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Biomedical subjects

N Thatcher

Publications and source records attributed to N Thatcher.

At least 181 records · Page 10Linked to original sources
PubMed1989

Lack of correlation between peripheral blood lymphokine-activated killer (LAK) cell function and clinical response in patients with advanced malignant melanoma receiving recombinant interleukin 2.

A phase-I/II study of recombinant interleukin 2 (rIL-2) was performed in 31 melanoma patients. The first dose of rIL-2 was given intrasplenically followed 4 hr later by an i.v. dose and 3 further i.v. doses on alternate days. Three courses of treatment were planned at 3-week intervals. The maximum tolerated single dose was 11 x 10(6) Cetus U/m2. Haematological and immunological data were available on 20 patients. Post-treatment response to rIL-2 therapy was evident from (i) a rapid depletion of peripheral blood lymphocytes (PBL) with a rebound at 4-7 days (2 times pre-treatment values); (ii) an increase in the number of IL-2 receptor-positive lymphocytes (4-15 times pre-treatment values); (iii) an increase in the number of "positive" patients with cytotoxic (anti-K562) peripheral blood mononuclear cells (PBMC) from 30% to 80%; (iv) amplified killing of K562 by positive patients in relation to pre-treatment values; and (v) the induction of PBMC cytotoxicity (in 45% of patients) against the NK-resistant, LAK-sensitive target, Mel I. Partial clinical responses to rIL-2 treatment were observed in 4 patients, but these were not reflected in the PBMC LAK activity or the other parameters examined.

Cytotoxicity, Immunologic↗
PubMed1989

Comparative pharmacokinetics and alkylating activity of fractionated intravenous and oral ifosfamide in patients with bronchogenic carcinoma.

20 patients with advanced non-small cell lung cancer were treated with ifosfamide and mesna 1.5 g/m2 daily for 5 days; 10 received the drug by mouth and 10 i.v. Both schedules resulted in a reduction in the elimination half-life with an increased total and nonrenal clearance of ifosfamide over the 5-day period. Oral administration resulted in an unacceptably high incidence of encephalopathy(5/10) which was not seen in the i.v. group. In two patients this encephalopathy manifested itself as coma which lasted for 24 to 48 h but was fully reversible and in the other three cases as somnolence occurring for more than 50% of the patients' waking hours. Nadir blood counts and response rates were similar in both arms. The encephalopathy suggests that there are metabolic differences between the i.v. and oral routes and that a metabolite rather than the parent drug is responsible for this syndrome. In addition it was shown that the total and nonrenal clearance of the drug was significantly less when the drug was administered orally. None of the pharmacokinetic parameters either singly or in combination predicted for ifosfamide toxicity. No correlation between the creatinine clearance and ifosfamide renal clearance was demonstrated suggesting tubular reabsorption of the drug. In conclusion, ifosfamide cannot be given orally at the conventionally employed i.v. doses.

Administration, Oral↗
PubMed1989

Prolongation of ifosfamide elimination half-life in obese patients due to altered drug distribution.

The pharmacokinetics of intravenous ifosfamide were determined in 16 patients with carcinoma of the bronchus. In all 25% (4) of these patients were obese (i.e. greater than 20% over their ideal body weight). The terminal elimination half-life (t1/2 beta) was found to be higher in the obese group than in the control group (6.36 h, range 5.77-7.45 h) vs 4.95 h, range 1.82-6.48 h) (P less than 0.05). This prolongation of the elimination half-life was due to an increased volume of distribution (Vd beta) in the obese group (42.81 1, range 35.49-51.90 l) vs 33.70 l range (17.76-50.62 l) (P less than 0.05). There was therefore no significant difference in total plasma clearance between the obese and normal groups. No correlation of ifosfamide plasma half-life was observed with total body weight (TBW) or ideal body weight (IBW). However, a significant positive correlation was observed between the percentage of IBW and plasma half-life. A strong positive correlation was observed between IBW and the plasma clearance of ifosfamide. The Vd beta correlated with both TBW and the percentage of IBW, but not with IBW itself. When Vd beta was normalised for IBW, there was a strong positive correlation with the percentage of IBW, suggesting that ifosfamide distribution into the TBW is higher than that into the IBW.

