Walter Krischke

Untersuchungen zur kurzzeitigen Induktions- und zyklischen Erhaltungstherapie beim inoperablen kleinzelligen Bronchialkarzinom

Since July 1978 one hundred and three consecutive patients with unresectable small cell bronchogenic carcinoma were treated with a combination of doxorubicin, cyclophosphamide and vincristine (ACO). In limited disease patients (64) the second chemotherapy course was followed by prophylactic cranial irradiation, the fourth by irradiation towards primary disease sites. Complete responders were randomised to either receive etoposide or no further maintenance therapy. Objective responses were reached in 88/100 evaluable patients, with 72% of complete remissions in limited-stage disease and 33% in extensive disease, respectively. The actuarial median survival time for limited disease patients was 15.8 months compared to 9.3 months in extensive disease (p less than 0.005). 29 of the 100 patients remain still alive, 4 for more than 24 months without disease recurrence. The survival advantage of patients reaching complete remissions relative to those who did not is highly significant (p less than 0.001). Acute gastrointestinal and hematological side effects were common, with possibly three drug-related deaths from infections during transient granulocytopenia (mean nadir: 600-900 cells/mm3). The present induction regimen using only four courses of chemotherapy produces high complete remission rates on roentgenography and bronchoscopy and improved survival in the majority of patients. Thus far any effectiveness of etoposide-maintenance therapy following ACO could not be substantiated.SummarySince July 1978 one hundred and three consecutive patients with unresectable small cell bronchogenic carcinoma were treated with a combination of doxorubicin, cyclophosphamide and vincristine (ACO). In limited disease patients (64) the second chemotherapy course was followed by prophylactic cranial irradiation, the fourth by irradiation towards primary disease sites. Complete responders were randomised to either receive etoposide or no further maintenance therapy. Objective responses were reached in 88/100 evaluable patients, with 72% of complete remissions in limited-stage disease and 33% in extensive disease, respectively. The actuarial median survival time for limited disease patients was 15.8 months compared to 9.3 months in extensive disease (p<0.005). 29 of the 100 patients remain still alive, 4 for more than 24 months without disease recurrence. The survival advantage of patients reaching complete remissions relative to those who did not is highly significant (p<0.001). Acute gastrointestinal and hematological side effects were common, with possibly three drug-related deaths from infections during transient granulocytopenia (mean nadir: 600–900 cells/mm3). The present induction regimen using only four courses of chemotherapy produces high complete remission rates on roentgenography and bronchoscopy and improved survival in the majority of patients. Thus far any effectiveness of etoposide-maintenance therapy following ACO could not be substantiated.ZusammenfassungSeit Juli 1978 wurden 103 Patienten mit inoperablem kleinzelligem Bronchialkarzinom mit der Zytostatikakombination Adriamycin, Cyclophosphamid und Vincristin (ACO) behandelt. Im Stadium „limited disease“ (n=64) erfolgte während des zweiten Chemotherapiekurses eine prophylaktische Schädelbestrahlung, nach dem vierten eine konsolidierende thorakale Bestrahlung. Nach Erreichen einer kompletten Remission erhielten die Patienten prospektiv randomisiert Etoposid oder keine weitere spezifische Therapie. Ein objektives Ansprechen konnte bei 88/100 auswertbaren Patienten erzielt werden. Im Stadium „limited disease“ fanden sich 72%, im Stadium „extensive disease“ nur 33% komplette Remissionen. Im Stadium „limited disease“ betrug die hochgerechnete mediane Überlebenszeit 15,8, im Stadium „extensive disease“ 9,3 Monate (p<0.005). Es leben noch 29 Patienten, 4 rezidivfrei länger als 24 Monate. Patienten mit kompletter Remission hatten eine statistisch signifikant (p<0.001) längere Überlebenszeit als Patienten mit geringerem Ansprechen. Regelmäßig traten gastrointestinale und hämatologische Nebenwirkungen auf, drei Patienten starben während der Induktionsphase an Infektionen. Die kurzzeitige Induktionsbehandlung verbesserte jedoch den Krankheitsverlauf subjektiv und objektiv. Bisher ist kein positiver Effekt der zyklischen Etoposid-Gabe nach ACO festzustellen.

