial 30874. EORTC GU Group.
The aims of the trial were to establish the response rate and determine the toxicity of combination chemotherapy with ifosphamide, vincristine and cisplatin (HOP regimen) in advanced metastatic seminoma and to study the role of post-chemotherapy consolidation treatment. Patients with bulky metastatic non-alpha-fetoprotein-producing seminomas were eligible for this phase II study [serum human chorionic gonadotropin < 200 U l-1 (< 40 ng l-1)] if they presented with abdominal masses > or = 10 cm or had extra-gonadal seminoma or had relapsed after previous radiotherapy. The HOP regimen consisted of four 3-weekly cycles of the following drug combination: ifosphamide (days 1-5, 1.2 mg m-2 day-1), vincristine (day 1, 2 mg) and cisplatin (days 1-5, 20 mg m-2 day-1). Residual masses persisting 6 months after chemotherapy could be considered for consolidation surgery or radiotherapy. Maximal response to the HOP chemotherapy (evaluated at any time) was based on the WHO criteria. The median observation time was 2.5 years (range 1.8-5.5 years). Thirteen institutions treated 42 eligible patients within the study (testicular cancer stage > or = IID, 25; extragonadal, 5; relapse after previous radiotherapy, 12). Two patients were not evaluable for response owing to premature treatment discontinuation. Maximal response was as follows: complete remission (CR), 26 (65%); partial remission (PR) 11 (28%); no change (NC), 2 (5%); progressive disease (PD), 1 (3%). Four patients have died, three from their malignancy (two without previous irradiation and one with prior radiotherapy). The fourth patient died of treatment-related toxicity. The 3 year survival for all 42 eligible patients was 90%. Dose reduction and treatment postponement were necessary in 25 and 14 patients respectively. Ten patients experienced granulocytic fever. Previously irradiated patients tolerated chemotherapy as well as non-irradiated patients. Immediately after HOP chemotherapy a mass persisted in 16 of 17 patients with retroperitoneal masses of > or = 100 mm at presentation. Three of these residual lesions were resected within the following 6 months showing complete necrosis. Four lesions dissolved spontaneously during the first year of follow-up. Nine lesions persisted for > or = 1 year (one after consolidation radiotherapy) without leading to relapse. Four of seven patients with mediastinal lesions achieved CR and three a PR after HOP chemotherapy. The HOP chemotherapy regimen is highly effective in patients with advanced metastatic seminoma or those relapsing after previous radiotherapy, but is associated with a high risk of toxicity, in particular myelotoxicity.
Aged↗
Four cycles of BEP versus an alternating regime of PVB and BEP in patients with poor-prognosis metastatic testicular non-seminoma; a randomised study of the EORTC Genitourinary Tract Cancer Cooperative Group.
We have investigated whether an alternating induction chemotherapy regimen of PVB/BEP is superior to BEP in patients with poor-prognosis testicular non-seminoma. A total of 234 eligible patients were randomised to receive an alternating schedule of PVB/BEP for a total of four cycles or four cycles of BEP. Poor prognosis was defined as any of the following: lymph node metastases larger than 5 cm, lung metastases more than four in number or larger than 2 cm, haematogenic spread outside the lungs, such as in liver and bone, human chorionic gonadotrophin > 10,000 IU l-1 or alphafetoprotein > 1000 IU l-1. The complete response (CR) rates to PVB/BEP and BEP were similar, 76% and 72% respectively (P = 0.58). In addition, there was no significant difference in relapse rate, disease-free and overall survival at an average follow-up of 6 years. The 5-year progression-free and survival rates in both treatment groups were approximately 80%. The PVB/BEP regime was more toxic with regard to bone marrow function; the frequencies of leucocytes below 1000 microliters-1, leucocytopenic fever and platelets below 25,000 microliters-1, throughout four cycles were 28% vs 5% (P < 0.001), 16% vs 5% (P = 0.006), and 10% vs 1% (P = 0.001) respectively. Neuropathy also occurred more often in the PVB/BEP arm: 47% vs 25% (P = 0.001). This study shows that an alternating regimen of PVB/BEP is not superior to BEP and that it is more myelo- and neurotoxic.
