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Biomedical subjects

N Thatcher

Publications and source records attributed to N Thatcher.

At least 199 records · Page 11Linked to original sources
PubMed1987

Ifosfamide, etoposide, and thoracic irradiation therapy in 163 patients with unresectable small cell lung cancer.

One hundred sixty-three patients with small cell lung cancer were treated with six courses, at 3-week intervals, of ifosfamide (5 g/m2) with mesna and etoposide. Thoracic radiotherapy was delivered to the limited stage (LS) patients. The complete response rate (CR, determined clinically and radiologically) was 76% for the 78 LS patients with a further 14% partial response (PR). The majority of the CRs were confirmed on a follow-up bronchoscopy. The CR rate was 27% for extensive stage (ES) patients with another 38% undergoing a partial response. The median survival for LS patients was 11 months, (16 months for CR confirmed by rebronchoscopy) and 8 months for ES patients. The 2-year actuarial survival for LS patients is 27%, follow-up ranges from 12 months to 30 months with a median of 22 months. Toxicity was not severe for the patient population, of whom only 20% had a good performance status before chemotherapy. Parental antibiotics were required on 4% of all 844 chemotherapy courses and 12% of courses were delayed due to side effects. The majority of responses occurred within the first two courses of chemotherapy and there was a corresponding improvement in the patients' symptoms and performance status. The regimen produced rapid tumor response with corresponding improvement in symptoms without marked toxicity and allowed further treatment development.

Adult↗
PubMed1987

Pretreatment prognostic factors and scoring system in 407 small-cell lung cancer patients.

In 407 patients with small-cell lung cancer (SCLC), 61 pretreatment variables were evaluated in a Cox multiple regression analysis to assess their prognostic value. All patients received short-term intensive regimens (cyclophosphamide, etoposide and methotrexate or ifosfamide and etoposide, both followed by thoracic irradiation if complete response was noted). Lactate dehydrogenase (p = 0.001), tumour stage (p = 0.0001), serum sodium (p = 0.0009), pretreatment Karnofsky performance score (p = 0.0121), alkaline phosphatase (p = 0.0186) and serum bicarbonate (p = 0.0321) were the important prognostic factors. Once these variables were taken into account no other variable provided additional prognostic information. A simple scoring system ("Manchester Score") using these variables was established and shows little loss of information compared to the Cox analysis. The score distinguishes 3 prognostic groups, the best of which contains all long-term survivors, whereas the bad prognostic group contains no patient surviving longer than one year. The scoring system may help to design new treatment strategies and may also facilitate the comparison of different studies.

Carcinoma, Small Cell↗
PubMed1987

A phase I study of rDNA alpha-2b interferon as a 6-week continuous intravenous infusion.

Sixteen patients with advanced malignancy were treated with rDNA alpha-2b interferon using a continuous 6-week i.v. schedule. Patients received 1 microgram, 3 mu [corrected], 5 mu and 7 mu/m2/day via a portable infusion pump system, all therapy being on an outpatient basis. The dose-limiting toxicity occurring at 7 mu/m2/day [corrected] was lethargy and somnolence. Five million units (mu) was the maximum tolerated dose but significant nausea, anorexia and lethargy affected 4/5 patients at this level. A dose of 3 mu/m2/day was well tolerated, producing little disturbance of normal activity in the majority of patients. Suppression of WBC and platelets was seen at all doses but was not dose-limiting. There was increasing severity of derangement of hepatic transaminases with increasing dose, and the occurrence of liver toxicity appeared to correlate with nausea, anorexia and lethargy. Assay of serum interferon during the infusion showed that this system maintained a constant level of interferon in the blood. However, the increase did not show a linear pattern with increasing dose, suggesting saturation of metabolic inactivation at 7 mu/m2/day. We recommend that a dose of 3 mu/m2/day be used in future studies of prolonged infusions of alpha-2 interferon.

Adult↗
PubMed1987

Immunoscintigraphy with 99mTc labelled F(ab')2 fragments of an anti melanoma monoclonal antibody (225.28S) in patients with metastatic malignant melanoma.

Immunoscintigraphy was performed in 25 patients with malignant melanoma using a 99mTc labelled monoclonal antibody (225.28S). In four cases, imaging was repeated following treatment with recombinant gamma interferon. In 11 cases, tissue samples of metastatic lesions were investigated for the expression of melanoma associated antigens by immunohistochemical techniques. Overall, 59% of known lesions were detected by imaging. The highest rates of detection were in bone, liver and lymph nodes and the lowest in lung, stomach and bowel. Six lesions were detected which had not shown up on routine clinical and radiological examination. There was no evidence of enhanced or induced HMW-MAA expression following interferon treatment. This technique has been found to be useful in staging patients and has been free from side effects.

