Search PubMed⌕ Search

Biomedical subjects

J A Ledermann

Publications and source records attributed to J A Ledermann.

At least 37 records · Page 2Linked to original sources
PubMed1995

Phase I clinical and pharmacokinetic study of leucovorin and infusional hepatic arterial fluorouracil.

PURPOSE: A phase I and pharmacokinetic trial was performed between October 1993 and June 1994 to determine the maximum-tolerated dose of hepatic arterial infusion (HAI) of fluorouracil (5-FU) and intravenous (IV) leucovorin (folinic acid; FA) in patients with hepatic metastases from colorectal cancer. PATIENTS AND METHODS: Forty-three patients received 310 courses of HAI chemotherapy administered over 48 hours every 2 weeks. The regimen consisted of FA 200 mg/m2 by IV infusion over 2 hours, followed by a loading dose of 5-FU 400 mg/m2 by HAI over 15 minutes, followed by a 22-hour infusion of 5-FU at doses ranging from 0.8 to 1.84 g/m2, with identical chemotherapy on day 2. Pharmacokinetic studies were performed to determine peak and steady-state plasma concentrations (Css) of 5-FU. RESULTS: Severe diarrhea and cardiac and neurologic toxicity were dose-limiting at 1.84 g/m2. The recommended dose for the 22-hour component of the schedule was 1.6 g/m2 and was associated with tolerable toxicity. A Css of 2.2 +/- 0.8 mumol/L for 5-FU was achieved on the recommended schedule, which compares favorably with conventional IV 5-FU regimens. Among 30 patients assessable for response, there were four complete responses and seven partial responses, and 12 patients with stable disease and seven with progressive disease, reported after 3 months (ie, six cycles) of therapy. CONCLUSION: A regimen that combines 5-FU and FA has been identified for regional chemotherapy in patients with hepatic metastases from colorectal cancer. The systemic levels of 5-FU achieved are similar to the conventional IV de Gramont regimen using an identical schedule of 5-FU and FA, which implies that this chemotherapy has the best of both worlds, ie, a regional advantage in delivering high drug concentrations to the target organ with adequate systemic cover for extrahepatic micrometastases.

Adult↗
PubMed1994

Detection of the neural cell adhesion molecule (NCAM) in serum of patients with small-cell lung cancer (SCLC) with "limited" or "extensive" disease, and bone-marrow infiltration.

The neural cell adhesion molecule (NCAM) is a tumour-related antigen found on the surface of small-cell lung cancer (SCLC). NCAM exists in several molecular forms, including a soluble isoform. We have measured serum levels of NCAM using an enzyme immunoassay with 2 antibodies, NCC-LU-246 and NCC-LU-243, that react with different epitopes on the NCAM molecule. NCAM activity from 83 patients with active SCLC, either pre-treatment, progressing or in relapse was significantly higher than in 70 patients on follow-up. Overall, 40% of patients with active SCLC and 7% patients on follow-up had serum levels of NCAM > 2SD above controls; 61% of patients with relapsed SCLC had elevated levels of NCAM. Pre-treatment NCAM levels were significantly higher in 35 patients with "extensive" disease than in 19 patients with "limited" disease. Serum NCAM activity was also significantly higher in patients with tumour infiltration of the bone marrow. This difference could not be explained solely by the presence of "extensive" disease. Serum NSE levels in these patients were correlated with NCAM activity. The presence of raised serum NCAM in active disease and in patients in relapse suggests that this antigen could be used as a target for antibody-directed therapy of micrometastases.

Antibodies↗
PubMed1994

Detection of small-cell-lung-cancer cells in bone-marrow aspirates by monoclonal antibodies NCC-LU-243, NCC-LU-246 and MLuC1.

We have used immunocytochemistry to identify tumor cells in bone-marrow aspirates of patients with small-cell lung cancer and we have compared the results with conventional histomorphology. The monoclonal antibodies (MAbs) used were NCC-LU-243 and NCC-LU-246 (cluster 1) and MLuC1 (cluster 6); 108 slides (52 patients) incubated with NCC-LU-246, 106 (51 patients) with NCC-LU-243 and 69 with MLuC1 (36 patients) were evaluated. Bone-marrow biopsies (83) were also obtained from 50 of these patients; 48/108 bone marrow aspirates were positive for cluster-1 antigen and 22/69 were positive for MLuC1. Immunocytochemistry with anti-NCAM MAbs detected bone-marrow localization in 38/83 bone-marrow aspirates compared with 9/83 bone-marrow biopsies, while MLuC1 was positive in 18/60 and bone-marrow biopsies in 6/60. Moreover, bone-marrow aspirates were positive for cluster-1 antigen in 7/17 patients with limited disease at diagnosis. Patients with positive bone-marrow biopsies had significantly shorter survival. No differences were found between patients with positive and those with negative marrow aspirates.

