K. Possinger

Randomized Clinical Trial Comparing Mitoxantrone with Epirubicin and with Doxorubicin, each Combined with Cyclophosphamide in the First-Line Treatment of Patients with Metastatic Breast Cancer

Two hundred and twenty-four patients with advanced breast cancer were enrolled in a multicenter prospective randomized clinical study and received either doxorubicin (40 mg/m2), or epirubicin (40 mg/m2) or mitoxantrone (12 mg/m2) each combined with cyclophosphamide (600 mg/m2) i.v. In the patient collective the following response rates were observed: complete response 12.1%; partial response 30.6%; stable disease 40.5%; progressive disease 16.8%. A complete response was observed significantly less often in patients where more than one organ site was involved as compared to those patients with only one metastatic site. The mean time period required to reach a best response was 3.7 months. There was no significant difference between the response rates in the three arms. In comparing the observed toxicities in 1,434 treatment cycles, there was a significant difference with regard to leukocytopenia (mitoxantrone arm exhibiting more than either epirubicin and doxorubicin) although infections did not occur more frequently in the mitoxantrone arm; with regard to alopecia, mitoxantrone and epirubicin arms both exhibited less than doxorubicin. It is noteworthy that no patient who had previously received adjuvant chemotherapy achieved a complete response (p = 0.006). The overall significance of these findings can only be clearly evaluated when survival times can be measured.

Prognostic Subgroups: The Key Factor for Treatment Outcome in Metastatic Breast Cancer

Background: Since prolongation of survival by chemotherapy has been questioned, palliation balanced with an acceptable quality of life is the primary aim in treating patients with metastatic breast cancer. Patients and Methods: 224 patients from 11 centers were randomized to treatment with 40 mg/m2 of Adriamycin or with 40 mg/m2 of epirubicin or with 12 mg/m2 of mitoxantrone each in combination with 600 mg/m2 of cyclophosphamide every 3 weeks. A special monitoring system including follow-up until death guaranteed valid information on response criteria, survival and quality of life. Results: Treatment outcome was not statistically different between the three groups in terms of best response rate, response duration, time to progression or survival. There were, however, statistically significant differences between the three treatment groups in terms of toxicity and quality of life. Most important, treatment outcome was influenced by the following negative prognostic factors: disease-free interval less than 18 months; metastases at more than one organ site; performance status according to WHO > 1; prior adjuvant chemotherapy; age less than 40 years. Conclusions: This meticulously monitored prospectively randomized study shows that prognostic factors are more important than the chosen treatments for the outcome in metastatic breast cancer patients.

Prädiktive Tumorteste im chemotherapeutischen Behandlungskonzept maligner Erkrankungen

In order to determine the pre-therapeutical effectiveness of cytotoxic drugs in metastasizing tumours, two in vitro test methods were examined for their predictive validity: the short-term incubation of tumour cells with cytotoxic drugs and radioactive labelled precursors of the DNA- or RNA-synthesis, and the testing of the cloning ability of tumour cells, pre-incubated with cytotoxic drugs. The short-term incubation techniques were directed in two directions: the testing of sensitivity and the testing of resistance. Both methods can only be carried out using strong proliferating tumours. With methodical, pharmalogical and biological problems, the sensitivity test results in a relatively minor correlation between the in vitro and in vivo reactions. Contrary to this the resistance test allows a predictive, clinically utilizable judgement of primary and secondary forms of the tumour-cell resistance of specific cytotoxic drugs. The consecutive measurement of the proliferative activity of tumours before and after a systematic chemotherapy also seems to be an able parameter concerning the clinically expected effectiveness of cytotoxic drugs. Compared to the other in vitro tests the tumour-cell clonogenic assay demonstrates two main advantages: firstly, all cytotoxic drugs can be analysed by this test method, and secondly, little proliferating tumours can also examined. Nevertheless, this test method seems to be more suitable for predicting tumour-cell resistance than the sensitivity of cytotoxic drugs.SummaryIn order to determine the pre-therapeutical effectiveness of cytotoxic drugs in metastasizing tumours, two in vitro test methods were examined for their predictive validity: the short-term incubation of tumour cells with cytotoxic drugs and radioactive labelled precursors of the DNA-or RNA-synthesis, and the testing of the cloning ability of tumour cells, pre-incubated with cytotoxic drugs. The short-term incubation techniques were directed in two directions: the testing of sensitivity and the testing of resistance. Both methods can only be carried out using strong proliferating tumours. With methodical, pharmalogical and biological problems, the sensitivity test results in a relatively minor correlation between the in vitro and in vivo reactions. Contrary to this the resistance test allows a predictive, clinically utilizable judgement of primary and secondary forms of the tumour-cell resistance of specific cytotoxic drugs. The consecutive measurement of the proliferative activity of tumours before and after a systematic chemotherapy also seems to be an able parameter concerning the clinically expected effectiveness of cytotoxic drugs. Compared to the other in vitro tests the tumour-cell clonogenic assay demonstrates two main advantages: firstly, all cytotoxic drugs can be analysed by this test method, and secondly, little proliferating tumours can also examined. Nevertheless, this test method seems to be more suitable for predicting tumour-cell resistance than the sensitivity of cytotoxic drugs.

