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  • 1
    ISSN: 1432-0843
    Keywords: Key words: ADR-529 – Cardioprotection – Metastatic breast cancer
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract. The purpose of this study was to determine the maximal tolerable dose (MTD) of epirubicin and ADR-529 given in combination with cyclophosphamide, 5-fluorouracil, and tamoxifen. A total of 64 breast cancer patients with locally advanced disease or a first metastatic event were included. Using fixed doses of cyclophosphamide, 5-fluorouracil, and tamoxifen, cohorts of ten patients were treated with escalating doses of epirubicin and ADR-529. With the use of protocol criteria specifying evaluation after the first course, the MTD was not reached. Dose reductions carried out due to hematologic toxicity during the first four courses made it impossible to escalate doses of epirubicin beyond 80 mg/m2 given together with ADR-529 600 mg/m2. The vascular toxicity of ADR-529 necessitated central venous access in a number of patients. For phase III evaluation of ADR-529 given together with cyclophosphamide, epirubicin, 5-fluorouracil, and tamoxifen (CEF/TAM) we recommend using epirubicin/ADR-529 at 60/600 mg/m2. Together with evaluation of the cardioprotective properties of ADR-529, we recommend evaluating the impact of ADR-529 on the efficacy of cytotoxic therapy and investigating further the toxicity of ADR-529.
    Type of Medium: Electronic Resource
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  • 2
    ISSN: 1432-0843
    Keywords: ADR-529 ; Cardioprotection ; Metastatic breast cancer
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract The purpose of this study was to determine the maximal tolerble dose (MTD) of epirubicin and ADR-529 given in combination with cyclophophamide, 5-fluorouracil, and tamoxifen. A total of 64 breast cancer patients with locally advanced disease or a first metastatic event were included. Using fixed doses of cyclophosphamide, 5-fluorouracil, and tamoxifen, cohorts of ten patients were treated with escalating doses of epirubicin and ADR-529. With the use of protocol criteria specifying evaluation after the first course, the MTD was not reached. Dose reductions carried out due to hematologic toxicity during the first four courses made it impossible to escalate doses of epirubicin beyond 80 mg/m2 given together with ADR-529 600 mg/m2. The vascular toxicity of ADR-529 necessitated central venous access in a number of patients. For phase III evaluation of ADR-529 given together with cyclophosphamide, epirubicin, 5-fluorouracil, and tamoxifen (CEF/TAM) we recommend using epirubicin/ADR-529 at 60/600 mg/m2. Together with evaluation of the cardioprotective properties of ADR-529, we recommend evaluating the impact of ADR-529 on the efficacy of cytotoxic therapy and investigating further the toxicity of ADR-529.
    Type of Medium: Electronic Resource
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  • 3
    ISSN: 1432-0843
    Keywords: Pharmacokinetics ; ADR-529 ; Epirubicin ; Metastatic breast cancer ; High-pressure liquid chromatography
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract A high-pressure liquid chromatographic method for determination of the bisdioxopiperazine derivative ADR-529 (ICRF-187), a compound proven effective in protection against anthracycline-induced cardiotoxicity, has been developed. The limit of quantitation was 5 ng/ml using a narrow-bore 5-μm silica column and UV detection. The method was used for determination of pharmacokinetic profiles of ADR-529 after a 3-weekly i.v. administration of different doses of ADR-529 (600–1000 mg/m2) together with different doses of epirubicin (E, 60–100 mg/m2), fixed-dose cyclophosphamide (C, 600 mg/m2), fixed-dose 5-fluorouracil (F, 600 mg/m2), and daily administration of tamoxifen (T, 30 mg; CEF-T) in the treatment of patients with metastatic breast cancer. Pharmacokinetic parameters for epirubicin were also determined. The aim of the study was to determine (1) whether the pharmacokinetics of ADR-529 as part of a combination with CEF-T changes with increasing doses of ADR-529 and increasing doses of epirubicin and (2) whether the pharmacokinetics of epirubicin in the same combinations is altered with the administration of increasing doses of ADR-529. A total of 82 patients were included. A crossover study including 16 of the patients showed no significant difference in epirubicin pharmacokinetic parameters when epirubicin was given with or without concomitant administration of ADR-529. Apart from minor changes in the distributional half-lives, the pharmacokinetic parameters of epirubicin were not altered with increasing doses of ADR-529, nor were the pharmacokinetic parameters of ADR-529 itself. Escalating doses of epirubicin did not significantly alter the pharmacokinetic parameters of ADR-529 with the exception of a 30% increase in the terminal half-life and a decrease in total body clearance when the epirubicin dose was raised from 60 to 100 mg/m2. We conclude that concomitant administration of ADR-529 does not alter the distribution and elimination of epirubicin in doses suitable for preventing the anthracycline-induced cardiotoxicity.