Adult↗
PubMed1987

Phase I/II study of recombinant human granulocyte colony-stimulating factor in patients receiving intensive chemotherapy for small cell lung cancer.

Twelve patients with advanced small cell carcinoma of the bronchus were treated by continuous infusion of recombinant human granulocyte colony-stimulating factor (rhG-CSF) at the following dose levels: 1 microgram, 5 micrograms, 10 micrograms, 20 micrograms and 40 micrograms kg-1 day-1 for 5 days. No toxicities resulted from the treatment and in all 12 patients the number of peripheral neutrophils increased rapidly to a maximum of 100 x 10(9) l-1 at 10 micrograms kg-1 day-1. The neutrophils were shown to be functionally normal in tests of their mobility and bactericidal activity. During the phase II part of the study the patients were treated by a combination of intravenous adriamycin 50 mg m-2, ifosfamide 5 g m-2 by i.v. infusion with mesna 8 g m-2 on day 1, and etoposide 120 mg m-2 on days 1, 2 and 3 also intravenously. The chemotherapy regime was repeated every 3 weeks. RhG-CSF was given to each patient for 14 days on alternate cycles of chemotherapy and reduced the period of absolute neutropenia considerably (median of 80%), with a return to normal, or above normal, neutrophil counts within 2 weeks after day 1 of chemotherapy. Six severe infective episodes were observed during the cycles of chemotherapy which did not include rhG-CSF, while no infective episodes occurred when patients were treated with rhG-CSF. These results demonstrate the utility of rhG-CSF in restoring functional neutrophils to patients undergoing intensive chemotherapy.

Aged↗
PubMed1987

Multicentric reticulohistiocytosis.

A case of multicentric reticulohistiocytosis associated with a pleural mesothelioma is reported. The cutaneous and joint manifestations resolved after treatment with cyclophosphamide, and the remission persisted until the patient's death 3 years later. As corticosteroids have such an unpredictable effect on this condition, cyclophosphamide may be regarded as the treatment of choice until more cases can be assessed.

Aged↗
PubMed1987

Phase I clinical trial of methylene dimethane sulfonate.

Methylene dimethane sulfonate is the first member of the homologous series of straight-chain diol sulfonates. It was selected for phase I testing because of high activity in the rat Yoshida sarcoma system and a possible novel site of alkylation due to its small molecular size. Methylene dimethane sulfonate was administered as a rapid iv bolus infusion to 39 patients at doses ranging from 14 to 225 mg/m2. Nausea and vomiting were not severe but total alopecia occurred in the majority of patients at doses greater than 100 mg/m2. The dose-limiting toxic effect was thrombocytopenia, which was cumulative with lower, more prolonged nadirs following successive courses. The median time to platelet count nadir was 21 days, with recovery by 35 days. A minor response was seen in one patient with an adenocarcinoma of the lung. The recommended dose for phase II studies is 125 mg/m2 for patients who have received prior chemotherapy and 150 mg/m2 for those who have not, in an every 35-day schedule.

Adult↗
PubMed1986

Treatment of metastatic melanoma by 24-hour DTIC infusions and hemibody irradiation.

Forty-three patients with widely metastatic melanoma were studied. Visceral metastases were present in 79% of the patient group, including five patients with brain metastases. No patients were excluded because of "early death," etc., from analysis. All 43 patients received 24-hour DTIC infusions. Dosages for individual patients ranged from 350 mg/M2 to 2.5 g/M2, a maximum of 6 courses being given. A total of 155 courses was administered. Hemibody irradiation (HBI) was delivered after 1 or 3 courses of DTIC to the area of maximum disease in 23 patients. Fourteen of the 43 patients responded to DTIC chemotherapy (with one complete response), a response rate of 33%. Seven of the chemotherapy responders also responded in other sites to subsequent HBI, a response rate of 30% (7/23). No patient responded to HBI and not to DTIC. Median survival was 4 months (range, 1-15), and nine patients are still alive at 3 to 15 months. Toxicity was generally mild, although there was one possible treatment-related death. Further exploration of DTIC infusion chemotherapy and HBI would be of interest.

Adult↗
PubMed1986

Randomized study of Corynebacterium parvum adjuvant therapy following surgery for (stage II) malignant melanoma.