[Resistance testing of cytostatic agents on human tumors (author's transl)].

An in vitro short term incubation of human tumors with different cytostatic agents and their corresponding radioactive precursors of cell metabolism allows detection of those drugs which are inefficacious on the examined tumor. The pretherapeutical knowledge of those substances keeps the patient from unnecessary and damaging cytotoxic treatment. The in vitro and in vivo correlation of this technique was tested on 3 different groups of tumor patients: 1. Chemotherapeutically treated tumor patients with primary or secondary induced resistance against the applied cytostatic agents: all substances which clinically did not influence the tumor growth at the moment of the test also were inefficient in the in vitro test system. 2. Tumor patients who were treated according to a clinical therapy regimen contrary to the results of the in vitro testing: corresponding to the test, no influence on tumor growth was seen. 3. Tumor patients who were treated according to the results of the resistance test: after 8 weeks observation none of these patients had any signs of tumor progression.SummaryAn in vitro short term incubation of human tumors with different cytostatic agents and their corresponding radioactive precursors of cell metabolism allows detection of those drugs which are inefficacious on the examined tumor. The pretherapeutical knowledge of those substances keeps the patient from unnecessary and damaging cytotoxic treatment.The in vitro and in vivo correlation of this technique was tested on 3 different groups of tumor patients:1.Chemotherapeutically treated tumor patients with primary or secondary induced resistance against the applied cytostatic agents: all substances which clinically did not influence the tumor growth at the moment of the test also were inefficient in the in vitro test system.2.Tumor patients who were treated according to a clinical therapy regimen contrary to the results of the in vitro testing: corresponding to the test, no influence on tumor growth was seen.3.Tumor patients who were treated according to the results of the resistance test: after 8 weeks observation none of these patients had any signs of tumor progression.ZusammenfassungDie Kurzzeitinkubation menschlichen Tumormaterials in vitro mit verschiedenen Cytostatika unter Zusatz der entsprechenden radioaktivmarkierten Stoffwechselpräkursoren zeigt mit hoher Sicherheit diejenigen Cytostatika auf, die gegenüber dem untersuchten Tumor wirkungslos sind. Durch prätherapeutische Kenntnis solcher Substanzen kann der Patient vor überflüssiger und zusätzlich schädigender cytostatischer Therapie bewahrt werden. Die In-vitro-in-vivo-Korrelation des Testsystems wurde an 3 verschiedenen Gruppen überprüft:1.Tumor-Patienten die cytostatisch therapiert worden waren, deren Tumoren aber entweder primär therapieresistent waren oder aber nach anfänglicher Tumorrückbildung sekundär Resistenzen entwickelten: sämtliche Cytostatika, die zum Zeitpunkt der Testung klinisch keinen Einfluß auf das Tumorwachstum hatten, erwiesen sich auch im In-vitro-Test als wirkungslos.2.Tumor-Patienten, die entgengen den In-vitro-Testergebnissen nach klinischen Therapieschemata behandelt worden waren: bei dieser Gruppe konnte, in Übereinstimmung mit dem Testergebnis, klinisch keine Beeinflußung des Tumorwachstums festgestellt werden.3.Tumor-Patienten, die entsprechend den Ergebnissen der Tumorresistenztestung behandelt wurden. Aus den klinischen Therapieprogrammen wurden diejenigen Substanzen eliminiert, die sich im In-vitro-Test als resistent erwiesen hatten: in keinem Fall dieser Gruppe war es nach einem Beobachtungszeitraum von 8 Wochen zu einer Progression des Tumorwachstums gekommen.

