Effects of tamoxifen and octreotide LAR on the IGF-system compared with tamoxifen monotherapy.

The insulin-like growth factor (IGF)-system was evaluated in 150 breast cancer patients participating in a randomised phase III trial comparing octreotide pamoate and tamoxifen with tamoxifen+placebo. Alterations in the IGF-system in the two treatment arms and individual changes with respect to outcome were compared. Serum IGF-I and -II, free IGF-I, and insulin-like growth factor binding protein 1-3 (IGFBP1-3) were measured by radioimmmunoassay (RIA)/immunoradiometric assay (IRMA) and IGFBPs by Western ligand blots (WLB) before and during treatment. Combined treatment caused a higher increase in IGFBP-1 and larger suppression of total and free IGF-I, IGF-II, and IGFBP-3 (P<0.01 for all), but less suppression of IGFBP-2 (P<0.05) compared with tamoxifen monotherapy. An increase in IGFBP-2 25% was associated with decreased progression-free survival (PFS) in the total patient population and combined treatment group. Similar response rates and time to progression in the treatment arms suggests moderate suppression of circulating IGF-I has no influence on clinical outcome.

Cyclosporine as maintenance therapy in patients with severe psoriasis.

BACKGROUND: Low-dose cyclosporine therapy for severe plaque psoriasis is effective. Most side effects can be controlled by patient monitoring, with appropriate dose adjustment or pharmacologic intervention, or both, if indicated. Prevention or reversibility of laboratory and chemical abnormalities may be achieved by discontinuation of therapy after the induction of clearing. However, relapse occurs rapidly on discontinuation. Maintenance therapy with cyclosporine after induction has not been fully evaluated. OBJECTIVE: Our purpose was to compare a regimen of 3.0 mg/kg per day of oral cyclosporine with placebo in maintaining remission or improvement in patients with psoriasis. METHODS: After a 16-week unblinded induction phase in which 181 patients received cyclosporine, 5.0 mg/kg per day (an increase up to 6.0 mg/kg per day and a decrease to 3.0 mg/kg per day were allowed, if required, to achieve efficacy or tolerability, respectively), those patients showing a 70% decrease or more in involved body surface area (BSA) entered the 24-week maintenance phase and were randomly assigned to either placebo, cyclosporine, 1.5 mg/kg per day, or cyclosporine, 3.0 mg/kg per day. Patients were considered to have had a relapse when BSA returned to 50% or more of the prestudy baseline value. Clinical efficacy, adverse effects, and laboratory values were monitored regularly throughout both study phases. RESULTS: During induction, cyclosporine at approximately 5.0 mg/kg per day produced a reduction in BSA of 70% or more in 86% of the patients. During maintenance, the median time to relapse was 6 weeks in both the placebo and cyclosporine 1.5 mg/kg per day groups, but was longer than the 24-week maintenance period in the 3.0 mg/kg per day group (p < 0.001 vs placebo). By the end of the maintenance period, 42% of the patients in the 3.0 mg/kg per day cyclosporine group had a relapse compared with 84% in the placebo group. Changes in laboratory values associated with the higher induction dosage generally exhibited partial or complete return toward mean prestudy baseline values during the maintenance phase, with the greatest degree of normalization in the placebo group. CONCLUSION: Cyclosporine, 3.0 mg/kg per day, adequately and safely maintained 58% of patients with psoriasis for a 6-month period after clearing of their psoriasis with doses of approximately 5.0 mg/kg per day.

Clinical and magnetic resonance imaging changes correlate in a clinical trial monitoring cyclosporine therapy for multiple sclerosis. The MS Study Group.

