Phase II studies with carboplatin in non-small cell lung cancer.

Since 1987, we have evaluated carboplatin alone or in combination with etoposide in two separate phase II trials of patients with non-small cell lung cancer (NSCLC) who had not received prior chemotherapy. Single-agent carboplatin produced a 20% response rate in 51 patients treated with 390 mg/m2 intravenously every 4 weeks. A 3-day schedule of etoposide 140 mg/m2 on days 2, 3, and 4, and carboplatin 150 mg/m2 on days 1 and 5 also resulted in a 26.7% response rate in 46 patients. Myelosuppressive toxicity associated with carboplatin/etoposide was substantially greater than that seen with carboplatin alone. Carboplatin as a single agent is active in previously untreated patients with advanced NSCLC. The two-drug combination of carboplatin and etoposide also shows activity in NSCLC similar to other combination chemotherapeutic regimens based on comparable prognostic factors in untreated patients. Further evaluation of carboplatin as part of combination chemotherapy in NSCLC is warranted.

Phase II study with paclitaxel for the treatment of advanced inoperable non-small cell lung cancer.

Paclitaxel is a plant product isolated from the bark of the Western yew (Taxus brevifolia) that promotes the formation and stabilization of microtubules. This leads to growth arrest in the G2/M phase of the cell cycle. Paclitaxel has demonstrated significant antineoplastic activity in different tumor types, most notably in ovarian and breast carcinoma. In two Phase II trials (Eastern Cooperative Oncology Group [ECOG]/M.D. Anderson) in patients with previously untreated Stage IIIB-IV non-small cell lung cancer (NSCLC), response rates of 21% and 24% were reported. We are performing a Phase II trial investigating the efficacy of paclitaxel in patients with inoperable Stage IIIB-IV NSCLC. Forty-three patients were treated, 31 males and 12 females, with a median age of 59 years (range, 29-75), ECOG performance status 0-2, Stage IIIB 30%, Stage IV 70%. Patients were treated every 3 weeks with 225 mg/m2 as a 3-h infusion with standard premedication. Preliminary efficacy results from 37 patients include partial remissions in eight (21.6%) patients, no change in 22 (59.5%) and disease progression in seven (19%) patients. Eight patients are still receiving therapy. The hematologic toxicities (n = 43) were mild, and no World Health Organization (WHO) Grade 4 neutropenia was observed. Nonhematologic toxicities were Grade 1/2 polyneuropathy in 97.6%, Grade 1-3 myalgia/arthralgia in 76%, and Grade 1-3 nausea/vomiting in 18.6% of the patients. In conclusion, paclitaxel is an active single agent in this patient population. Mild hematologic toxicities were observed in the 3-h infusion setting (compared with 24-h infusion) and therapy was well tolerated.(ABSTRACT TRUNCATED AT 250 WORDS)

Phase II study of carboplatin in untreated, inoperable non-small-cell lung cancer.

A total of 51 previously untreated patients with non-small-cell lung cancer (NSCLC) were treated with 130 mg/m2 carboplatin given every 4 weeks as an i.v. infusion on days 1, 3, and 5. Ten patients achieved a partial response and five, a minor response. The overall response rate was 20% (95% confidence limits, 8%-32%). The median duration of response was 3 months and the median overall survival was 4.5 months. Leucopenia, thrombocytopenia and anemia of WHO grade 3 occurred in 4%-6% of patients and grade 3 nausea and vomiting was observed in 8% of our subjects. Grade 4 thrombocytopenia occurred in 3 (6%) patients. Apart from nausea and vomiting, nonhematologic toxicities above grade 2 were not observed. Further trials using carboplatin in NSCLC as a single agent or in combination with other chemotherapeutic agents or radiation are warranted.

Predominant cutaneous infiltration by OKT6- and OKT8-positive cells in a case of Sézary syndrome.

Using an immunoperoxidase (skin biopsy) and an immunofluorescence (peripheral blood, bone marrow punctate) technique, and monoclonal antibodies raised against peripheral mature lymphocytes, T helper subsets, T suppressor subsets, and Langerhans cells, we found a predominant dermal infiltration with lymphocytes of the suppressor phenotype and a predominant epidermal infiltration with Langerhans cells in a patient with Sézary syndrome (cutaneous T-cell lymphoma, CTCL). Repeated peripheral blood examinations showed an increased percentage of lymphocytes of the helper phenotype. A bone marrow examination revealed a ratio of suppressor/helper subsets of 1:4. The findings in the skin seem to be inconsistent with most of the results of previous studies in patients with CTCL; the significance of these findings is discussed.

Pulmonary metastasizing hemangiopericytoma.

Hemangiopericytomas are rare tumors, originating from pericytes of the small vessels, that can appear anywhere in the body. From the histological picture it is difficult to determine whether or not they are malignant. The metastasizing rate depends upon the tumor's location and varies from 50 to 80%. Local recurrences occur in roughly 50% of the cases. Hemangiopericytoma is normally surgically treated because radio- and chemotherapy are generally less effective. There is limited experience in treating metastasizing hemangiopericytomas with chemotherapy. We treated 2 patients with pulmonal metastasizing hemangiopericytoma: In 1, the tumor originated in the brain and in the other, the left knee. Both patients had chemotherapy over an extended period of time. By means of x-ray, histological, and electronmicroscopical examinations we report on the course of the diseases.

A randomized trial with mitomycin-C/ifosfamide versus mitomycin-C/vindesine versus cisplatin/etoposide in advanced non-small-cell lung cancer.

