W. Queißer

Phase I Clinical Trial of Lobaplatin (D-19466) after Intravenous Bolus Injection

Backgrund : Lobaplatin, D-19466, l,2-diamminomethyl-cyclobutane-platinum-(II)-lactate, is a new watersoluble platin complex which showed a better therapeutic index than cisplatin or

Etoposide, Adriamycin, and Cisplatinum (EAP) Combination Chemotherapy for Advanced Gastric Cancer

In a multicenter trial, 49 patients with histologically proven advanced gastric cancer were treated with a combination chemotherapy consisting of etoposide 120 mg/m2 d 4, 5, 6 adriamycin 20 mg/m2 d 1, 7 and cisplatinum 40 mg/m2 d 2, 8. Therapy was repeated every 4 weeks, 45 patients were evaluable for response after 8 weeks of treatment. Eight patients achieved a partial remission (PR: 18%), 17 patients had no change (NC: 38%), and 20 patients showed tumor progression (P: 44%). Four patients with primarily inoperable tumor and without distant metastases who achieved a partial remission, underwent second look operation with curative intention. All 4 patients died within 12 months after second look operation due to tumor recurrence. Median survival time of all patients was 9 months. Toxicity was considerable. WHO grade 3/4 toxicity appeared in 20-30% of patients (nausea, vomiting, loss of appetite, leucopenia). After 3 cycles complete alopecia was present in 70% of patients. Severe infection, requiring treatment, occurred in 10 patients. Five patients discontinued therapy because of intolerable subjective toxicity. The observed response rate of 18% objective partial remissions is disappointing and does not give support to the communications reporting response rates over 50% with EAP and other regimens including cisplatinum. In conclusion, and considering the high subjective and objective toxicity of this regimen, it can not be recommended for standard use in patients with advanced gastric cancer.

Adjuvant radio-chemotherapy with 5-fluorouracil and leucovorin in stage II and III rectal cancer: 12 Months vs. 6 months of therapy - A study of the Association for Medical Oncology of the German Cancer Society

Background: Postoperative radio-chemotherapy has been established as standard treatment for stage II and III rectal cancer patients. However, modulation and schedule of administration of 5-fluorouracil (5-FU) therapy are still subject of discussion. In a prospectively randomized study we compared 12 vs. 6 months of 5-FU/leucovorin (LV) chemo-radiotherapy in locally advanced or node-positive rectal cancer. Patients and Methods: Patients with stage II and III rectal cancer were postoperatively stratified according to tumor stage and type of operation and randomly assigned to one of two treatment arms: Patients in arm A received a total of 12, patients in arm B a total of 6 cycles of 5-FU (450 mg/m2 ) and LV (100 mg/m2 ), days 1–5, every 4 weeks. During the 2nd cycle local radiation up to 50.4 Gy was performed and dose-reduced chemotherapy (5-FU 350 mg/m2 ) was administered weekly. Study endpoints were disease-free and overall survival as well as toxicity. Results: From 1993 to 1997 263 patients were enrolled in the study. 40 patients had to be excluded from analysis, leaving 223 patients available for evaluation. After a median follow-up of 34.4 months, tumor relapse was seen in 89/223 (39.9%) patients, 11/223 (4.9%) patients presented with local recurrence only, 60/223 (26.9%) with distant metastases only and 18/223 (8.1%) with both local and distant relapse. 61/223 (27.4%) of the patients had died. With respect to disease-free survival (p = 0.77) and overall survival (p = 0.24), no statistically significant differences in the two treatment arms were observed. Furthermore, testing the equivalence of the 3-year recurrence rates and 3-year survival rates in the two treatment arms showed statistically significant equivalence for recurrence (p = 0.03) and survival rates (p = 0.03). As reported previously, there is no increase in toxicity with the 12-month regimen. Conclusions: Our results indicate that prolonged chemotherapeutic treatment over 12 months has no relevant advantage over a 6-month protocol with 5-FU and medium-dose LV. The combination of 5-FU and medium-dose LV is well tolerated by the majority of patients, and even prolonged therapy is not associated with increased toxicity.

Oral Administration of Idarubicin as First Line Cytostatic Therapy in Patients with Metastasized Breast Cancer and Favourable Prognosis

Idarubicin is a new anthracycline derivative with therapeutic efficacy in metastatic breast cancer. In a phase II trial we treated 23 patients with advanced breast carcinoma and favourable prognostic factors. Oral dose of idarubicin was 15 mg/m2 day 1-3 repeated every 3 weeks. All patients were pretreated with hormones. Idarubicin was administered as first line chemotherapy. 20 patients were evaluable for response: 3 patients achieved partial remission, 12 patients stable disease; tumour progression occurred in 5 patients. 3 patients were not evaluable for response because only 1 treatment cycle was administered. Main toxicites were leukopenia (median WHO-grade: 2,r:0-4), nausea and vomiting (median: 1,r:0-4) and alopezia (median: 1,r:0-3). 1 patient died in septic shock: Immediately after the administration of one idarubicine cycle, she was extensively irradiated because of bone metastasis. The fatal course of the disease in this patient does not depend only on the idarubicin therapy, but also on the extensive bone infiltration and on intensive radiation therapy. Idarubicin proved to be an effective drug in metastatic breast cancer with low systemic toxicity and the advantage of oral administration. The drug is an enrichment of therapeutic armament, especially in patients with soft tissue and bone metastasis.