Adult↗
PubMed1989

Effect of in vivo administration of interferon gamma on expression of MHC products and tumour associated antigens in patients with metastatic melanoma.

IFN-gamma is an effective inducer of MHC class II antigen expression in cell lines of malignant melanoma. To investigate the possibility that IFN-gamma may increase MHC class I and II and melanoma tumour associated antigens in vivo, immunohistochemical analyses of biopsies from six patients with metastatic disease undergoing IFN-gamma treatment were performed. Before IFN-gamma treatment, the melanomas were class I positive and class II negative. After treatment, class I expression was neither enhanced nor class II expression induced in any tissue sample regardless of biopsy time or dose of IFN-gamma. TAA was similarly unchanged. However, in one of the six patients a primary cell line was established and IFN-gamma induced expression of MHC products. The possible reasons for lack of MHC induction are discussed, although qualitative changes in antigen expression cannot be excluded on the basis of qualitative immunocytochemical techniques alone.

Aged↗
PubMed1989

Expression of epidermal growth factor receptor (EGF-R) in non-small cell lung cancer. Use of archival tissue and correlation of EGF-R with histology, tumour size, node status and survival.

A total of 152 non-small cell lung cancers (NSCLC) were studied retrospectively to determine the relationship between epidermal growth factor receptor (EGF-R) status and the histological type, tumour size, nodal status and prognosis. EGF-R status was assessed on routinely embedded paraffin sections with an antibody to the cytoplasmic domain of the tumour (F4 antibody). EGF was demonstrated in all tumour types and every squamous and large cell carcinoma was positive for the antibody. Most tumours showed heterogeneity of staining. EGF expression was seen statistically more frequently in well differentiated tumours. Patients with 50% or more tumour cells showing positivity tended to have an improved survival but this result failed to reach statistical significance. There was no relationship between the size of the primary tumour or the lymph node status. Other cells, such as mucinous glands, bronchial epithelial cells and macrophages stained positively with the monoclonal antibody. EGF receptor status, with the antibodies presently available, adds little to help in either diagnosis or prognosis. Interpretation of data has to be guarded since the antibody was seen in some normal cells.

Carcinoma, Non-Small-Cell Lung↗
PubMed1989

Carboplatin, ifosfamide and etoposide with mid-course vincristine and thoracic radiotherapy for 'limited' stage small cell carcinoma of the bronchus.

Forty-two patients with small cell lung cancer were treated with a combination of carboplatin, ifosfamide and etoposide. Vincristine was given on day 14 of each course, the courses being repeated every 28 days for a maximum of six. Thoracic radiotherapy was given 4 weeks after the last course of chemotherapy but no prophylactic cranial radiotherapy was administered. Thirty patients had clinically limited state disease, the remaining patients having contralateral neck lymphadenopathy and/or pleural effusions. Elevated enzyme levels (alkaline phosphatase, LDH, ALT, GGT) were noted in 69% of patients. Twenty-four patients (57%) achieved a complete response (CR) when assessed one month after the end of treatment. A further 21% of patients had a partial response (PR). Median duration of CR was 14 months and of PR 8 months. Cerebral metastases were the sole site of relapse in 13% of the CR patients. Myelosuppression was severe with a median nadir of neutropenia of 0.2 x 10(9) cells 1-1. However, 74% of the patient group received all six courses of chemotherapy and only 16 courses (7%) were delayed because of toxicity. There were three deaths associated with treatment-related neutropenia. The median survival of the total group was 14 months, with an actuarial 2 year survival of 37% and a minimum follow-up of 18 months. [A recent analysis, March 1989, demonstrated a 33%, 2 year actual survival.]