Magnetic resonance imaging (MRI) was used to monitor cyclosporine therapy for chronic progressive multiple sclerosis in a multicenter clinical trial and an analysis was performed to determine whether there was a correlation between clinical changes and MRI changes. MRI was performed on 163 patients at the onset and completion of the 2-year study. Burden of disease (BOD, lesion load) was quantitated by a single observer using a computer program. Active lesions were also identified. The Expanded Disability Status Scale (EDSS) score was determined every 3 months MRI data did not show any effect of cyclosporine treatment on BOD progression (mean 24.5% increase/yr) or lesion activity. However, there was a statistically significant positive correlation between the baseline total BOD value and the baseline EDSS score (r = 0.221, p = 0.005) and a positive correlation between the percent changes in BOD from baseline to exit and EDSS score (r = 0.186, p = 0.018). The study supports the concepts that MRI is a useful technique in monitoring therapeutic trials and that MRI is a direct measure of pathology.

A double-blind study of the effectiveness of cyclosporine in amyotrophic lateral sclerosis.

In a double-blind placebo-controlled trial of cyclosporine in amyotrophic lateral sclerosis, no differences were observed in the monthly rate of progression or the relative risk of progression in comparing 38 patients randomized to the placebo group and 36 patients randomized to the cyclosporine group. In comparing three subgroups of patients, cyclosporine appeared to benefit men who entered the study within 18 months of the onset of first symptoms, whereas it was of no value to women or to men who entered later than 18 months. For the men with recent onset of disease, the relative risk of progression was 0.403; the monthly rate of progression was 5.2 +/- 1.1 points with placebo and 3.5 +/- 0.7 points with cyclosporine. These provocative results support the need for a full study of cyclosporine in men with recent onset of disease.

Levamisole as an adjuvant to chemotherapy in extensive bronchogenic carcinoma: a Veterans Administration Lung Cancer Group Study.

A randomized trial of 381 patients with extensive lung cancer compared immunochemotherapy with levamisole (150 mg/m2 orally three times a week), cyclophosphamide (700 mg/m2 IV every three weeks) and CCNU (70 mg/m2 orally every six weeks) with the same chemotherapy without levamisole. When disease progressed, doxorubicin hydrochloride or doxorubicin hydrochloride plus levamisole was used. Hematologic toxicity required reduction of the levamisole dosage to 2.5 mg/kg (100 mg/m2) three times a week, every other week. When corrections are made for all variables, levamisole itself had a negative influence on survival. Patients given 150 mg/m2 had a shorter median time to treatment failure (P = 0.02), lower response rate (P = 0.02) more toxicity (P = 0.08), and shorter median survival (P = 0.08). Patients with 10% or greater weight loss had significantly shorter survival (P = 0.006). The regimen with the reduced dosage of levamisole also was more toxic (P = 0.05) but otherwise did not differ from the control regimen. The cause of the adverse effect of levamisole is unknown. It did not occur because of an excess of toxic deaths or because smaller doses of cytotoxic drugs were given to patients treated with levamisole. Neither the initial lymphocyte count nor the Candida skin test reactions had a significant effect on the study endpoints when correction was made for dominant prognostic factors such as the initial performance status and weight loss.

Phase III study of intermittent carmustine (BCNU), cyclophosphamide, and prednisone versus intermittent melphalan and prednisone in myeloma.

A prospective randomized trial in patients with previously untreated multiple myeloma was performed comparing carmustine (BCNU), cyclophosphamide, and prednisone (BCP) to melphalan (Alkeran) and prednisone (AP). Induction response rates, remission duration, and survival were similar with both regimens. Hematologic toxicity was greater with AP. Crossover studies in patients who relapsed did not illustrate any significant activity with either drug treatment program. Therefore, BCP can be utilized as initial therapy in myeloma because of comparable remission rates and less hematologic toxicity.

Influence of cell type on failure pattern after irradiation for locally advanced carcinoma of the lung.