    Type of Medium: Electronic Resource
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  • 4
    ISSN: 1432-0843
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary Pharmacokinetic analysis of epirubicin and its metabolites epirubicinol and 7-deoxy-13-dihydro-epirubicinol aglycone during the first and the fourth courses of treatment was performed in 78 patients with metastatic breast cancer. The patients were treated every 3 weeks with epirubicin given as 10-min i.v. infusions at four different dose levels: 40, 60, 90 and 135 mg/m2. In most cases (76 of 78 cases), plasma concentration-time curves fitted to a three-compartmental pharmacokinetic model. The terminal half-life of epirubicin was independent of dose and duration of treatment. Large interindividual differences were demonstrated (meant 1/2γ, 21.6±7.9 h; range, 10.6–69 h;n=110). In two subjects, extremely long half-lives and high serum bilirubin concentrations indicated impaired liver function. No correlation was found between the half-life and levels of liver alanine aminotransferase (ALAT) or serum creatinine. The metabolite epirubicinol appeared quickly after epirubicin administration and its half-lives were shorter than that of the parent compound (meant 1/2γ, 18.1±4.8 h; range, 8.2–38.4 h;n=105).Formation of the aglycone metabolite was delayed and the half-life of this metabolite was shorter than that of epirubicin (meant 1/2γ, 13±4.6 h; range, 2.7–29 h;n=104). The AUC of epirubicin and the total AUC (drug and metabolites) were linearly proportional to the dose, with the former value constituting two-thirds of the latter. A correlation was found between AUC and the plasma concentration of epirubicin at two time points (2 and 24 h after administration). The proposed model was AUC=9.44×c 2+62.5×c 24+157.7 (r=0.953).
    Type of Medium: Electronic Resource
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  • 5
    ISSN: 1432-0843
    Keywords: Key words Pharmacokinetics ; ADR-529 ; Epirubicin ; Metastatic breast cancer ; High-pressure liquid chromatography
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract  A high-pressure liquid chromatographic method for determination of the bisdioxopiperazine derivative ADR-529 (ICRF-187), a compound proven effective in protection against anthracycline-induced cardiotoxicity, has been developed. The limit of quantitation was 5 ng/ml using a narrow-bore 5-μm silica column and UV detection. The method was used for determination of pharmacokinetic profiles of ADR-529 after a 3-weekly i. v. administration of different doses of ADR-529 (600 – 1000 mg/m2) together with different doses of epirubicin (E, 60 – 100 mg/m2), fixed-dose cyclophosphamide (C, 600 mg/m2), fixed-dose 5-fluorouracil (F, 600 mg/m2), and daily administration of tamoxifen (T, 30 mg; CEF-T) in the treatment of patients with metastatic breast cancer. Pharmacokinetic parameters for epirubicin were also determined. The aim of the study was to determine (1) whether the pharmacokinetics of ADR-529 as part of a combination with CEF-T changes with increasing doses of ADR-529 and increasing doses of epirubicin and (2) whether the pharmacokinetics of epirubicin in the same combinations is altered with the administration of increasing doses of ADR-529. A total of 82 patients were included. A crossover study including 16 of the patients showed no significant difference in epirubicin pharmacokinetic parameters when epirubicin was given with or without concomitant administration of ADR-529. Apart from minor changes in the distributional half-lives, the pharmacokinetic parameters of epirubicin were not altered with increasing doses of ADR-529, nor were the pharmacokinetic parameters of ADR-529 itself. Escalating doses of epirubicin did not significantly alter the pharmacokinetic parameters of ADR-529 with the exception of a 30% increase in the terminal half-life and a decrease in total body clearance when the epirubicin dose was raised from 60 to 100 mg/m2. We conclude that concomitant administration of ADR-529 does not alter the distribution and elimination of epirubicin in doses suitable for preventing the anthracycline-induced cardiotoxicity.
