Marleen de Pauw

Cardiovascular Side Effects of Diethylstilbestrol, Cyproterone Acetate, Medroxyprogesterone Acetate and Estramustine Phosphate Used for the Treatment of Advanced Prostatic Cancer: Results from European Organization for Research on Treatment of Cancer Trials 30761 and 30762

Two randomized trials were started in 1976 by the European Organization for Research on Treatment of Cancer urological group. Trial 30761 compared 1 mg. diethylstilbestrol orally 3 times daily to 250 mg. oral cyproterone acetate daily and to 500 mg. medroxyprogesterone acetate intramuscularly 3 times weekly for 8 weeks, then 200 mg. orally daily. Trial 30762 compared 3 mg. diethylstilbestrol to 560 mg. estramustine phosphate orally for 8 weeks and then 280 mg. daily. The 239 patients in study 30761 and 226 in study 30762 were evaluated for cardiovascular toxicity during treatment. Various types of side effects (fluid retention, hypertension, electrocardiographic changes, myocardial infarction and thromboembolic disease) and their degrees of severity were analyzed. In both studies the most frequent type of cardiovascular toxicity was represented by fluid retention. Cardiovascular toxicity as a whole was higher with diethylstilbestrol than with estramustine phosphate or medroxyprogesterone acetate therapy, and was the lowest with cyproterone acetate therapy. The risk of severe cardiovascular complications developing was the highest during the first 6 months of treatment. Increasing age, body weight greater than 75 kg. and, especially, the presence of previous cardiovascular disease represented adverse factors in the development of cardiovascular toxicity.

Multivariate Analysis of Prognostic Factors in Patients with Advanced Prostatic Cancer: Results from 2 European Organization for Research on Treatment of Cancer Trials

The European Organization for Research on Treatment of Cancer Genitourinary Group performed a multivariate statistical analysis of prognostic factors based on 436 patients entered between 1976 and 1981 in 2 randomized prospective trials that compared 4 different hormonal treatment regimens. Only previously untreated patients with advanced (stage T3/T4/M0 or M1) prostatic cancer were eligible. After identification of prognostic factors by means of univariate analyses a multivariate analysis using Coxs proportional hazards regression model was done. This test identified performance status (according to the Eastern Cooperative Oncology Group scale) as the most important factor, followed by acid phosphatase (more than 2 times normal) for stage M0 cancer patients, and alkaline phosphatase, T category and the presence or absence of associated chronic disease for stage M1 cancer patients. Based on these 4 variables nonbedridden patients with metastatic disease can be divided into 2 groups: poor and good risk patients, with median survivals of 1 and 3 years, respectively. This study shows that routine clinical and laboratory data already provide an excellent indication as to the prognosis.

Adjuvant Chemotherapy of Superficial Transitional Cell Bladder Carcinoma:Preliminary Results of a European Organization for Research onTreatment of Cancer Randomized Trial Comparing Doxorubicin Hydrochloride, Ethoglucid and Transurethral Resection Alone

Patients with superficial transitional cell carcinoma of the bladder were entered in a randomized clinical trial to compare the efficacies of transurethral resection alone or followed by bladder instillation of doxorubicin hydrochloride or ethoglucid (Epodyl) for 1 year. Results showed that adjuvant chemotherapy with the selected drugs prolonged the mean interval between recurrences. Mild systemic toxicity and chemical cystitis were observed in 3 and 3 per cent, respectively, of the patients given ethoglucid, and in 5 and 4 per cent, respectively, of those taking doxorubicin.

Early results of the EORTC randomized clinical trial on multiple fractions per day (MFD) and misonidazole in advanced head and neck cancer.

From Feb. 1981 to Oct. 1984, a randomized clinical trial was carried out in the EORTC Radiotherapy Group, comparing classical radiotherapy 70 Gy/7 weeks to MFD (3 X 1.6 Gy/day for 10 days, 3 weeks rest, followed by a boost to 67.2 or 72 Gy), with or without Misonidazole (1 g/m2 every irradiation day, total 12 to 14 g/m2) in advanced head and neck cancer (all T3 and T4, all N2, N3 and N1 greater than 3 cm). A total of 523 patients were entered in the study. At the time of analysis (4/85), the median follow-up time was 64 weeks. No significant differences in survival or locoregional control could be demonstrated between the three treatment arms at this time. Whereas early mucosal reactions were heavier in the MFD-arms, no differences in late effects (fibrosis, edema, xerostomy) were found between the three treatment arms. Five patients (all MFD + Misonidazole) died with local complications (edema, necrosis). All five had cancer of the laryngopharynx and 3 of them died from a hemorrhage. Factors affecting prognosis were tumor site, tumor stage, nodal status, and histological differentiation.

Adjuvant Chemotherapy for Superficial Transitional Cell Bladder Carcinoma: Long-term Results of a European Organization for Research and Treatment of Cancer Randomized Trial Comparing Doxorubicin, Ethoglucid and Transurethral Resection Alone

PURPOSE We compared the efficacy of transurethral resection alone or transurethral resection followed by bladder instillations of doxorubicin or ethoglucid for 1 year in patients with superficial bladder carcinoma, and followed them long term for the incidence of progression to muscle invasion. MATERIALS AND METHODS A total of 443 patients with superficial transitional cell carcinoma of the bladder was randomized. After randomization of 206 patients the control arm was closed to patient entry based on the results of an interim analysis showing a significant difference in favor of those receiving adjuvant chemotherapy. RESULTS Final analysis of treatment results for recurrence included 432 patients at a median followup of 3.4 years for time to first recurrence, 5 years for analysis of time to invasion (Category T2 disease or worse) and 10.7 years for duration of survival. Time to first recurrence was significantly prolonged by both drugs compared to transurethral resection alone (doxorubicin versus transurethral resection alone p < 0.001 and ethoglucid versus control p < 0.001). Recurrence rate per year was 0.30 for both adjuvant treatment arms and 0.68 for the resection only group. Progression to muscle invasion was rare (15.1% of cases) and not apparently different in the 3 treatment arms. Of the 423 patients death from any cause in 199 and from malignant disease in 59 was not correlated with treatment. However, there was a strong correlation between death from malignant disease, and T category and tumor grade. CONCLUSIONS In regard to time to first recurrence and recurrence rate per year this study indicates that adjuvant chemotherapy with doxorubicin and ethoglucid using the indicated schedule is superior to transurethral resection alone. However, progression in stage or survival was not influenced by the treatment regimen.