Adult↗
PubMed1989

A simple outpatient treatment with oral ifosfamide and oral etoposide for patients with small cell lung cancer (SCLC).

For the first time in a clinical study oral Ifosfamide was used: 65 elderly or unfit patients with small cell lung cancer (SCLC) were treated as outpatients with fractionated oral Ifosfamide and Etoposide. Forty patients (62%) had extensive stage (ED) disease. The median age of the patients was 66 years. In the 60 patients evaluable for response the objective response rate was 90% with a complete response (CR) rate of 32% and a partial response (PR) rate of 58%. The overall median survival of all 65 patients was 11 months (13 months for LD, 9.5 months for ED). In those patients with LD achieving a CR or a PR radiotherapy was given to the mediastinum. No prophylactic cranial irradiation was given. There was a rapid improvement in the responding patients' performance status and symptoms generally with the first treatment cycle. Overall haematological toxicity was mild, with intravenous antibiotics only being required in 4% of the courses and with only one treatment-related death from septicaemia. A higher than expected rate of CNS toxicity was seen (30%). This was generally mild and always fully reversible and consisted mainly of forgetfulness, occasionally hallucinations, nightmares and somnolence. In only one case did encephalopathy necessitate early termination of treatment. This raises the question of whether Ifosfamide metabolism differs quantitatively or qualitatively when given by the oral route as opposed to the usual intravenous route. We conclude that this simple outpatient based treatment gives a high response rate with rapid improvement in symptoms.

Administration, Oral↗
PubMed1989

Recombinant human granulocyte macrophage colony stimulating factor (rhGM-CSF) given as daily short infusions--a phase I dose-toxicity study.

Twenty patients with progressive metastatic solid tumours were entered into a study to evaluate the biological effects and toxicity of recombinant human granulocyte-macrophage colony-stimulating factor (GM-CSF). GM-CSF was given as half-hour intravenous infusions during two 10-day phases of daily treatments (separated by 10 days without GM-CSF) and over a final phase of 20 days of alternate day infusions. Doses were escalated in steps from 0.3 to 60 micrograms kg-1 day-1 between successive patient groups. Significant increases (P less than 0.005) of total leucocyte, neutrophil and eosinophil polymorph counts were seen over the periods of daily infusions (up to four-fold rises of total white count) at dose levels of 10 micrograms kg-1 and above. Counts produced at 30 micrograms kg-1 were significantly higher than at 10 micrograms kg-1 (P less than 0.025). Toxic side effects of GM-CSF included mild transient pyrexias, bone pain and pruritus. The maximum tolerated dose was 60 micrograms kg-1, which produced severe toxicity in 80% of patients. The toxicity at this dose included pericarditis and dyspnoea ascribed to a 'capillary-leak' syndrome. One patient receiving 60 micrograms kg-1 died as a result of a pulmonary embolus. Seven patients with previously rapidly progressive metastatic tumours experienced stabilisation of disease while receiving GM-CSF and one patient with a previously heavily pretreated metastatic soft tissue sarcoma underwent a greater than 50% reduction of tumour volume. Patients undergoing chemotherapy may benefit both from a reduction of the myelosuppressive effects of cytotoxic agents and from an antitumour effect if GM-CSF is incorporated into future regimens.

Colony-Stimulating Factors↗
PubMed1989

Recombinant interleukin-2 (rIL-2) given intrasplenically and intravenously for advanced malignant melanoma. A phase I and II study.

Recombinant interleukin-2 (rIL-2) was used to treat 31 patients with progressing metastatic malignant melanoma. Only three patients had disease confined to non-visceral sites; the median number of organ sites involved was four. The first dose of rIL-2 was given intrasplenically (to stimulate cytotoxic cells in high concentration) via a femoral artery catheter, and four further i.v. doses were given over 6 days. A total of three courses at 21-day intervals was planned. Doses were escalated in 15 patients from 1 x 10(6) to 16.4 x 10(4) Cetus units m-2. The maximum tolerated dose (11.0 x 10(6) U m-2) was used in the other 16 patients. Of the 71 courses, severe but transient toxicity requiring interruption of rIL-2 or additional care occurred on three courses (dyspnoea) and 15 from hypotension, but the patients' performance status improved. Four patients had partial tumour responses although in only one patient did response occur in all sites of disease. However, responses occurred in visceral sites and six patients are alive at 9-16 months. IL-2 is of use in advanced melanoma and does not need complicated ICU facilities.

