Showing papers by "Günther G. Steger published in 2000"

Glutathione in the prevention of cisplatin induced toxicities. A prospectively randomized pilot trial in patients with head and neck cancer and non small cell lung cancer.

Abstract: Purpose Glutathione has been shown to be an effective chemoprotector against cisplatin-induced side effects in patients with ovarian cancer. In view of this fact, we performed a randomized clinical pilot-trial in the management of other solid tumors in order to compare application of Glutathione to intensive hydration in patients undergoing chemotherapy with a regimen including cisplatin. Patients and methods Twenty patients suffering from advanced non small cell lung cancer (n = 6) or head- and neck cancer (n = 14) were enrolled in the study. All patients received 80 mg/m2 cisplatin along with etoposide or 5-fluorouracil every 4 weeks. Patients randomized to application of Glutathione (n = 11) received 5 g of Glutathione immediately before application of cisplatin followed by 2000 ml of normal saline. Patients in the control group (n = 9) received 2000 ml electrolyte infusion before and 2000 ml of normal saline with forced diuresis after cisplatin. Results The intensity of hematologic toxicity was significantly less pronounced in patients treated with Glutathione than in the control group (hemoglobin: 10.7 vs 9.5 mg% respectively, p = 0.039; white blood cell count 3.3 vs 2.2 x 103/microliter respectively, p = 0.004; platelets 167 vs 95 x 103/microliter respectively, p = 0.02), whereas in terms of non-hematologic toxicity no difference was observed. Objective remission occurred in 6 out of 11 evaluable patients from the group receiving Glutathione (55%; complete remission: 9%; partial remission: 46%), and in 4 out of 8 evaluable patients from the control group (partial remission: 50%). However, there was no statistical difference in terms of response and overall survival (13.5 months vs. 10.5 months) between the two groups. Conclusions Application of Cisplatin and Glutathione seems to be safe and feasible and the antitumoral efficacy of cisplatin is apparently not impaired by the concomitant use of Glutathione in patients with solid tumors.

Phase II study of gemcitabine in combination with cisplatin in patients with locally advanced and/or metastatic pancreatic cancer.

Abstract: The present phase II trial was performed to assess the efficacy and toxicity of polychemotherapy with gemcitabine and cisplatin in patients with locally advanced or metastatic carcinoma of the pancreas. Sixteen patients received six courses of an i.v. cytotoxic regimen consisting of gemcitabine (1000 mg/m2, days 1, 8 and 15) and cisplatin (35 mg/m2, days 1, 8 and 15) administered in 28-day intervals. Complete remission (CR) occurred in one patient (6%), partial remission (PR) in four patients (25%) and stable disease in seven patients (44%), whereas four patients (25%) developed progressive disease resulting in an overall response rate of 31%. Mean duration of responses (CR+PR) was 3.6 (range 0.7-8.5) months and mean time to progression was 7.4 (range 3.8-12.6) months. After a mean observation period of 11.5 months the overall survival was 9.6 months with 12 patients (75%) still being alive, which compares favorably with historical data of the administration of gemcitabine alone. The performance status improved in three (19%) and stabilized in eight (50%) out of 16 patients for 4 weeks or longer. Treatment-associated toxicity included alopecia of WHO grade III in all cases, leukopenia of WHO grades I and II in 10 patients (63%), grade III in five patients (31%), and thrombocytopenia grades I and II in four patients (25%), and grades III and IV in 10 patients (63%). We conclude that the administered dosage and schedule of gemcitabine and cisplatin in patients with locally advanced or metastatic cancer of the pancreas constitutes an active cytotoxic regimen associated with moderate toxicity.

Genetic analysis of multiple synchronous lesions of the colon adenoma-carcinoma sequence.

Abstract: The colorectal adenoma-carcinoma sequence represents a well-known paradigm for the sequential development of cancer driven by the accumulation of genomic defects. Although the colorectal adenoma-carcinoma sequence is well investigated, studies about tumours of different dignity co-existent in the same patient are seldom. In order to address the distribution of genetic alterations in different lesions of the same patient, we coincidently investigated carcinomas, adenomas and aberrant crypt foci in patients with sporadic colon cancer. By utilizing polymerase chain reaction, single-strand conformation polymorphism, heteroduplex-analysis, restriction fragment length polymorphism, protein truncation test and sequencing techniques we looked for mutations and microsatellite instability of APC, H-ras, K-ras, p53, DCC and the DNA repair genes hMLH1/hMSH2. In accordance with the suggested adenoma-carcinoma sequence of the colon, four patients reflected the progressive accumulation of genetic defects in synchronously appearing tumours during carcinogenesis. However, two patients with non-hereditary malignomas presented different genetic instabilities in different but synchronously appearing tumours suggesting non-clonal growth under almost identical conditions of the environment. Thus, sporadically manifesting multiple lesions of the colon were not necessarily driven by similar genetic mechanisms. Premalignant lesions may transform into malignant tumours starting from different types of genetic instability, which indicates independent and simultaneous tumorigenesis within the same organ.