The EORTC randomized trial on three fractions per day and misonidazole in advanced head and neck cancer: prognostic factors

In trial no. 22811 on a randomized comparison of multiple fractions per day (MFD), with or without misonidazole, to conventional fractionation in advanced head and neck cancer, a large number (523) of patients was entered in a short period of time. No differences in treatment results were obtained, but the study created an important database, allowing for detailed evaluation of the most important factors influencing prognosis. In univariate analysis, factors significantly influencing survival and locoregional control were: performance status, histological differentiation, tumor site, tumor and nodal staging, and tumoral and nodal volume. In multivariate analysis, significant factors for survival were nodal involvement, tumor stage, performance status, and tumor site. Significant factors for locoregional control were nodal involvement and total tumor burden. This analysis suggests that total tumor burden (volume) should be included in the interpretation of treatment results in head and neck cancer.

The EORTC randomized trial on three fractions per day and misonidazole (trial no. 22811) in advanced head and neck cancer: long-term results and side effects

From 1981 to 1984, a randomized study was done by the EORTC Radiotherapy Group comparing a fractionation schedule with three fractions per day (multiple fractions per day, MFD), with or without misonidazole, to conventional fractionation. The aim of the study was to obtain improved local and regional control and survival by shortening of the treatment time in the first 2 weeks of irradiation. Three fractions of 1.6 Gy/day (4-h interval) were given during 10 irradiation days to a total of 48 Gy. After 3-4-weeks interval, a boost was given to 67.2 or 72 Gy also in three fractions per day. This schedule was compared to an identical arm with misonidazole 1 g/m2/day and a third arm with conventional fractionation (70 Gy in 35 fractions, 7 weeks or 75 Gy in 44 fractions, 9 weeks). A total number of 523 patients was included in the study. Acute mucositis was much heavier in patients treated with three fractions per day (Van den Bogaert et al. Int. J. Radiat. Oncol. Biol. Phys. 8: 1649-1655, 1982). Early results, communicated in 1986 (Van den Bogaert et al. Int. J. Radiat. Oncol. Biol. Phys. 12: 587-591, 1986) showed no differences in treatment outcome between the three treatment arms. Long-term results and data on late effects are now available. Survival at 5 years was 18% (SE 1.9%) and locoregional control was 27% (SE 2.9%). No statistically significant differences could be observed between the three treatment arms.(ABSTRACT TRUNCATED AT 250 WORDS)

Maximum Androgen Blockade Using LHRH Agonist Buserelin in Combination with Short-Term (Two Weeks) or Long-Term (Continuous) Cyproterone Acetate Is Not Superior to Standard Androgen Deprivation in the Treatment of Advanced Prostate Cancer

This is the final analysis of EORTC GU Group Trial 30843 in which the treatment of advanced, metastatic prostate cancer with a combination of the LHRH agonist buserelin (nasal spray) and cyproterone acetate (Androcur), either continuously of only during the first 2 weeks, was compared with orchidectomy. There was no significant difference between the three arms as far as response rate, time to progression (subjective and objective) and duration of survival are concerned. Retrospective stratification according to the most important prognostic factors did not change the conclusions. Possible reasons for the difference with trial 30853, which used the same entry criteria but compared goserelin and flutamide with orchidectomy, are discussed. Reasons for using cyproterone acetate in combination treatment are the prevention of flare of the disease after LHRH agonists only and the prevention/reduction of toxicity in the form of hot flushes.

Long-term follow-up of non-seminomatous testicular cancer patients with mature teratoma or carcinoma at postchemotherapy surgery

From 1979 to 1983 the EORTC GU Group treated 239 patients with disseminated non-seminomatous testicular cancer with combination chemotherapy comprising cisplatin, vinblastine and bleomycin in a prospectively controlled trial. The protocol required complete resection of residual masses after induction chemotherapy, provided that serum tumour markers were normal. 102 patients were operated on. 27 patients had mature teratoma (teratoma differentiated) in the resected specimens and 23 had viable cancer. Follow-up data were available for 26 and 22 of these patients, respectively. 23 of 26 patients (88%) with mature teratoma are alive and disease free after a follow-up of 53-110 months (median 92 months). 3 patients developed progressive disease; 1 died. A peculiar case of growing mature teratoma on the forearm is described. 13 of 22 patients (59%) with residual carcinoma are alive and disease free after a follow-up of 74-112 months (median 95 months). The prognosis of patients with carcinoma is shown to be correlated with the completeness of surgery, which in turn is correlated with the initial tumour mass before chemotherapy.

Mitoxantrone in advanced renal cancer: A phase II study in previously untreated patients from the EORTC Genito-Urinary Tract Cancer Cooperative Group

Mitoxantrone at a dose of 15 mg/m2 i.v. q 3 weeks failed to produce responses in 29 adequately treated patients with measurable advanced renal cell carcinoma. The side-effects observed in this group of patients with a good performance status were generally mild. On the basis of this negative result, the application of mitoxantrone in this disease is not recommended.