Adult↗
PubMed1989

Alkylating agents.

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Alkylating Agents↗
PubMed1988

Double alkylating agent therapy with ifosfamide and cyclophosphamide for advanced non-small cell lung cancer. From the Manchester Lung Tumour Group.

Forty-five patients with advanced non-small cell lung cancer (NSCLC), with progressive inoperable tumors were treated. Twenty-three patients were of "limited" stage. Six patients had received previous thoracic radiotherapy. Patients with central nervous system (CNS) metastases, Karnofsky scores of less than 30 or more than 70, and patients over 70 years of age were excluded from the study. Cyclophosphamide (2.5 g/m2) was infused intravenously over 3 hours with the same Mesna dose. At the midpoint of the infusion, 3.5 g/m2 infosfamide was delivered as a bolus. Additional Mesna was administered over the next 8 hours. A maximum of four courses were given at three weekly intervals. One-hundred-thirty-eight courses were administered and 53% of patients completed all four treatments. The response rate was 38%, with three (7%) complete responses. Seven additional patients (15%) with stable disease symptomatically improved by two steps or more on the Karnofsky scale at the end of treatment. Median survival for all 45 patients was 7 months, range less than 1 to 25 months. Sixteen courses were complicated by Grade 3 thrombocytopaenia and/or leukopenia (Grade 4 on six occasions, Grade 3 on seven occasions) on the blood count taken immediately before chemotherapy. Intravenous antibiotics were required on 14% of the total number of courses; and three patients died of probable treatment related causes. Two episodes of severe ifosfamide encephalopathy occurred but recovery was complete, and four episodes of frank hematuria also occurred. The Karnofsky score was more than 70 in 33% of patients one month after the end of chemotherapy compared with 0% before treatment. Unlike many chemotherapeutic regimens for NSCLC, double alkylating agent treatment with ifosfamide and cyclophosphamide improved the performance status without major toxicity in a selected patient population. The overall survival, however, remains short and further alkylating agent combinations need to be considered in the future.

Aged↗
PubMed1988

24-hour cyclophosphamide infusion therapy for malignant mesothelioma of the pleura.

Thirteen patients with malignant mesothelioma of the pleura have been treated with 24-hour cyclophosphamide infusion (2.5 g/m2) therapy. There were no complete responders. Three patients (23%) had a partial response, and a further three patients who did not fulfil the criteria for objective response, had subjective benefit from therapy with increase in performance status. The overall median survival from the onset of therapy was 6 months (range 2-19 months). High dose cyclophosphamide offers no advantage over standard dose therapy.

Adult↗
PubMed1988

A phase I and pharmacokinetic study of amphethinile.

Amphethinile is a new spindle poison with a novel structure that has shown activity in the L1210, ADJ/PC6 and Walker carcinoma rodent tumours. In addition the agent appeared to have an improved therapeutic ratio compared to existing spindle poisons and is well absorbed when administered orally. The starting dose for the phase I study was 40 mg m-2 (1/10th mouse LD10) and further patients were studied at 200, 400, 800 and 1200 mg m-2, dose escalation being based on pharmacological monitoring. Significant toxic effects were seen only at 800 and 1200 mg m-2. At these doses patients experienced nausea and vomiting, light headedness during the infusion and varying degrees of lethargy following therapy. Two of six patients at 800 mg m-2 developed severe pain in the tumour bearing area 1-2 h after treatment and one experienced colicky abdominal pain. At 1200 mg m-2 two patients died within 48 h of treatment from what appeared to be vascular causes. Following these episodes the trial was discontinued. Neutropenia and alopecia occurred in two patients, one at 800 and one at 1200 mg m-2. These patients achieved the highest drug exposure in terms of area under the concentration x time curve. It was not possible to achieve an AUC consistently high enough to produce cytotoxic effects due to the occurrence of dose limiting toxicities thus amphethinile cannot at present be recommended for phase II testing by the i.v. route. The dose escalation scheme based on pharmacological monitoring resulted in a considerable saving in the duration of the trial. Further evaluation of this methodology is recommended.