192 evaluable patients with advanced inoperable non-small-cell lung cancer were treated with either mitomycin-C/ifosfamide (A), mitomycin-C/vindesine (B), or cisplatin/etoposide (C) in a prospective randomized trial. The response rates for each treatment arm were 30.0% (A), 22.7% (B), and 25% (C), respectively. There was no statistically significant difference (p = 0.4) between treatment arms. The median survival time was 27 weeks (A), 23 weeks (B), and 25 weeks (C), respectively. With regard to toxicity the combination mitomycin-C/vindesine was superior to treatment arms A and C. Nausea and vomiting (WHO 3 + 4) occurred only in 6.1% of the patients versus 43.3% of those treated with mitomycin-C/ifosfamide and 36.7% of those treated with cisplatin/etoposide. This difference is statistically highly significant (p = 0.0001). Because of its very low toxicity, especially for gastrointestinal symptoms, the combination mitomycin-C/vindesine was judged superior to the other combinations. None of these regimens, however, had a major impact on survival in advanced non-small-cell lung cancer.

Time course of exhaled hydrogen peroxide and nitric oxide during chemotherapy.

This study was designed to assess the effect of differential leukocyte depletion during chemotherapy by monitoring the levels of exhaled hydrogen peroxide H2O2 and nitric oxide (F(eNO)) present. In 39 patients with lung cancer (chronic obstructive pulmonary disorder up to stage II, median forced expiratory volume in one second 78% predicted), measurements were performed before a cycle of therapy (day 1), at least once during the cycle (day 8: n = 34; day 15: n = 19), and afterwards (days 21-29). There were significant changes in the level of H2O2, F(eNO) and peripheral blood cell differentials over the visits. The level of H2O2 was decreased only on day 15, with a median (difference between the upper and lower quartiles) fall of 31 (57)%, while F(eNO) was reduced only on day 8, by 22 (40)%. Neutrophil numbers were unchanged on day 8 and decreased by 59 (48)% on day 15, while monocyte numbers were decreased on day 8 by 87 (39)%. On days 21-29, values had returned to baseline. Taken together with previous findings, the parallel course of levels of exhaled hydrogen peroxide and neutrophil counts suggests that a major part of exhaled hydrogen peroxide is due to neutrophils via the conducting airways. In contrast, the production of exhaled nitric oxide seems to be primarily associated with monocytes.

[Chemoprevention of lung cancer. A review about previous studies, results and future developments]. / Chemoprävention beim Bronchialkarzinom: Uberblick über bisherige Studien, Ergebnisse und zukünftige Entwicklungen.

Despite improvements in the early detection of lung tumors, mortality from this type of disease is increasing world wide and the 5-year-survival rate still ranges below 10 %. The approach of chemoprevention offers the possibility to interfere with the process of cancerogenesis by the use of natural or synthetic chemical compounds and either to prevent DNA damage or to stepp the proliferation of premalignant cells that are already in place. With regard to bronchial carcinoma, chemoprevention in the first place implies cessation of smoking but the currently used procedures are not extremely efficient and many ex-smokers experience an increased risk of acquiring a lung tumor over a prolonged period of time (secondary prevention). In the past 20 years many details of the process of tumorigenesis have been revealed and this knowledge has promoted the targeted use of chemopretective compounds. In addition to the classics in the fields, such as vitamin A, beta-carotene, vitamins E, C and B12 as well as selenium, the last years have brought the development of new compounds, such as retinoids, dithiols, cyclooxygenase inhibitors, epidermal growth factors and others, the mechanismen of action of which provide interesting new approaches. In addition, the introduction of biomarkers, either genetic alterations or proliferation or differentiation, allows to monitor the process of tumorigenesis in its different stages, from early to late, and thereby offers the perspective to perform studies on chemoprevention more rapidly and effectively as in previous years. Thus, in combination with optimized, controlled study designs it is to be expected that in near future clinical studies on the effects on chemoprotective compounds will yield decisive data on their efficacy in chronic smokers as well as ex-smokers.

Megestrol acetate in cachectic patients with advanced bronchogenic cancer.

Megestrol acetate, a semisynthetic gestagen, is effective not only for endocrine therapy of advanced breast carcinoma, but also in treatment of cachectic patients with aggressive, hormone-independent tumors. 40 patients with therapy-resistant, advanced bronchogenic carcinoma of different histologic type, who had lost more than ten percent of their regular body weight within a prospective, non-randomized trial were treated with megestrol acetate at a dose of either 160 mg/day or 480 mg/day for 3-4 months. The average weight gain of all patients was 3.0 kg. Nearly all of them (80%) reported improved appetite and well-being. The weight gain in the group of patients receiving 160 mg/day was higher (80%) than in the group receiving 480 mg/day (50%), suggesting that the lower dose is as effective as the higher one for palliative treatment.

Treatment of cancer weight loss in patients with advanced lung cancer.

Megestrol acetate, a semisynthetic gestagen, is effective not only for endocrine therapy of advanced breast carcinomas, but also in the treatment of cachectic patients with aggressive, hormone-independent tumors. Sixty-six patients with therapy-resistant, advanced bronchogenic carcinomas of different histologic types, who had lost more than 10% of their regular body weight within a prospective, randomized trial, were treated with megestrol acetate at a dose of either 160 or 480 mg/day for 3-4 months. The mean weight gain for all patients was 2.5 kg. Nearly all of them (80%) reported improved appetite and well-being. The mean weight gain in the group of patients receiving 480 mg/day was higher (3.0 kg) than in the group receiving 160 mg/day (2.0 kg).