    Type of Medium: Electronic Resource
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  • 6
    ISSN: 1432-0843
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary Detailed pharmacokinetic analysis and subsequent evaluation of myelotoxicity were performed in 55 patients who had been randomized to 4 different doses of epirubicin (40, 60, 90 or 135 mg/m2 given i.v. every 3 weeks). A significantly positive correlation was demonstrated between the AUC and the myelotoxicity of epirubicin. A similar correlation was observed when the metabolite epirubicinol was also considered. The decrease in leucocyte count as expressed by the logarithmic ratio between nadir WBC and initial WBC was linearly correlated with the AUC of either epirubicin alone (r=−0.55,P〈0.001) or epirubicin and epirubicinol together (r=−0.63,P〈0.001). As a relationship between the concentration of epirubicin in a single plasma sample taken at 6 h following i.v. administration and the AUC of the drug has been established, a log-linear relationship between the expected decrease in leucocytes and the concentration at 6 h after administration could be calculated. The proposed model is expressed as the equation: log WBCnadir=log WBCinitial−0.0073×c 6 (ng/ml) −0.14.
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  • 7
    ISSN: 1573-7225
    Keywords: breast cancer ; database ; register
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract Objective: Clinical databases have been invented to monitor treatment outcomes, therapies or diseases, often in great detail. The traditional population-based cancer registry has been invented to collect a minimum of information about all incident cancers. Do clinical databases render population-based cancer registers obsolete as sources of cancer cases for epidemiological study? Methods: We compared the study base of first incident breast cancer cases in Denmark in 1978–1994 known from the national cancer register and from the national clinical database on breast cancer patients. The clinical database is used for monitoring protocoled treatment. Results: Combining the two data sources we found 48,522 first primary breast cancers in Denmark 1978–1994. Of these, 37,640 were included in both data sources, 2151 were included only in the clinical database, and 8731 were included only in the cancer register. A major part of the difference between the two data sources was due to treatment-focused data collection in the clinical database, and a minor part due to differences in the registration of second primaries, date of diagnosis and invasiveness. Conclusions: Cancer incidence data are sensitive to registration procedures and definitions. Clinical cancer databases cannot generally replace the traditional cancer register as a reliable data source for incident cancer cases in a national population.