Adult↗
PubMed1988

In vitro and in vivo analysis of the effects of recombinant human granulocyte colony-stimulating factor in patients.

Twelve patients with small cell lung cancer were treated with recombinant human granulocyte colony-stimulating factor, rhG-CSF, given by continuous infusion at doses ranging from 1 to 40 micrograms kg-1 day-1. Patients received the rhG-CSF before the start of intensive chemotherapy and after alternate cycles of chemotherapy. Several in vitro assays were performed using peripheral blood neutrophils and marrow progenitor cells collected from patients prior to and after infusion of the growth factor. Peripheral blood neutrophils were tested for mobility and phagocytic activity. In addition, in vitro clonogenic assays of marrow haemopoietic progenitor cells and analysis of bone marrow trephines and aspirates were carried out. We found that rhG-CSF in vivo has at least two main effects: (a) an early fall in peripheral neutrophils, within the first hour, followed by a rapid influx of mature neutrophils into the circulatory pool; (b) stimulation of proliferation and differentiation of neutrophil precursors in the bone marrow. Neutrophils released into the circulation were normal in tests of their mobility and phagocytic activity.

Antineoplastic Agents↗
PubMed1988

The value of tumour markers in lung cancer.

The pre-treatment serum levels of neuron-specific enolase (NSE), phosphohexose isomerase (PHI) and circulating immune complexes (CC) as tumour markers were compared to measurements of standard haematology and biochemical indices in 73 patients with lung cancer, as an aid to differentiation of tumour type, estimating disease extent, predicting response to therapy and prognosis. Elevated NSE greater than or equal to 12.5 ng ml-1, PHI greater than or equal to 55 mgl-1 levels were observed in 55% of cases for NSE, 90% for PHI and 49% for CC. NSE was significantly elevated in 61% (25/41) of patients with SCLC (P less than 0.005) compared to 41% (13/32) with NSCLC. CC levels were significantly raised in 72% (23/32) of patients with NSCLC (P less than 0.05) compared to 32% with SCLC. The levels of NSE and PHI were not related to tumour stage but CC was significantly raised in limited compared to extensive disease in SCLC (P less than 0.05). Serum albumin was significantly lower in NSCLC compared to SCLC, and median values of alkaline phosphatase, gamma-glutamyltranspeptidase and aminoaspartate transferase were significantly higher in patients with extensive disease. The pre-treatment serum values of NSE, PHI, and CC did not predict the response to therapy or prognosis in the 73 patients with lung cancer. The most important prognostic factor was the number of abnormal routine laboratory parameters (greater than 4) in this group of patients.

Adult↗
PubMed1988

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 (rh G-CSF) at the following dose levels: 1 microgram, 5 micrograms, 10 micrograms, 20 micrograms and 40 micrograms/kg/day 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 in one patient at 10 micrograms/kg/day. The neutrophils were shown to be functionally normal in tests of their mobility and bactericidal activity. During the Phase II part of the patients were treated using a combination of i.v. Adriamycin, Ifosfamide and Etoposide. The chemotherapy was repeated every 3 weeks. rh G-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. Ten severe infective episodes were observed during the 20 cycles of chemotherapy which did not include rh G-CSF, while only one infective episode occurred in 20 courses when treated with rh G-CSF. These results demonstrate the utility of rh G-CSF in restoring functional neutrophils to patients undergoing intensive chemotherapy.

Antineoplastic Combined Chemotherapy Protocols↗