Phase II Evaluation of Carboplatin in Advanced Esophageal Carcinoma

Eighteen patients with advanced squamous cell carcinoma of the esophagus without prior chemotherapy were treated with carboplatin. Based on experimental data a split dose of carboplatin of 130 mg/m2 g

Hepatotoxizität bei Etoposid-Ifosfamid-Kombinations-Chemotherapie

Bei zwei Patienten mit fortgeschrittenen Tumorleiden (Bronchialkarzinom, groszellig und Plattenepithelkarzinom) wird uber schwere hepatotoxische Nebenwirkungen nach Kornbinationschemotherapie mit Etop

Lebensqualität von Karzinom-Patienten unter Chemo- und Radiotherapie

156 Patienten mit fortgeschrittenen Bronchial- und Gastrointestinal-tumoren, die sich einer palliativen Chemo- und Radiotherapie unter-zogen, wurden in einer prospektiven Studie zur Veranderung ihrer Lebensqualitat unter Therapie untersucht. Als Mesinstrumente dien-ten ein Fragebogen (68 Fragen), eine lineare Analog-Skala und der Karnofsky-Index, die dreimal im Verlauf der Therapie zur Auswer-tung kamen. Die Auswertung des Fragebogens erbrachte als wichtig-sten Punkt eine Verbesserung des psychischen Befindens selbst bei Zunahme der Nebenwirkungen, wenn es bei den Patienten zu einer Tumorremission kam. Entwickelte sich jedoch eine Tumorprogres-sion, zeigte sich eine deutliche Mehrbelastung durch Nebenwirkungen und eine Verschlechterung des psychosozialen Befindens. Diese Ergebnisse bestatigen auch die Untersuchung der linearen Analog-Skala fur die tumorprogredienten Patienten. Der Karnofsky-Index zeigte eine hohe Korrelation fur die Beurteilung von krankheitsbezo-genen Inhalten und der Aktivitat des Patienten. In dieser Studie wird die Abhangigkeit von Therapieeffekt und Befinden des Patienten aufgezeigt. Es erscheint daher wichtig, Methoden zur Erfassung der Lebensqualitat in die Beurteilung onkologischer Therapien mit einzu-beziehen.

Phase I–II trial of doxifluridine (5′DFUR) administered as long-term continuous infusion using a portable infusion pump for advanced colorectal cancer

Doxifluridine, a new fluoropyrimidine analog, was administered to 21 patients with advanced colorectal carcinoma. The starting dose was 1.0 g/m2 given over 24 h for 90 consecutive days as a continuous infusion. Due to severe skin reactions (hand-foot syndrome), the dose was reduced stepwise to 0.75 g/m2/day. Twenty patients were evaluable for efficacy, one had an early non-toxic death. Seven out of 20 (35%) showed a partial response; disease stabilization was observed in 10 patients (50%) and three showed progressive disease after 3 months of treatment. All 17 patients who achieved a partial response or a stabilization of disease were treated until progressive disease was documented and some had therapy up to 46 weeks. Toxicity was minimal and mainly defined as hand-foot syndrome which occurred in 50% of the patients of whom three experienced severe reaction. There was no myelosuppression, renal or liver dysfunction, no cardiac alterations and only one patient experienced severe dizziness. Doxifluridine is active in advanced colorectal carcinoma when the drug is given as a continuous infusion for 90 consecutive days at a daily dose of 0.75 g/m2.

Lobaplatin (D-19466) in Patients with Advanced Non-Small-Cell Lung Cancer: A Trial of the Association for Medical Oncology (AIO) Phase II Study Group

Background: Lobaplatin, D-19466, 1,2-diaminomethyl cyclo-butane ρlatinum(II)lactate, is a new, water-soluble platinum complex which we expected would have a better therapeutic index than either cisplatin or carboplatin, since various murine and human tumor models had previously indicated effectiveness. Furthermore, a phase I study demonstrated that Lobaplatin was successful in the treatment of bronchogenic carcinomas. Patients and Methods: A total of 39 patients with inoperable advanced non-small-cell lung cancer (NSCLC), previously untreated by chemotherapy or radiotherapy, were included to receive Lobaplatin in a dose of 50 mg/m2 once every 4 weeks as a single bolus injection. Results: Of the 39 patients included, 33 were evaluable for response according to protocol. There were no complete remissions, and only 1 patient (3%) had a partial response. Most of the patients showed no change (54.5%), with the time to progression ranging between 8 and 28+ weeks. The data of 38 patients were used for the toxicity analysis. Nausea and vomiting were the leading clinical problems in nonhematological toxicity and appeared in 27 (71%) patients (in 18% of patients with WHO grade III). Regarding hematological toxicity, the leading problem was thrombocytopenia, with WHO grades III and IV in 6 and 5 patients, respectively. Conclusion: Lobaplatin was well tolerated when applied as a 50 mg/m2 single bolus intravenously in 4-week intervals. However, regarding its effectiveness, our phase II study found it to be only marginally effective in the dose and schedule used. Therefore, our results provide no support for further use of this treatment plan in patients with NSCLC.

Chemotherapy of Advanced Gastric Carcinoma

The results of current chemotherapeutic treatment for advanced gastric carcinoma are reviewed. Recent results of phase-II trials suggest that besides 5-fluorouracil, the nitrosoureas, adriamycin and mitomycin C, cis-platinum is also an effective drug in advanced gastric carcinoma. The favorable results obtained with the FAM-regimen in the late seventies, which were believed to be a significant step towards an improved treatment of gastric carcinoma, could not be confirmed, and several tested FAM-modifications were not able to improve treatment results. However, some recent investigations of cis-platinum within combination chemotherapy, i.e. with 5-fluorouracil and adriamycin (FAP), showed response rates beyond 30% and possibly a prolongation of median survival. These favorable data, which suggest an encouraging progress within the treatment of advanced gastric carcinoma, have to be confirmed in further controlled clinical trials.