    Type of Medium: Electronic Resource
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  • 8
    ISSN: 1432-2323
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Description / Table of Contents: Résumé Le rôle du traitement anti-oestrogénique du cancer du sein opéré après la ménopause chez les malades à hauts risques de récidive a été soumis à une étude prospective randomisée sur le plan national par le groupe Danois d'Etude du Cancer du Sein. Cette étude comporte d'une part 829 malades qui après mastectomie totale et radiothérapie postopératoire ont été traitées par le tamoxifen (RT + TAM) pendant un an et d'autre part 821 malades qui n'ont pas été soumises à un traitement complémentaire (RT). L'absence de récidive après 3 ans a été de 44% dans le premier groupe et de 40% dans le second. Dans les deux groupes le taux de la survie à 5 ans a été de 51% (p=0.53). Le pronostic basé sur les données rassemblées a été étudié en fonction de plusieurs facteurs: âge, degré d'anaplasie, volume de la tumeur, envahissement ganglionnaire. Le taux d'absence de récidive à 3 ans a été plus bas chez les malades traitées par l'association radiothérapie et tamoxifen mais il n'a de valeur significative que chez les malades âgées de 50 à 59 ans, présentant des tumeurs dont l'anaplasie est de stade I, le volume est inférieur à 5 cm et l'envahissement concerne 4 ganglions ou plus. La concentration oestrogénique a été dosée chez 291 de ces malades. La limite de 10 fmol/mg cytosol protéine et l'emploi du modèle des risques proportionnels Cox ont permis la distinction entre malades à hauts risques de récidive à 3 ans et les autres. Les malades dont le pouvoir récepteur oestrogénique est inférieur à 100 fmol/mg ne tirent aucun bénéfice du traitement endocrinien contrairement à ceux dont le pouvoir est supérieur. Le pouvoir récepteur progestéronique a été étudié chez 12% des malades. Celles qui ont un pouvoir positif ont un taux de récidive moins élevé quand elles sont traitées par RT + TAM par rapport à celles qui sont traitées seulement par RT (p=0.017).
    Abstract: Resumen La evaluación del valor del tratamiento antiestrógeno en pacientes postmenopáusicas con cáncer de seno con alto riesgo de enfermedad recurrente fue realizada en un ensayo nacional prospectivo y aleatorizado conducido por el Grupo Danés de Cáncer de Seno. Después de haber sido sometidas a mastectomía total y radioterapia postoperatoria, 829 pacientes fueron asignadas en forma aleatoria a tratamiento con Tamoxifén (RT + TAM) por 1 año, y 821 no recibieron tratamiento adicional (RT). La sobrevida libre de recurrencia (SLR) a los 72 meses es de 44% en el grupo RT + TAM, y de 40% en el grupo RT (p=0.003). La supervivencia global es de 51% en ambos grupos (p =0.53). Los datos han sido analizados con respecto a factores de pronóstico, incluyendo edad, grado de anaplasia, tamańo del tumor y ganglios positivos. La SLR es mayor en los subgrupos de pacientes tratadas con RT + TAM, pero es de significación sólo en los grupos de edad entre 50 y 59 años con tumores de anaplasia grado I, de tamaño menor de 5 cm y con 4 o más ganglios linfáticos positivos. Aún cuando se presentaron menos metastasis locales y distantes en las pacientes tratadas con RT + TAM, no se logró un aumento en la supervivencia global y aún en aquellos subgrupos de pacientes con las más significativas prolongaciones de la SLR no se pudo demostrar aumento de la supervivencia. La concentración de receptores de estrógeno fue medida en un subgrupo de 291 de las pacientes. Un límite bajo de 10 fmol/mg de proteína citosólica, distingue a las pacientes con prolongada SLR de aquellas con enfermedad recurrente temprana. Las pacientes con contenidos de receptores de estrógenos por debajo de 100 fmol/mg no derivaron beneficio de la terapia endocrina mientras aquellas con concentraciones superiores a 100 fmol/mg exhibieron una SLR significativamente más prolongada. Determinaciones de receptores de progesterona fueron realizadas en el 12% de las pacientes. Las pacientes con receptores de progesterona positivos tuvieron una menor tasa de recurrencia con el regimen RT + TAM que las pacientes con receptores de progesterona positivos manejadas con RT solamente (p=0.017). En conclusión, la terapia adyuvante con TAM aumenta la SLR en pacientes postmenopáusicas con cáncer mamario de alto riesgo. La eficacia está significativamente correlacionada con la edad de las pacientes y con ciertas características histopatológicas y bioquímicas de los tumores. El valor pronóstico de las determinaciones de RE se logra al emplear un límite bajo en la positividad RE el cual esencialmente sirve para distinguir los tumores RE negativos de los RE positivos. El valor de predicción de las determinaciones de RE y de RPg en cuanto al efecto de la terapia adyuvante parece depender sólo de las concentraciones de RE y RPg en el tejido tumoral, puesto que las más bajas tasas de recurrencia se presentan en pacientes con las más altas concentraciones.