Gegenwärtiger Stand der Chemotherapie des Magen- und kolorektalen Karzinoms

Anemie je nejcastějsim přiznakem myelodysplastickeho syndromu (MDS). Kromě substitucni lecby je možne ovlivnit anemii MDS take erytropoezu stimulujicimi proteiny (EPS) v monoterapii nebo v kombinaci s růstovým faktorem pro granulocytarni řadu (G-CSF): monoterapie epoetinem alfa, resp. beta ve standardnich davkach (30 000–40 000 U/týden), ve vysokých davkach (60 000–80 000 U/týden), monoterapie darbopoetinem (150–300 ug/týden), nebo v kombinaci s G-CSF (300–600 ug/týden). Při hodnoceni erytroidnich odpovědi podle kriterii Mezinarodni pracovni skupiny (IWGc) nebyl pozorovan podstatný rozdil v poctu odpovědi na monoterapii epoetinem alfa a darbopoetinem (57,6 % vs. 59,4 %), statisticky významný rozdil je u obou skupin proti pacientům s podpůrnou peci. Kombinace s G-CSF zvysuje procento odpovědi zejmena u pacientů s RARS (až na 70 %) a ovlivňuje delku přežiti ve srovnani s pacienty bez lecby. Nejlepsi odpověď na lecbu EPS (s nebo bez G-CSF) maji MDS pacienti s nizkým rizikem (IPSS nizke, středni 1, s nizkou hladinou endogenniho EPO (< 500 IU/l) a malou nebo žadnou potřebou transfuzi (≤ 2 TU erytrocytů/měsic)).

Hemmung der 3H-TdR-Aufnahme in Tumorzellen nach Zytostatikagabe als Maß therapeutischer Wirksamkeit

SummaryIn 36 Walker-ascites-carcinosarcoma bearing rats the reduction of 3H-TdR-incorporation into tumor cells after cytotoxic treatment as an potential prognostic factor for efficacy of chemotherapy was tested. Twelve rats each were i.p. treated with 1 mg/kg bw. DDP resp. 0.8 mg/kg bw. Adriamycin. Twelve rats were injected with 0.2 mg phys. NaCl and served as control. Survival of rats served as criterion of therapeutic efficacy. There was a significant correlation between reduction of 3H-TdR-uptake in tumor cells after cytotoxic therapy and survival.In 36 Walker-ascites-carcinosarcoma bearing rats the reduction of 3H-TdR-incorporation into tumor cells after cytotoxic treatment as an potential prognostic factor for efficacy of chemotherapy was tested. Twelve rats each were i.p. treated with 1 mg/kg bw. DDP resp. 0.8 mg/kg bw. adriamycin. Twelve rats were injected with 0.2 mg phs. NaCl and served as control. Survival of rats served as criterion of therapeutic efficacy. There was a significant correlation between reduction of 3H-TdR-uptake in tumor cells after cytotoxic therapy and survival.

In-vitro-Resistenztestung von Tumoren gegenüber Zytostatika

Untersuchungen an Yoshida-Sarkomen und Walker-Karzinomen der Ratte erbrachten fur die Zytostatikaresistenztestung menschlicher Tumoren wichtige Befunde. Es konnte gezeigt werden, das die Ein-bauquoten tritiierter Stoffwechselprakursoren der DNS- und RNS-Synthese in Aszitestumorzellen und Zellen solider Geschwulste mit und ohne Zytostatikazusatz reproduzierbar sind. Unter den gewahlten Versuchsbedingungen waren der Anteil der proliferierenden Zellen, die Dauer der einzelnen Zellzyklusphasen und der Tumorgenerations-zeit vor und nach Explantation gleich. Durch Supravitalfarbungen mit Lissamingrun und Trypanblau und durch »γ-Release-Untersuchun-gen« 51Cr-markierter Tumorzellen konnte nachgewiesen werden, das durch die im In-vitro-Testverwendeten Zytostatikakonzentrationen wahrend der ersten 4 h nach Explantation keine vermehrte Zytozidie hervorgerufen wird.