Tumor inhibiting [1,2-bis(fluorophenylethylenediamine]platinum-(II) complexes. Part I: synthesis

Abstract The synthesis of the diastereomeric 1,2-bis(2-,3- and 4-fluorophenyl)ethylenediamines 4–6, 10–12 from meso-1,2-bis(2-hydroxyphenyl)ethylenediamine and 2-, 3- and 4-fluorobenzaldehyde by a diaza-Cope-rearrangement and their conversion into the [1,2-bis(2-, 3- and 4-fluorophenyl)ethylenediamine]dihaloplatinum (II) complexes (Hal = Cl, 13–18; Hal = I, 19–24) with K2PtHal4 is described. From the diiodoplatinum(II) complexes (19–24) the better water soluble diaqua[1,2-bis(2-, 3- and 4-fluorophenyl)ethylenediamine]platinum(II) sulfates (25–30) and [1,2-bis(4-fluorophenyl)ethylenediamine]dinitratoplatinum (II) complexes (31 and 32) are obtained by reacting with Ag2SO4 or AgNO3. On the P388D1 leukemia cell line the racemic platinum (II) complexes are more active than their meso-analogues and equiactive with cis-platin. The position of the fluorine atom and the kind of the leaving group do not influence the activity.

4′-Epi-doxorubicin — A clinical phase-II trial in solid tumors

Summary4′-Epi-doxorubicin is a new anthracycline analog with reduced cardiac toxicity in animal studies. A phase-II study was performed in 17 patients predominantly with non-small-cell lung cancer. All suffered from recurrent or advanced tumors and 7 of 16 evaluable patients had been pretreated with an alternative chemotherapy. 4′-Epi-doxorubicin was applied at a dose of 75 mg/m2 every 3–4 weeks. The median total dose was 280 mg (range: 130–250 mg). Only one patient with epidermoid lung cancer (overall response rate: 6%) showed a minor response and stable disease was observed in six other patients with bronchogenic carcinoma. Myelosuppression was rare and moderate: Leukocytopenia of less than 2,000/mm3 occurred in 25% of patients and thrombocytopenia of less than 100,000/mm3 in 8% of patients. The frequency of alopecia and gastrointestinal side effects was 88% and 80%, respectively. Persistent electrocardiographic alterations were recorded in 2 of 14 (14%) patients. One of four patients revealed a marked reduction of left ventricular ejection fraction in radionuclide cardiography. It is concluded that 4′-epi-doxorubicin is not superior to adriamycin in this low-prospect treatment area, but studies with increased doses appear necessary in adriamycin-sensitive tumors because of recent reports from phase-III trials showing reduced cardiac and gastrointestinal toxicity with 4′-epi-doxorubicin in comparison with adriamycin.

A simple method of delayed processing of tumor tissue in a soft agar clonogenic assay

SummarySarcoma 180 tumor tissue from C57 mice was processed in a soft agar clonogenic assay immediately after removal from the animal and after various methods of storage. The sensitivity to the antineoplastic drug cis-platinum was not affected by different storage methods. The highest yield of colony forming cells per 100 mg tumor tissue was 2.3x104 cells following immediate processing of fresh tumor material. A 24-h storage of solid tumor tissue at 4°C as well as cryopreservation of solid tumor tissue or cryopreservation of a single cell suspension prepared from fresh tumor specimens were found to reduce this value to 24%–37%. Storage of a tumor single cell suspension for 24h at 4°C however, proved to be a useful and simple method of delayed processing of tumor in a soft agar clonogenic assay. The observed cell yield was 1.91x104 colony forming cells, 83% of the immediately processed value. If this procedure is suitable for use with human tumor material obtained from biopsies and surgery, the 24 h time interval would be useful for transport from hospital to an appropriate special laboratory. This would result in the broader application of the human soft agar clonogenic assay in predictive testing and drug screening.

Vindesine/Cisplatin chemotherapy in relapsed or primarily resistant small-cell carcinoma of the lung

SummaryThirty-eight pretreated patients with primarily resistant [6] or relapsed [32] small-cell lung cancer were treated with a combination of vindesine (3–4 mg/m2) and cisplatin (60–100 mg/m2). Eight patients responded to this therapy with three (8%) complete and five (13%) partial remissions. Minor responses were noted in 12 (32%) additional patients. Chemotherapeutic response was rare in regions of prior irradiation. In the complete remission group survival from start of vindesine/cisplatin therapy lasted 61, 48 and 38 weeks, respectively. In the “less-than-complete-remission” group median survival was 12 weeks. Nausea and vomiting were the prominent side-effects, while only mild to moderate myelosuppression was noticed in most cases. The vindesine/cisplatin combination showed significant activity in heavily pretreated small-cell lung carcinoma. However, the remission rates remain low in this unfavourable condition, which might be due to pronounced chemotherapeutic resistance in previously irradiated areas.