    Notes: Abstract The role of anti-estrogen treatment of postmenopausal breast cancer patients with high risk of recurrent disease is evaluated in a nationwide, prospective, randomized trial conducted by the Danish Breast Cancer Group. After total mastectomy and postoperative radiotherapy, 829 patients were randomized to treatment with tamoxifen (RT + TAM) for 1 year and 821 were randomized to no further therapy (RT). The recurrence-free survival (RFS) after 72 months of life-table analysis is 44% in the RT + TAM treated group, and 40% in the RT group (p=0.0003). Survival is 51% in both treatment groups (p=0.53). The data have been further analyzed with respect to prognostic factors such as age, degree of anaplasia, tumor size, and positive nodes. The RFS is lower in all subsets of patients treated with RT + TAM, but is only significant in patients 50–59 years of age, with tumors of anaplasia grade I, with tumors less than 5 cm, or with 4 or more positive lymph nodes. Estrogen receptor concentrations were measured in a subset of 291 of these patients. A cut-off limit of 10 fmol/mg cytosol protein and the use of a Cox proportional hazards model distinguished between patients with long RFS and those with early recurrent disease. Patients with an estrogen receptor content below 100 fmol/mg did not benefit from the endocrine therapy, while those with concentrations above 100 fmol/mg had a significantly longer RFS. Progesterone receptor determinations were performed in 12% of the patients. Progesterone receptor-positive patients had a lower rate of recurrence when treated with RT + TAM compared to the receptor-positive patients in the RT group (p=0.017).
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  • 9
    ISSN: 1573-7217
    Keywords: breast cancer ; dose response ; tamoxifen
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary In order to establish the optimal dose of tamoxifen in the treatment of advanced breast cancer in postmenopausal women, a randomized trial comparing 90 mg daily with the currently recommended dose of 30 mg daily was conducted. Sixty-eight patients were treated with the high dose and 75 patients with the low dose. The rate of response was 36 and 37% (p = 0.74), respectively. The time to response, duration of response, and the time to treatment failure were also identical at the two dose levels. Only a few side effects were observed, and they were equally distributed among the two treatment groups. It is concluded that a 30 mg daily dose of tamoxifen seems to be as effective as 90 mg.
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  • 10
    ISSN: 1573-7217
    Keywords: breast cancer ; estrogen receptor ; progesterone receptor ; risk factors ; tamoxifen
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary The role of antiestrogen treatment in high risk postmenopausal patients with primary breast cancer is currently evaluated in a nationwide, prospective randomized trial conducted by the Danish Breast Cancer Cooperative Group. The primary treatment is total mastectomy and radiotherapy. As of February 1, 1982, 720 women were randomized to treatment with tamoxifen (30 mg daily for 1 year) and 691 women were randomized to no further therapy. Life-table analysis after 36 months shows a difference in recurrence rates of 9% (p = 0.19) in favor of the tamoxifen-treated patients. The material has been analyzed with respect to established prognostic factors such as age, degree of anaplasia, tumor size, and number of positive nodes. The rates of recurrent disease are lower in all subsets of patients treated with tamoxifen, but are only statistically significant in patients 50–59 years of age or with 4 or more positive lymph nodes. Regardless of treatment, ER negative patients have a 23% higher recurrence rate than ER positive patients after 18 months of analysis (p = 0.0033); this represents an approximate doubling of risk, and is independent of age, degree of anaplasia, tumor size, or lymph node status. With regard to PgR status, there is 11% higher recurrence rate in the PgR negative than in the PgR positive patients (p = 0.097).
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