Treatment of patients with advanced nonsmall cell lung carcinoma using docetaxel and gemcitabine plus granulocyte-colony stimulating factor.

BACKGROUND: A combination regimen comprised of docetaxel, gemcitabine, and granulocyte-colony stimulating factor (G-CSF) was studied in patients with advanced nonsmall cell lung carcinoma (NSCLC) to determine its antitumor efficacy and tolerance. METHODS: Thirty-four patients with advanced measurable NSCLC (3 patients with Stage IIIB and 31 patients with Stage IV disease) were treated with an intravenous combination chemotherapy regimen comprised of docetaxel, 80 mg/m(2), on Day 1 and gemcitabine, 1000 mg/m(2), on Days 1 and 10; G-CSF, 5 microg/kg, was administered subcutaneously between Days 2 and 8. Treatment cycles were repeated every 3 weeks. All patients were evaluable for toxicity and response assessment. A total of 163 courses was administered. RESULTS: Objective tumor response was noted in 17 patients (50%; 95% confidence interval, 32. 5-67.5%), including 2 complete responses (6%) and 15 partial responses (44%). There was no change in 10 patients (29%) and 7 patients developed progressive disease. The median duration of response was 6.5 months (range, 3-15 months) and the median time to disease progression for all patients was 6.8 months (range, 1.8-18 months). The median overall survival time was 13.0 months (range, 2. 5-23+ months) with a 1-year survival rate of 55.8%. Myelosuppression was the most frequently encountered adverse reaction, although World Health Organization Grade 3 or 4 leukocytopenia and/or granulocytopenia occurred in only 18% and 24% of patients, respectively. Other toxicities generally were mild to moderate, and always fully reversible. CONCLUSIONS: With a response rate of 50% and a median survival time of 13 months, the drug combination described in the current study appears to have significant activity against advanced metastatic NSCLC. Due to its fairly good tolerance and ease of administration, further investigation of this regimen appears warranted.

Mitomycin C, vinorelbine, carboplatin plus granulocyte-macrophage colony-stimulating factor for treatment of advanced non-small cell lung carcinoma.

BACKGROUND: The therapeutic potential of chemotherapy in the treatment of recurrent or metastatic non-small cell lung carcinoma (NSCLC) seems modest. Thus, the search for novel agents and combination regimens with a superior therapeutic index has a high priority. The present combination regimen consisting of mitomycin C, vinorelbine, carboplatin and granulocyte-macrophage colony-stimulating factor (GM-CSF) was chosen because of the known activity of these agents in NSCLC and their potential drug synergism without (nonhematologic) cross-toxicity. To prevent/counteract neutropenia that was assumed to represent the dose-limiting toxicity, the hematopoietic growth factor GM-CSF was routinely adminstered. The objective of our trial was to determine the antitumor efficacy and tolerance of this combination regimen in patients with advanced NSCLC. PATIENTS AND METHODS: Forty consecutive patients with nonresectable, measurable NSCLC (stage IIIB, 7; stage IV, 33) were treated with an intravenous combination chemotherapy regimen consisting of mitomycin C 8 mg/m2 on day 1, vinorelbine 40 mg/m2 on days 1 and 21, and carboplatin 250 mg/m2 on days 1 and 21; GM-CSF 5 microg/kg was administered subcutaneously on days 2-8 and 22-28. Treatment cycles were repeated every 6 weeks. All patients are evaluable in terms of toxicity and response assessment. A total of 123 courses was administered. RESULTS: Objective tumor response was notes in 16 patients (40%; 95% confidence interval 24.9-56.7%), including 3 (7.5%) complete and 13 partial responses. There was no change in 12 (31.5%) patients, and 12 had progressive disease. Median duration of response was 6 (range 3-15) months, the median time to progression for all patients was 6.2 (range 1-17.5) months, and the projected median survival time was 8.7 (range 1-23.3) months; the 1-year survival rate was 27.5%. Myelosuppression was the most frequently encountered adverse reaction; WHO grade 3 or 4 granulocytopenia and/or thrombocytopenia occurred in 42.5 and 12.5%, respectively. Other toxicities were generally mild to moderate, and always fully reversible. CONCLUSION: With a 40% major response rate and disease stabilization in one additional third of our patients, this drug combination seems to have significant activity against advanced metastatic NSCLC. Due to its subjective tolerance and ease of administration, further investigation of this regimen in the palliative-intent care setting seems warranted.