Antineoplastic Combined Chemotherapy Protocols↗
EORTC (30885) randomised phase III study with recombinant interferon alpha and recombinant interferon alpha and gamma in patients with advanced renal cell carcinoma. The EORTC Genitourinary Group.
In the treatment of renal cell carcinoma both complete (CRs) and partial remissions (PRs) have been obtained using recombinant (r) interferon alpha (IFN-alpha), with response rates ranging from 0 to 31% (mean 16%). rIFN-gamma is a potent immunostimulating agent, but the clinical experience of its use is limited and results are conflicting. In a phase II study with the combination of rIFN-alpha 2c (Boehringer Ingelheim) and rIFN-gamma (Genentech, supplied by Boehringer Ingelheim) in 31 eligible patients, a response rate of 25% was recorded. Based on this observation a randomised phase III study was initiated to investigate the possible advantage of the addition rIFN-gamma to rIFN-alpha 2c treatment. Treatment consisted of rIFN-alpha 2c 30 micrograms m-2 = 10 x 10(6) IU m-2 s.c. twice weekly in arm A and the same dose of rIFN-alpha combined with rIFN-gamma 100 micrograms m-2 = 2 x 10(6) IU m-2 in arm B. Eligibility criteria included documented progression of disease; patients with bone lesions only and overt central nervous system metastases were excluded. Between November 1988 and September 1990, 102 patients were entered into the study. An interim analysis showed a response in 7/53 (13%) patients (two CRs and five PRs) in the rIFN-alpha 2c monotherapy arm and in 2/45 (4%) (one CR and one PR) patients in the combination arm. This difference was not statistically significant (P = 0.17). The probability of missing an eventual 10% advantage for the combination is 0.001. The numbers are insufficient to rule out a negative effect of the addition of rIFN-gamma. The dose intensity of IFN-alpha 2c for the two treatment arms was the same. The addition of rIFN-gamma does not improve the response rate of rIFN-alpha 2c monotherapy. A possible detrimental effect cannot be excluded.
Adult↗
The design of clinical trials for new therapies in bladder cancer. Is it time for new strategies?
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Clinical Trials as Topic↗
Identifying patients with a high risk of relapse in quiescent Crohn's disease. The GETAID Group. The Groupe d'Etudes Thérapeutiques des Affections Inflammatoires Digestives.
No reliable identification of quiescent Crohn's disease (CD) patients with a high risk of relapse is available. The aim of this study was to develop a prognostic index to identify those patients. Untreated adult patients with quiescent disease (not induced by surgery) included in three phase III clinical trials were analysed retrospectively with respect to time to relapse. Nineteen factors related to biology, disease history, and topography were investigated. A relapse was defined as either a CD Activity Index (CDAI) > or = 200, a CDAI > or = 150 but over the baseline value by more than 100, or acute complications requiring surgery. The inclusion criteria were fulfilled by 178 patients. The median follow up was 23 months. The Cox model retained the following bad prognostic factors: age < or = 25 years, interval since first symptoms > 5 years, interval since previous relapse < or = 6 months, and colonic involvement (p < 0.001). Bootstrapping confirmed the variable selection. Patients were classified into three groups with an increasing risk of relapse (p < 0.001). The worst risk group was composed of patients presenting at least three of the four bad prognostic factors. These results make possible the design of clinical trials in quiescent CD patients with a high risk of relapse.
Adolescent↗
Tryptophan metabolites, pyridoxine (vitamin B6) and their influence on the recurrence rate of superficial bladder cancer. Results of a prospective, randomised phase III study performed by the EORTC GU Group. EORTC Genito-Urinary Tract Cancer Cooperative Group.
This double-blind randomised phase III trial was designed to assess the effect of pyridoxine administration on the recurrence of Ta and T1 transitional cell tumours of the bladder. The trial accrued 291 patients and showed no significant difference between the pyridoxine and placebo treatment groups with respect to the time to first recurrence or the recurrence rate. Adjustment for the main prognostic factors, namely the recurrence rate prior to entry, the number of tumours at entry, the G grade and the levels of the tryptophan metabolites kynurenine plus acetyl kynurenine at entry do not change the overall conclusions.