Antibodies, Monoclonal↗
PubMed1994

Radioimmunotherapy of metastatic colorectal tumours with iodine-131-labelled antibody to carcinoembryonic antigen: phase I/II study with comparative biodistribution of intact and F(ab')2 antibodies.

Studies in animal tumour models of colorectal cancer suggest that F(ab')2 antibody fragments to carcinoembryonic antigen (CEA) labelled with iodine-131 give superior therapy compared with intact anti-CEA antibody. The purpose of this study was to investigate this hypothesis in patients. Ten patients received intact A5B7 IgG1 mouse monoclonal antibody (MAb) to CEA and nine patients received the F(ab')2 fragment of the same antibody. The biodistribution for each molecule was compared using quantitative single-photon emission computerised tomographic (SPECT) gamma-camera imaging. Tumour responses were seen in both groups and myelosuppression was the limiting toxicity. F(ab')2 localised more rapidly than intact antibody in tumour, giving a mean percentage injected activity per kg at 4.25 h after injection of 8.2% for F(ab')2 compared with 4.4% for intact antibody (P < 0.05). No significant difference in antibody clearance from, or cumulative dose per unit administered activity (cGy MBq-1) to, tumour was seen. Distribution in blood was similar for both the intact and fragment antibody. These findings are consistent with more rapid penetration of the smaller F(ab')2 into tumour masses. More efficient early uptake will give higher maximum dose rates to the tumour which is valuable for radioimmunotherapy (RIT) when low dose rates may limit effectiveness of treatment. F(ab')2 fragments may provide a substantially enhanced method of delivering RIT.

Adult↗
PubMed1994

The selection of antibodies for targeted therapy of small-cell lung cancer (SCLC) using a human tumour spheroid model to compare the uptake of cluster 1 and cluster w4 antibodies.

Spheroids of a small-cell lung cancer (SCLC) cell line POC were used to evaluate the uptake and penetration of two antibodies recognising different SCLC antigens. Spheroids approximately 300-400 microns in diameter were incubated with 1 microgram ml-1 125I-labelled NY.3D11, an antibody which reacts with the cluster 1 group antigen (neural cell adhesion molecule; NCAM) and [125I]SWA11, which binds to the cluster w4 antigen. The rate of uptake of both antibodies was similar; an initially rapid phase was seen during the first 8 h and maximum uptake occurred by 24 h. The mean uptake per spheroid at 24 h was 0.97 ng for [125I]NY.3D11 and 0.45 ng for [125I]SWA11. An objective measurement of antibody penetration into spheroids was developed using a computerised image analysis of immunostained sections of spheroids. The concentration of antibody and incubation times were varied. Both antibodies penetrated the spheroids to a depth of 50 microns after 30 min. This increased to about 100 microns after 4 h incubation with 1 or 100 micrograms ml-1 SWA11. The results with 1 microgram ml-1 NY.3D11 were similar, but in the presence of 100 micrograms ml-1 NY.3D11 penetration into the spheroid was deep and diffuse. These results demonstrate a major concentration-dependent difference in the uptake and penetration of cluster 1 and cluster w4 antibodies in this spheroid model and they have implications for the selection of antibodies for targeted therapy of SCLC.

Antibodies, Monoclonal↗
PubMed1994

The long-term outcome of patients who relapse after chemotherapy for non-seminomatous germ cell tumours.

OBJECTIVE: To examine the long-term survival of a group of patients with non-seminomatous germ cell tumours, who relapse after chemotherapy and are retreated with a cisplatin and etoposide-based regimen. PATIENTS AND METHODS: At the Charing Cross Hospital between 1979 and 1988 38 patients in relapse were seen. The median interval after primary therapy was 8 months. They were treated with an intensive cisplatin and etoposide-based regimen with cycles repeated at 7-10 day intervals, and with surgery in 22 patients. RESULTS: Forty-seven per cent of patients entered a second complete remission and 88% of these remain disease free. The overall survival was 46% with a median follow-up of more than 4.3 years. Surgery was performed in 14 of 18 patients who entered a second complete remission. Adverse risk factors before initial chemotherapy and the time to relapse did not predict outcome but patients with unresectable radiological masses after relapse therapy had a poor outcome despite normalization of serum tumour markers. The tumours of 68% of patients initially treated with cisplatin-based regimens and 62% of patients who also received etoposide remained responsive to conventional doses of these drugs at relapse. CONCLUSIONS: This study demonstrates that there is a group of patients with relapsed teratoma who can be cured without the need for very high dose chemotherapy and autologous bone marrow rescue.