Determination of turnover of androstenedione to estrone via aromatase in estrogen receptor positive and negative human breast cancer cell lines [Poster 48]

Abstract In one estrogen receptor (ER) negative (MDA-MB-231) and two ER positive human breast cancer cell lines (T-47-D,SK-BR-3) we measured aromatase activity by [3H]water assay and estrone (E1) production by thin-layer chromatography. Compared with ether extraction and charcoal method, lyophilization proved to be the most sensitive technique to measure the quantity of [3H]water. The extremely low contamination of the water soluble phase by [1s-3H]androstenedione (0.02%), as well as the lack of errors due to conjugated steroids, offers the possibility to measure changes of cellular aromatase activity even at very low levels. In contrast to SK-BR-3 and MDA-MB-231 cells, we found no aromatase activity in T-47-D cells. There was no coincidence between ER status and aromatase activity. Proliferation of tumor cells was parallel with a continuous increase of aromatase activity and E1 production during mitogenic growth phase reaching highest levels at the transition from log to plateau-phase.

[Influence of hydroxyurea on DNA synthesis of human bone marrow in vivo (author's transl)].

SummaryFour patients, who suffered from malignant, disseminated tumors but had a morphologically intact bone marrow, where given a peroral Hydroxyurea (HU) infusion in a concentration of about 5×10−4 mol over a period of 10 h. As indicator of the DNA synthesis the 3H-TdR-incorporation of bone marrow, gained by puncture before, during, and/or after HU application, was measured. While using HU, the DNA synthesis was extensively inhibited. Fourteen to 16 h after discontinuing the HU it increased by the factor 1.5 to 2 of the initial value, i.e., before treatment. This is interpreted as a partial synchronization of bone marrow cells where effects of cell depletion and recruitment are not to be entirely excluded, Toxicity, such as the decrease of peripheral blood cells or nausea, did not occur.ZusammenfassungBei vier an disseminierten Tumoren erkrankten Patienten mit morphologisch intaktem Knochenmark wurde eine perorale Hydroxyurea-Infusion (HU) in einer Konzentration von etwa 5×10−4 Mol über 10 h durchgeführt. Als Parameter der DNS-Synthese wurden die 3H-Thymidin-Einbauraten am durch Punktion gewonnenen Knochenmark vor, während und/oder nach HU-Behandlung gemessen. Die DNA-Synthese war während der HU-Applikation weitgehend inhibiert und stieg 14–16 h nach Absetzen des Medikaments um den Faktor 1,5 bis 2 des Ausgangswertes an. Als Erklärung dient eine partielle Synchronisation von Knochenmarkszellen, wobei Zelldepletions- und Recruitmenteffekte nicht sicher auszuschließen sind. Klinisch faßbare toxische Wirkungen wie Verminderung peripherer Blutzellen oder Unverträglichkeit traten nicht auf.Four patients, who suffered from malignant, disseminated tumors but had a morphologically intact bone marrow, where given a peroral Hydroxyurea (HU) infusion in a concentration of about 5 x 10(-4) mol over a period of 10 h. As indicator of the DNA synthesis the 3H-TdR-incorporation of bone marrow, gained by puncture before, during, and/or after HU application, was measured. While using HU, the DNA synthesis was extensively inhibited. Fourteen to 16 h after discontinuing the HU it increased by the factor 1.5 to 2 of the initial value, i.e., before treatment. This is interpreted as a partial synchronization of bone marrow cells where effects of cell depletion and recruitment are not to be entirely excluded, Toxicity, such as the decrease of peripheral blood cells or nausea, did not occur.