One hundred and fifteen patients with histologically proven primary cutaneous melanoma were entered into a randomized prospective study following surgical removal of clinically obvious regional metastases. The study started in 1977 and was completed in June 1982. Fifty-eight patients (10 with regional skin metastases and 48 with regional node metastases) were in the control group and 57 (15 regional skin, and 42 regional node metastases) received adjuvant C. parvum. Other clinical features were well balanced for each group. C. parvum, 2 mg/m2 IV was repeated eight times at three weekly intervals. The schedule was based on previous work which indicated significant increase in killer cell activity. There was no serious toxicity and 22 patients exhibited tachyphylaxis. Seventeen patients in the control group (11 tumour free) are alive at 24-80 months, and 20 patients in the C. parvum group (12 tumour free) are alive 24-76 months from randomization. No statistically significant difference (P greater than 0.05) was observed between the two patient groups for overall survival (median 26 months) or relapse free survival (median 8 months) from the date of randomization. Nor was the overall survival from the date of primary surgery (median 52 months, range 4-237) or the relapse free survival, median 28 months, range 2-225, significantly different between the two groups of patients. The relapse pattern in the two groups, and survival after relapse were no different though the response rate to actinomycin D and DTIC chemotherapy was significantly higher in the control (48 per cent) than in the C. parvum (23 per cent) group. Toxicity to chemotherapy was not significantly affected by previous C. parvum treatment. Although there were trends for better survival, in the C. parvum patient group, statistically significant activity has not been noted in this study.

Adjuvants, Immunologic↗
PubMed1986

A simple quantitative HPLC assay for ifosfamide in biological fluids.

A high performance liquid chromatography method is described for measuring Ifosfamide (I) in human serum. This involves solvent extraction, reverse phase HPLC and UV detection at 190 nm. Standard curves of peak height x detector sensitivity versus I concentration in serum were linear with a lower limit of detection of 100 ng/ml. Authentic 14C-labelled I cochromatographed with standard I and with I found in serum from treated patients. The concentration-time curves of I determined by both HPLC and gas chromatography were indistinguishable. We conclude that this method is suitable for determining I pharmacokinetics in biological specimens.

Carbon Radioisotopes↗
PubMed1986

Bioavailability of ifosfamide in patients with bronchial carcinoma.

The pharmacokinetics of ifosfamide (I) were determined in ten patients with bronchogenic carcinoma. In seven patients, doses of 1 and 2 g (I) were given both as a bolus orally and later intravenously and were well tolerated. A further three patients received 5 g (I) as a single oral dose but in two this produced reversible CNS toxicity and severe vomiting. The area under the curve (AUC, microgram . h . l-1) for the 1-g dose was the same following oral and i.v. treatment and this was also true for the 2-g doses. There was a proportionate increase in the AUC for the 5-g oral dose, indicating 100% bioavailability at all three dose levels. We conclude that doses up to 2 g by mouth represent a well-tolerated alternative route of administration.

Administration, Oral↗
PubMed1986

Ifosfamide by bolus as treatment for advanced non-small cell lung cancer.

Ifosfamide at 5 g/m2 was given as a bolus to 48 patients with advanced progressing non-small cell lung cancer. Mesna (5 g/m2) was also given with the ifosfamide, both over 30 min. Further mesna was then given p.o. (3 g/m2) at 4, 8, and 12 h. If oral mesna was not acceptable then one or, if necessary, two 4-h to 6-h infusions (3 g/m2) were administered. A maximum of six courses at 3-weekly intervals was prescribed. A total of 174 courses was administered, and oral mesna was given during 64 courses: discharge was considered possible within 8-10 h after 55% of courses. Haematological toxicity was mild and no renal dysfunction was noted. Two patients became drowsy shortly after ifosfamide, but recovered 24-36 h later. The objective response rate was 29%, with one complete responder. A further 31% of patients (symptomatic responders) with stable disease symptomatically improved after the chemotherapy, by 20 or more points on the Karnofsky scale. The median survival was 5 months for the whole group, and 8 months each for the objective and symptomatic responder groups. Most patients' Karnofsky and respiratory scores improved with the chemotherapy. Ifosfamide with mesna can be given by short infusions, and the mesna given p.o. prevents any urothelial toxicity. Further exploration of short-infusion ifosfamide and mesna therapy would reduce hospitalization and allow for day-case regimens.

Adult↗
PubMed1986

Corynebacterium parvum followed by chemotherapy (actinomycin D and DTIC) compared with chemotherapy alone for metastatic malignant melanoma.