[Stenosis of the extracranial carotid artery]. / Stenose der extrakraniellen Arteria carotis.

Magnetic resonance angiography (MRA) as well as intraarterial digital subtraction angiography (DSA) were performed in 45 patients suffering from cerebrovascular disease, both procedures within one week of each other. MRA und DSA were evaluated separately for every patient retrospectively by two experienced radiologists on consensus basis. The results were then compared using catheter angiography as gold standard. Evaluation was confined to the common and internal carotid arteries (CCA, ICA) in the neck subdivided into 5 grades of stenosis. A comparative assessment was impossible in 9% cases due to motion artifacts and patient malposition. Out of 18 verified CCA stenoses 13 were demonstrated by MRA and 39 out of 44 ICA stenoses were assessed by MRA. There was a highly significant correlation between degree of stenosis detected by the two methods. Spearman Rank correlation coefficients of 0.824 and 0.913 were found for CCA and ICA, respectively.

A decade of oral anticoagulant treatment to maintain autologous vein grafts for femoropopliteal atherosclerosis.

To determine whether long-term oral anticoagulant treatment was effective in improving graft performance and preventing major amputation following vein bypass surgery for femoropopliteal atherosclerosis, a clinical trial was conducted in one single center and continued during 10 years. After 130 patients had electively received a femoropopliteal vein graft, they were randomly assigned to a therapy group (treatment with phenprocoumon [n = 66]) or to a control group (n = 64) that remained without any anticoagulant treatment. Primary end points of the study were graft reocclusion and limb loss. The median durations of primary patency and limb salvage were significantly longer for treated patients than that for controls. In addition, survival in the therapy group was longer. Following autologous vein bypass surgery in the treated group, the results were superior in terms of graft patency, limb salvage, and survival.

Plasma levels of endothelin in chronic renal failure and after renal transplantation: impact on hypertension and cyclosporin A-associated nephrotoxicity.

1. Plasma levels of endothelin were measured in 30 patients with chronic renal failure, 32 patients on chronic haemodialysis treatment and 25 renal graft recipients with stable renal graft function. 2. In patients with chronic renal failure as well as in patients on regular haemodialysis treatment, mean plasma levels of endothelin were significantly increased (4.59 +/- 2.09 pg/ml, 10.08 +/- 3.12 pg/ml, respectively) when compared with normal subjects (1.88 +/- 0.6 pg/ml, P less than 0.01, P less than 0.001, respectively). 3. In the group with chronic renal failure a positive correlation between the plasma level of endothelin and the plasma concentration of creatinine was observed (P less than 0.003). 4. Renal graft recipients on cyclosporin A with stable renal graft function had a normal plasma level of endothelin suggesting that cyclosporin A nephrotoxicity is not mediated by endothelin. 5. Hypertensive patients with chronic renal failure or on regular haemodialysis and hypertensive renal graft recipients did not differ from the corresponding normotensive population with regard to the plasma level of endothelin, demonstrating that an increased plasma level of endothelin does not play a major role in the pathogenesis of renal hypertension.

Obliterations of the proximal subclavian artery: to bypass or to anastomose?

A clinical series has been analysed to determine which of two similar, extrathoracic "extraanatomic" methods of treating proximal blocks of the subclavian artery is the superior option. From 1975 until 1988 direct carotid-subclavian anastomosis was used in 32 patients and carotid-subclavian bypass in 19. There were no statistically significant differences for the probability of postoperative survival (p less than 0.877 Breslow; p less than 0.774 Mantel), intraoperative blood loss or the duration of anaesthesia. Those patients who had undergone subclavian artery repair had a significantly longer survival than those following carotid bifurcation endarterectomy (p less than 0.002 Breslow, p less than 0.0002 Mantel). As patients with subclavian lesions have a reasonable life-expectancy, they may possibly experience late complications of their vascular repair. Therefore it seems important to select the most durable operation, and direct carotid subclavian anastomosis has a significantly greater patency rate than bypass (p less than 0.006 Breslow, p less than 0.006 Mantel). Patients with preoperative symptoms of cerebrovascular insufficiency had a lower probability of survival than those with upper extremity claudication, although this did not reach statistical significance (p less than 0.205 Breslow; p less than 0.198 Mantel).