Patterns of failure after treatment for carcinoma of the lung were analyzed by the major WHO cell types. Only diagnoses of the review panel of the Veterans Administration Lung Group were used. First sites of progression were analyzed for 185 patients in a clinical trial, and cause of death was evaluated in 300 consecutive autopsies from VALG studies. Clinical progression was similar for all cell types--20% failed locally and 30% developed metastases. Carcinomatosis or brain metastasis caused death in only 27% of patients with squamous, in over half with large cell and adenocarcinoma, and in 70% of patients with small cell carcinoma. Complications of the local tumor (infection, hemorrhage, and respiratory failure) caused death in 50% of patients with squamous, in 1/3 with large cell and adenocacrinoma, and in 21% of those with small cell carcinoma. These clinical and autopsy data suggest the need for aggressive treatment of the local tumor in all cell types, and systemic therapy for small cell carcinoma. Both local and systemic approaches are needed for large cell and adenocarcinoma.

Combined chemotherapy for squamous cell carcinoma of the lung.

One hundred sixty-seven patients with extensive well-differentiated and 120 patients with extensive poorly differentiated squamous cell carcinoma of the lung received chemotherapy as part of a randomized study by the Veterans Administration Lung Group. Chemotherapy was administration at random using one of the following four regimens: (1) cyclophosphamide alone; (2) cyclophosphamide plus 1-(2-chloroethyl)-3-cyclohexyl-1-nitrosourea (CCNU); (3) doxorubicin (adriamycin) plus cyclophosphamide; and (4) doxorubicin plus CCNU. With data on survival as the criteria for evaluation, it has been shown that combined chemotherapy using doxorubicin plus cyclophosphamide achieves greater median survival for patients with squamous cell cancer of the lung than single-drug chemotherapy using cyclophosphamide, under the conditions of this study; however, prolongation of life is still minimal, and better treatment is required. About 20 percent of the patients receiving any of the four regimens developed serious toxic effects from therapy with the drugs.

Clinical report of the treatment of locally advanced lung cancer.

This paper discusses the results of the treatment of 345 patients entered in the Veterans Administration Lung Group Protocol 13L. The study was activated March 1972, and closed for the patient accesion March 1975. All patients had a histological diagnosis of primary lung cancer considered clinically non-resectable or inoperable. Patients were equally randomized into two groups, radiotherapy alone or radiotherapy with chemotherapy. The analysis of the data included: treatment regimen, radiation dose, initial performance status, performance status change, cell type, duration of survival, quality of survival and age. The strongest influence on median survival was the level of radiation dose. The small cell carcinoma patients treated with radiotherapy and chemotherapy showed significant improvement in the median survival (38.2 weeks) over the patients treated with radiotherapy alone (20.6 weeks). The patients treated with radiotherapy and chemotherapy also showed improvement in performance status more frequently than the patients treated with radiotherapy alone. Other parameters of the analysis will be presented.

Prognostic grading and significance of ventricular premature beats after recovery from myocardial infarction.

A 6-hour taped electrocardiogram recording was obtained prior to hospital discharge on 193 patients less than 66 years of age with a definite or probable myocardial infarction. All ventricular premature beats (VPBs) were identified on the 6-hour recording, and the various VPB characteristics were related to a complicated course (CC) defined as cardiac death or myocardial reinfarction within 4 months after hospital discharge. Only three univariate VPB characteristics (multiform pattern, bigeminal rhythm, and frequency greater than or equal to 20/hr) were significantly associated with a 4-month posthospital CC. By use of bivariate and multivariate combinations of these three VPB characteristics, a two-grade prognostic stratification system was derived: Grade I VPBs (CC = 8%) included patients with less than 20 VPB/hr but with neither multiform nor bigeminal beats: Grade II VPBs (CC = 31%, P less than 0.001) contained patients with greater than or equal to 20 VPBs/hr or with multiform or bigeminal beats or both. Patients with Grade II VPBs had more severe cardiac disease, but when patients were stratified by the clinical severity of their cardiac disease, Grade II VPBs identified patients with higher CC rates. The clinical significance of these findings together with a critical analysis of the prognostic stratification method are discussed.