Administration, Oral↗
[Introduction to the statistical aspects of planning clinical oncologic phase III studies].
A phase III clinical trial is a comparative study in which one assesses the relative efficacy of a treatment or treatments. It generally has one of the following objectives: 1. To determine the effectiveness of a new treatment relative to the natural history of the disease, for example when comparing a new treatment to not treatment or to placebo in an adjuvant setting. 2. To determine if a new treatment is more effective than the best current standard therapy (at the risk of increasing the toxicity). 3. To determine if a new treatment is as effective as the best current standard therapy but is associated with less severe toxicity or a better quality of life (equivalence trial). Clinical trials must be properly designed in order to answer such questions with a high degree of certainty. The purpose of this paper is to present several concepts which must be taken into account during the process of designing a clinical trial.
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↗
The final analysis of the EORTC Genito-Urinary Tract Cancer Co-Operative Group phase III clinical trial (protocol 30805) comparing orchidectomy, orchidectomy plus cyproterone acetate and low dose stilboestrol in the management of metastatic carcinoma of the prostate.
This report is the final analysis of an EORTC Genito-Urinary Group Phase III trial (Protocol 30805) comparing orchidectomy, orchidectomy plus cyproterone acetate 50 mg 3 times a day and stilboestrol 1 mg daily in the management of metastatic carcinoma of the prostate. Three hundred and twenty-eight eligible patients admitted into the study have been followed up for a median period of 4 years. There was no difference in time to metastatic progression and overall survival between the treatment arms. The cardiovascular toxicity of stilboestrol 1 mg daily has resulted in more cardiovascular deaths as compared with the orchidectomy treatment arm. The outcome for individual patients has been determined by on-study prognostic factors, especially the performance status, rather than the treatment given.
Adenocarcinoma↗
The EORTC Central Office/Data Center.
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Clinical Trials as Topic↗
Design and analysis of prostate cancer trials.
This paper presents an overview of various statistical concepts related to the design and analysis of prostate cancer trials: the need for randomization, stratification for prognostic factors, sample size determination, trial objectives, the choice of a control group, patient entry criteria, the number of treatments to be compared, the choice of endpoints, analysis by the intent to treat principle, interim statistical analysis and early stopping rule, and subgroup analyses.
Clinical Trials as Topic↗
Comparability of prostate trials.
The present overview of advanced prostate cancer required the identification of randomized clinical trials studying the question of maximal androgen blockade versus the classic castration therapy. The heterogeneity of the trials concerned the type of castration (surgical or chemical) and the type of antiandrogen (flutamide, Anandron, or cyproterone acetate) added to castration. This paper reviews the different types of heterogeneity that might exist among trials that are involved in the overview: study design, randomization procedure, treatment evaluation, statistical evaluation, and data maturity. In order to overcome these various types of heterogeneity and to compare like with like, the treatment comparison should be stratified a posteriori by question (i.e., type of castration or type of anti-androgen studied) and by study. In this way, one may draw valid conclusions. Of course, those trials with a larger number of patients and a longer follow-up will contribute more to the overview's results.
Androgen Antagonists↗
Short-term versus long-term addition of cyproterone acetate to buserelin therapy in comparison with orchidectomy in the treatment of metastatic prostate cancer. European Organization for Research and Treatment of Cancer--Genitourinary Group.
In an open, multicenter, three-armed, randomized study, we compared the effects of short-term (2 weeks) and continuous addition of the antiandrogen cyproterone acetate to the luteinizing hormone-releasing hormone agonist buserelin to those of orchidectomy in patients with advanced prostate cancer. No significant differences among the three treatment arms with respect to response rate, subjective response, time-to-progression, overall survival, and cancer deaths were observed. It was concluded that the short-term or continuous addition of cyproterone acetate to buserelin administered intranasally did not improve treatment results compared to orchidectomy only.
Adult↗