Thromboxane A2 and prostacyclin generation in the microvasculature of patients with atherosclerosis--effect of low-dose aspirin.

Generation of thromboxane A2 (TxA2) and prostacyclin (PGI2) at the site of platelet-vessel wall interaction, i.e. in blood emerging from a standardized injury of the microvasculature made to determine skin bleeding time was investigated in 7 patients with atherosclerosis (angiographically verified obstructions of the femoral arteries) and in 7 normal control subjects apparently free of atherosclerotic lesions. Similar amounts of TxA2 (measured as thromboxane B2, TxB2) were generated at the site of plug formation in the patients with peripheral vascular disease (PVD) and in the control subjects. Significantly lower levels of PGI2 (measured as 6-keto-prostaglandin F1 alpha, 6-keto-PGF1 alpha) were found in blood from an injury of the microvasculature in the patients compared with the controls. These data do not suggest a major role of the platelet prostaglandin metabolism in the development of atherosclerosis. However, decreased synthesis of PGI2 by endothelial cells might contribute to the development and/or progression of atherosclerotic lesions. In the patients with PVD, low-dose aspirin (50 mg/day for 7 days) resulted in a greater than 90% inhibition of the TxB2 production at the site of plug formation. Following low-dose aspirin 6-keto-PGF1 alpha levels were below 20 pg/ml (limit of sensitivity of our radioimmunoassay procedure) in the majority of the samples. We therefore conclude that in patients with PVD a decreased synthesis of PGI2 by endothelial cells might contribute to the progression of atherosclerosis. Furthermore, low-dose aspirin treatment results in a similar inhibition of the platelet prostaglandin generation as recently observed in healthy subjects.

Accidental overdose of mitoxantrone in three patients.

Mitoxantrone is a new effective antineoplastic agent with activity against a wide range of tumors. Compared with the anthracycline drugs doxo- and daunorubicin, it exhibits a clearly lower toxicity and, most importantly, a reduced cardiotoxicity. The analysis of the side-effects recorded after accidental overdosage of the drug gives additional insight into its tolerability. Here we describe our observations in three patients who inadvertently received 100 mg m-2 (two pts) and 183 mg m-2 (one pt) as single slow bolus injections. The main side-effects were moderate nausea and vomiting, shaking chills, and profound but reversible neutro- and thrombocytopenia. There was no immediate cardiac toxicity. One patient with extensive previous daunomycin exposure developed congestive heart failure after 4 months. Two patients were not evaluable for late cardiac complications because of early death due to tumor progression.

Vein bypass surgery for femoro-popliteal arteriosclerosis: influence of different risk factors on patient survival and the importance of anticoagulant treatment.

For femoro-popliteal arteriosclerosis the autologous saphenous vein graft implanted in reverse has evolved as the standard procedure, but the impact of postoperative anticoagulant treatment upon patient survival in particular remains uncertain. Patients undergoing elective surgery during the years 1970-86 (n = 668) were analysed using Kaplan-Meier estimates. This demonstrated that the preoperative status of the patient exerted a significant influence on the probability of survival (P less than 0.0001 Mantel). Anticoagulants started postoperatively significantly prolonged the life of the patients (P less than 0.0001). Of the various risk factors the patient's age had the most important influence (P less than 0.0001), whereas the presence or absence of diabetes mellitus (P less than 0.064) and the duration of the operation (P less than 0.407), were not significant. Using the proportional hazards regression model to test the validity of a prognostic factor, while other variables were checked, we found preoperative clinical status (P less than 0.0001), the patient's age (P less than 0.0001) and anticoagulant treatment (P less than 0.0001) to be of statistical importance.