Seventy-nine patients with Stage III widely metastatic melanoma were prospectively randomised to a 'no treatment' control group who received on tumour progression DTIC (250 mg/m2 i.v. daily X 5) and Actinomycin D 1.5 mg/m2 on Day 1. A total of six courses at 3-week intervals was given. Chemotherapy was only given on progression of disease. The other group received initially Corynebacterium parvum (2 mg/m2) every 3 weeks for a maximum of eight courses and then the same chemotherapy on evidence of progressive disease. Minimum follow up time is 3 yr. The chemotherapy response rate (control 37%, C. parvum 24%) was not statistically different nor was the effect of chemotherapy on the site of individual metastases. Radiotherapy responses for irradiated soft tissue disease again were not significantly different, between the two patient groups. No significant differences in survival (control group median, 4 months, range 1-46; C. parvum median 3 months range 1-35) were observed and only one patient is alive at 35 months. The pattern of relapse was also similar in both groups. Reduction in haematological toxicity consequent on chemotherapy was not observed in the C. parvum-treated patients. No additional benefit was observed when C. parvum was followed by DTIC and Actinomycin D chemotherapy compared with the results from the chemotherapy given alone, although C. parvum on this schedule had minimal toxicity.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed1986

A phase II study of cyclophosphamide as a 24-hr infusion in advanced non-small cell lung cancer.

Twenty patients with progressive non-small cell lung cancer who had received no prior chemotherapy were treated with 24-hr infusions of cyclophosphamide at a dose of 2.5 g/m2. The median number of courses administered was three (range one to six). There was one PR and one CR, an overall response rate of 10% (95% confidence limits 2-32%). A further six patients experienced excellent relief of distressing symptoms, unresponsive to other measures, as a result of the chemotherapy. The median survival for the 20 patients was 18.5 weeks (range 4-75 weeks). The median leukocyte nadir count was 1.1 X 10(9)/1 and median platelet nadir count 226 X 10(9)/1. There were no episodes of cystitis and gastrointestinal toxicity was moderate. This study has not shown any advantage for the infusion schedule over conventional bolus regimens, but further dose escalation or more prolonged infusion times may improve results.

Adult↗
PubMed1986

A retrospective study of thirty-two patients with small-cell bronchogenic carcinoma and inappropriate secretion of antidiuretic hormone.

Thirty-two patients with inappropriate secretion of antidiuretic hormone (ADH) complicating small-cell carcinoma of the bronchus were identified from a total of 226 patients with small-cell carcinoma of the bronchus treated at the Christie Hospital, Manchester, between 1978 and 1984. Basic data were collected from patients' files concerning the extent of the tumour, symptoms of inappopriate secretion of antidiuretic hormone, biochemical findings, treatment, the course of the inappropriate secretion of ADH and that of the underlying tumour. The data were then analysed and compared with results of previous studies. The response of the inappropriate secretion of ADH to treatment was found to be a significant prognostic factor. Further data were collected to determine the reason for this but it was difficult to drawn any firm conclusions.

Carcinoma, Bronchogenic↗
PubMed1986

Expression of epidermal growth factor receptor (EGF-R) in human lung tumours.

Epidermal growth factor receptor (EGF-R) expression was assessed in 63 lung tumour samples with a monoclonal antibody (EGF-R1) by indirect immunoperoxidase staining on cryostat sections. All 15 small cell lung cancer samples were negative whereas over 80% of the 48 non small lung cancer stained positively. In 30 bronchial biopsies two monoclonal antibodies against the cytoplasmic part of the EGF-R were evaluated. These antibodies showed weaker staining than EGF-R1. No additional or enhanced staining as compared with EGF-R1 was observed, suggesting a lack of enhanced expression of a truncated EGF-R analogous to the v-erb-B oncogene product. Monoclonal antibodies against the EGF-R may be helpful diagnostically in differentiating small cell from non small cell lung cancer and may also be important in elucidating biological differences in primary lung cancer.

Adenocarcinoma↗
PubMed1986

Pulmonary carcinoid tumours: a clinico-pathological study of 35 cases.

A clinico-pathological study of 35 bronchial carcinoid tumours was undertaken. Age, T stage, N stage, lymph node involvement, number of lymph nodes involved and number of cigarettes smoked per day were the clinical variables affecting survival. The histological variables related to survival were; mitotic count, necrosis, nuclear pleomorphism, vascular and lymphatic permeation and an undifferentiated growth pattern. All these features could be detected with routine histological stains, whereas immunocytochemical methods for demonstrating neuron specific enolase were of no help in assessing the prognosis. However there was a tendency for a well differentiated neuroendocrine carcinoma to stain strongly in some areas with carcinoembryonic antigen.

Adenoma↗