Adolescent↗
PubMed1994

Received dose-intensity: a randomized trial of weekly chemotherapy with and without granulocyte colony-stimulating factor in small-cell lung cancer.

PURPOSE: A prospective randomized trial to determine if granulocyte colony-stimulating factor (G-CSF) could increase the received dose-intensity (RDI) of weekly chemotherapy in patients with small-cell lung cancer (SCLC). PATIENTS AND METHODS: Forty patients with SCLC with good prognostic features (all patients with limited disease [LD], and extensive-disease [ED] patients with Eastern Cooperative Oncology Group [ECOG] 0 or 1 and plasma alkaline phosphatase levels < 1.5 times the upper limit of normal) were randomized to receive weekly chemotherapy with or without G-CSF. G-CSF (5 micrograms/kg) was self-administered subcutaneously on days when chemotherapy was not given. Chemotherapy consisted of cisplatin 50 mg/m2 intravenously (IV) on day 1 and etoposide 75 mg/m2 IV on days 1 and 2 alternating weekly with ifosfamide 2 g/m2 IV (with mesna) and doxorubicin 25 mg/m2 on day 1, for a total of 12 courses. Dose modifications (dose reductions and treatment delays) were made according to defined hematologic criteria. RESULTS: Dose reductions were made at some point during treatment in 12 of 17 patients in the control arm and in 11 of 23 patients in the G-CSF arm (P = .20). The proportion of patients experiencing dose reductions due to leukopenia was significantly higher in the control arm (nine of 17) compared with the G-CSF arm (four of 23, P < .04). Cycle delays due to leukopenia were similar in both arms of the study. The RDI was 82% of projected in the control arm (95% confidence interval [CI], 79% to 84%) and 84% in patients receiving G-CSF (95% CI, 82% to 87%) (P value not significant). CONCLUSION: In this randomized trial, G-CSF significantly decreased dose reductions due to neutropenia. However, administration of G-CSF did not decrease dose reductions or treatment delays to a level that would allow an increase in received dose-intensity. Nonhematologic toxicities such as increased creatinine concentration also prevented an increase in the RDI in the G-CSF arm.

Adult↗
PubMed1993

Biodistribution and tumour localisation of 131I SWA11 recognising the cluster w4 antigen in patients with small cell lung cancer.

The biodistribution of radiolabelled SWA11, a mouse monoclonal antibody recognising the cluster w4 group antigen associated with small cell lung cancer (SCLC) was studied in patients with SCLC. Five patients were injected intravenously with approximately 5 mCi of 131I conjugated to 1 mg of SWA11. The half-life of the radiolabel in blood was short but there was a prolonged second phase of clearance with a half-life of about 40 h. Tumour was detected by gamma camera imaging two patients. However, most of the whole body radioactivity was located in the bone marrow. At least 35% of the radioactivity in blood 18 h after injection was bound to circulating granulocytes and this probably accounted for the unusual biodistribution of the radiolabel in man. This study shows that the biodistribution of radiolabelled SWA11 in man differs from human tumour xenograft models and that the antibody in unsuitable for targeting therapy to SCLC in man.

Antibodies, Monoclonal↗
PubMed1993

Biology of lung cancer.

New treatments of lung cancer are likely to develop from a greater understanding of the biology of lung tumors and the mechanisms of carcinogenesis and tumor progression. It is clear that numerous molecular genetic changes are present in lung cancer. Some of these changes, eg, mutated oncogenes, are found in other tumors. They provide clues about the carcinogenesis and pathogenesis of lung cancer. The relationship between these genetic changes and prognosis is becoming clearer. Study of membrane receptors for growth signaling and interaction of cells with their environment has identified factors relevant to prognosis and possible targets for therapy. Model systems to interfere with growth signaling have been developed.

Antigens, Neoplasm↗
PubMed1992

Factors influencing variability of localisation of antibodies to carcinoembryonic antigen (CEA) in patients with colorectal carcinoma--implications for radioimmunotherapy.