Sequential administration of interferon γ and interleukin-2 in metastatic renal cell carcinoma: results of a phase II trial

Abstract: Background: Because of the known efficacy of several cytokines in the treatment of advanced renal cell cancer (RCC), we have conducted a phase II trial of the efficacy and toxicity of subcutaneous interferon γ (IFNγ) and interleukin-2 (IL-2). Methods: 63 patients with progressive metastatic RCC were treated with 100 μg recombinant IFNγ1b administered three times weekly during weeks 1 and 2 and with 4.5 MU recombinant IL-2 administered on 4 consecutive days during weeks 3 and 4, every 6 weeks. Results: 11% of patients had an objective response (CR: 3%, PR: 8%), 33% had SD. Toxicity was generally mild. The median duration of remissions (CR + PR) was 9.6 months; the median duration of SD 8 months. A significant survival benefit was evident at a median observation time of 51 months for patients (44%) responding to therapy (P < 0.0001). Conclusions: we conclude that sequential treatment with IFNγ and IL-2 may prolong survival in patients with metastatic RCC responding to therapy.

Relationship between in vivo drug exposure of the tumor interstitium and inhibition of tumor cell growth in vitro: a study in breast cancer patients.

Abstract: A novel approach is described to simulate effect site pharmacodynamics of anticancer drugs. This approach is based on (i) the in vivo measurement of unbound, interstitial drug pharmacokinetics (PK) in solid tumor lesions in patients and (ii) a subsequent pharmacodynamic (PD) simulation of the time versus drug concentration profile in an in vitro setting. For this purpose, breast cancer cells (MCF-7) were exposed in vitro to the time versus interstitial tumor concentration profiles of 5-fluorouracil (5-FU) and methotrexate (MTX) from primary breast cancer lesions in patients. This led to a maximal reduction in the viable cell count of 69% on day 4, and of 71% on day 7 for 5-FU and MTX, respectively. This effect was dependent on the initial cell count and was characterized by a high interindividual variability. For 5-FU there was a significant correlation between the maximum antitumor effect and the intratumoral AUC (r = -0.82, p = 0.0005), whereas no correlation could be shown for MTX (r = 0.05, p = 0.88). We conclude, that the in-vivo-PK / in-vitro-PD model presented in this study may provide a rational approach for describing and predicting pharmacodynamics of cytotoxic drugs at the target site. Data derived from this approach support the concept that tumor penetration of 5-FU may be a response-limiting event, while the response to MTX may be determined by events beyond interstitial fluid kinetics.

Monotherapy with docetaxel in second- or third-line treatment of anthracycline-resistant metastatic breast cancer.

Abstract: Nineteen breast cancer patients pretreated with one or two anthracycline-containing regimens for visceral metastases received i.v. docetaxel 100 mg/m2 on day 1, q 21d. Docetaxel was administered as second-line therapy in 11 patients, whereas eight patients received docetaxel in a third-line setting. In the second-line setting, complete response (CR) was achieved in two (18%), partial response (PR) in four (36%) and stable disease (SD) in three (27%) patients resulting in a response rate (RR) of 54%. In the third-line setting three (38%) patients experienced PR (RR 38%) and two (25%) SD. In the second-line setting, median time to progression was 6.5+/-3.9 months (range 2.1-15.8) versus 4.7+/-5.5 months (range 0.6-15.9) in the third-line setting. Median overall survival was 9.6+/-8.0 months (range 2.7-25.8) versus 11.2-6.1 months (range 4.8-18.7). Overall, no patient experienced treatment-limiting toxicities. We conclude that docetaxel induced responses in 48% of anthracycline-resistant patients enrolled into the present study. The safety profile of docetaxel was manageable and tolerable. Docetaxel represented efficacious treatment in patients with metastatic breast cancer progressing despite previous anthracycline-containing chemotherapy.

Vinorelbine and interferon-α2c as second-line therapy in metastatic renal cell carcinoma

Abstract: Second-line treatment of patients with metastatic renal cell carcinoma (MRCC) progressing under therapy with biological response modifiers (BRM) is an unresolved issue. Thirty-seven patients with MRCC progressing under treatment with BRM received vinorelbine i.v. at a dose of 30 mg/m2 q 22 days and

Paclitaxel-containing high-dose chemotherapy in high-risk breast cancer patients.

Abstract: Despite standard-dose adjuvant chemotherapy, the prognosis for patients with breast cancer and extensive axillary lymph node involvement at diagnosis is poor. The efficacy of a paclitaxel-containing, high-dose chemotherapy protocol in 21 high-risk breast cancer patients is assessed. After standard-dose chemotherapy followed by peripheral blood stem cell (PBSC) mobilization, high-dose therapy with paclitaxel, carboplatin, and cyclophosphamide and CD34-selected PBSC rescue was given. Hematologic reconstitution after high-dose therapy was rapid. Main toxicity included diarrhea grade I or II in about half of the patients and infections were observed in 19%. Five-year probabilities for relapse and failure-free survival were 32% and 62%, respectively. High-dose consolidation with paclitaxel, carboplatin, and cyclophosphamide achieves a high failure-free survival in patients with high-risk breast cancer with acceptable toxicities and stable, long-term hematopoietic reconstitution. Evaluation of the benefit of hi...