Tumour localisation of anti-tumour antibodies varies greatly between patients. Factors which may be responsible for this have been investigated in 56 patients with colorectal carcinoma with a view to improving radioimmunotherapy. Thirty-seven to seventy-four MBq of 125-I labelled mouse monoclonal antibody to CEA, was given intravenously and tumour resected 70-480 h later. Percentage injected activity kg-1 (% inj.act kg-1) in tumour, was inversely correlated with the time interval between injection and operation (P = 0.004). To assess the influence of other parameters on localisation, patients were divided into two time groups according to time interval between injection and operation, 70-120 h (n = 33) and 144-480 h (n = 23). In neither group was there a significant correlation of % inj.act kg-1 with time. The % inj.act kg-1 in tumour showed a significant correlation with that in the blood for both groups (P = 0.005 and P = 0.01). There was no significant correlation for either time group between % inj.act kg-1 in tumour and serum CEA values, the per cent of tumour cells positive for CEA and vascularity. Tumour to blood ratios varied considerably (range 0.3-28.5:1) suggesting that factors other than time and persistence of activity in the blood contribute to efficient targeting. Tumour to blood ratios were inversely correlated with % inj.act kg-1 in blood for the 70-120 h group (P = 0.007), and were positively correlated with % inj.act kg-1 in tumour (P = 0.012). Autoradiography showed that antibody localised predominantly on tumour cells but was distributed heterogeneously, was not solely related to the expression of antigen and in some cases accumulated in necrotic more than viable areas of tumour. Penetration of antibody into malignant acinar structures was poor and CEA-positive cells closer to the blood supply were targeted to a greater extent than distant cells. Preoperative administration of radiolabelled antibody to CEA may be helpful in selecting patients with favourable localisation for radioimmunotherapy.

Antibodies, Monoclonal↗
PubMed1991

A phase-I study of repeated therapy with radiolabelled antibody to carcinoembryonic antigen using intermittent or continuous administration of cyclosporin A to suppress the immune response.

The anti-mouse antibody response was examined in patients receiving repeated i.v. therapy with radiolabelled mouse monoclonal antibody (MAb) to carcinoembryonic antigen (CEA): 131I anti-CEA was given approximately every 2 weeks with cyclosporin A, to suppress the anti-mouse antibody response. Two schedules of cyclosporin A--intermittent therapy for 6 days with each course of anti-CEA and continuous therapy--were compared. Suppression of the immune response in the intermittent high-dose (3 patients) and continuous low-dose groups (4 patients) was equivalent, but the latter regimen was less toxic. Repeated therapy led to the formation of small amounts of anti-mouse antibody, but provided that cyclosporin A was continued it did not prevent further therapy or lead to an increase in the rate of clearance of anti-CEA from blood. Without cyclosporin A no more than 2 courses of antibody therapy could be given. Patients received up to 4 doses of 131I anti-CEA. The nadir platelet count was related to the half-life of 131I anti-CEA in blood. Thrombocytopenia limited the amount of 131I anti-CEA that could be given and determined the interval between treatments. Effective suppression of the anti-antibody response is possible and this study has determined that myelosuppression is the principal obstacle to repeated therapy with radiolabelled antibody.

Adult↗
PubMed1991

Outcome of patients with unfavorable optimally cytoreduced ovarian cancer treated with chemotherapy and whole abdominal radiation.

There is a subgroup of patients with Stage II or III ovarian cancer whose survival is poor despite optimal cytoreduction of tumor and abdominopelvic radiation. This study examined whether the survival of these patients, who have tumor with unfavorable histopathological characteristics and/or small residual disease, could be improved by giving chemotherapy before radiation. Forty-four out of fifty-one eligible patients, seen between 1981 and 1985, with Stage II or III disease were entered into the study. Following six courses of cisplatin-based chemotherapy, 33 (75%) received abdominopelvic radiotherapy. Survival was compared to that of 48 eligible matched control patients, treated with radiation between 1978 and 1981. The median follow-up is 6.6 years. The median survival was extended from 2.4 to 5.7 years (P = 0.13), and 42.6% of patients receiving combined therapy were free of relapse at 5 years, compared to 21.6% (P = 0.03) in the historical control group, treated with abdominopelvic irradiation alone. Only 2 of 44 patients in the combined group required surgery for bowel obstruction, as did 1 of 48 in the control group. Tolerance and toxicity of the combined approach were acceptable. Although we cannot be certain that the entire benefit we observed was not attributable to the chemotherapy alone, there is evidence that the radiotherapy may have been additive. Chemotherapy followed by abdominopelvic radiotherapy seems a reasonable management policy in these patients.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed1991

Weekly etoposide, methotrexate and actinomycin D, alternating with cyclophosphamide plus vincristine (EMA/CO): a phase II study in advanced gastric carcinoma.

A total of 27 patients with measurable/evaluable metastatic or locally advanced gastric carcinoma were given combination chemotherapy comprising etoposide, methotrexate, actinomycin D, cyclophosphamide and vincristine (EMA/CO). Ten achieved partial remission, giving a response rate of 37% (95% CI; 21.7%-66.3%), 12 attained stable disease, whereas five had disease progression despite treatment. Drug toxicity was moderate to severe. Five of those who achieved partial remission underwent an attempt to resect residual disease which was successful in only three patients.

Adenocarcinoma↗