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Biomedical subjects

E M Rankin

Publications and source records attributed to E M Rankin.

At least 37 records · Page 2Linked to original sources
PubMed1993

Effects of interleukin-3 on myelosuppression induced by chemotherapy for ovarian cancer and small cell undifferentiated tumours.

Two clinical studies were undertaken to study the toxicity profile and effects of interleukin-3 (rhIL-3) on chemotherapy-induced myelosuppression. Fifteen patients with recurrent ovarian carcinoma were treated with high dose carboplatin (800 mg m-2). All patients received 5.0 micrograms/kg/d rhIL-3 subcutaneously but timing and duration of rhIL-3 treatment differed. Constitutional symptoms were the major toxicity and in addition to the carboplatin-induced nausea and vomiting the combination was poorly tolerated. In 5/15 patients receiving high dose carboplatin rhIL-3 administration was discontinued due to nephrotoxicity (2 x), hypotension, severe malaise and bone pain. In this study, rhIL-3 ameliorated chemotherapy-induced neutropenia as well as thrombocytopenia and reduced the requirement for platelet transfusions in the second cycle of chemotherapy. However, rhIL-3 failed to prevent cumulative platelet toxicity. In the second study 12 patients with small cell undifferentiated cancers were treated with carboplatin, etoposide and ifosfamide. Three dose levels of rhIL-3 were explored (0.125, 5.0 and 7.5 micrograms/kg/d). In this study, toxicity of the treatment was mild, however, no beneficial haematologic effects of rhIL-3 could be demonstrated. In conclusion, the haematological effects of rhIL-3 were modest and dependent on the chemotherapeutic regimen, timing and duration of rhIL-3 treatment (in relation to the expected nadir). In general rhIL-3-induced toxicity was mild, but combination with high dose carboplatin could be hazardous if rhIL-3 is initiated at 24 h after the cytostatic agent.

Adult↗
PubMed1992

Randomised study of two doses of cisplatin with cyclophosphamide in epithelial ovarian cancer.

Cisplatin is generally accepted to be the most active cytotoxic agent for the treatment of ovarian cancer but the optimum dose remains unclear. We have performed a randomised trial to assess the importance of cisplatin dose in the treatment of advanced epithelial ovarian cancer. Patients were randomly assigned treatment with 50 mg/m2 (low dose) or 100 mg/m2 (high dose) cisplatin plus 750 mg/m2 cyclophosphamide, for a maximum of six cycles with intervals of 3 weeks. We planned to recruit 300 patients, but an interim analysis on the first 165 indicated a highly significant survival difference (p = 0.0008). Recruitment was therefore stopped and the trial patients were followed-up for 12 months longer. The relative progression rate (high-dose/low-dose) after 12 months' extra follow-up was 0.55 (95% confidence interval 0.37-0.81, p = 0.003) and the relative death rate 0.53 (0.34-0.81, p = 0.003). Overall median survival was 69 weeks in the low-dose group and 114 weeks in the high-dose group. Residual disease extent before chemotherapy had an important influence--patients with lesions of less than 2 cm did best; if given high-dose cisplatin their median survival was 3 years. 56 low-dose and 45 high-dose patients completed six cycles of chemotherapy; 15 and 9 patients, respectively, were withdrawn early because of progressive disease and treatment was stopped in 6 and 25, respectively, because of unacceptable side-effects or patient refusal. Toxic effects were significantly greater in the high-dose group, especially those on the nervous system and ears, alopecia, vomiting, and anaemia. Although the higher dose of cisplatin clearly leads to better results in terms of survival, its overall clinical benefit in the management of ovarian cancer will depend on further improvements in measures to alleviate toxic effects.

Adult↗
PubMed1992

A phase I study of prolonged continuous infusion of low dose recombinant interleukin-2 in melanoma and renal cell cancer. Part I: Clinical aspects.

The optimal schedule for recombinant interleukin-2 (rIL-2) administration is unclear. Because the clinical and immunological effects of prolonged continuous exposure to rIL-2 are unknown, we have conducted a phase I study to assess the toxicity and feasibility of continuous low dose infusion of rIL-2 (EuroCetus) using central venous access with a portable infusion device on an out-patient basis. Twenty-two patients entered the study, 13 with melanoma and nine with renal cell cancer, age range 26-66 years (median 51), performance status less than or equal to 1. They were treated with one of the following doses per m2 per 24 h: 0.18 x 10(6) IU, 0.6 x 10(6) IU, 1.8 x 10(6) IU, 3 x 10(6) IU, 6 x 10(6) IU and 9 x 10(6) IU. Toxicity was evaluable in 20 patients receiving greater than or equal to 3 weeks treatment duration or in whom treatment was discontinued prematurely because of toxicity. Constitutional symptoms consisting of fatigue, malaise and fever up to 40 degrees C without significant organ dysfunction occurred with doses greater than or equal to 1.8 x 10(6) IU m-2. The maximum tolerated dose was 6 x 10(6) IU m-2 24 h-1. In all patients toxicity reached a peak at 3 weeks and resolved thereafter despite continued rIL-2 treatment. Peripheral blood eosinophilia (up to 66% of white blood cell count) followed the same pattern. An infection of the central venous access occurred in 55% of the patients but this was mostly asymptomatic. Thirteen patients were treated greater than or equal to 6 weeks and were evaluable for tumour response. A partial remission occurred in a patient with melanoma with a dose of 1.8 x 10(6) IU rIL-2 m-2 24 h-1.

Adult↗
PubMed1992

A randomised study comparing standard dose carboplatin with chlorambucil and carboplatin in advanced ovarian cancer.

A total of 161 previously untreated patients with FIGO stage III or IV epithelial ovarian cancer were randomised after surgery to receive six courses of either carboplatin 400 mg m-2 alone (Arm A) or carboplatin 300 mg m-2 with chlorambucil 10 mg day-1 for 7 days (Arm B). The median progression free survival (PFS) was similar: arm A: 45 weeks; arm B: 61 weeks (P = 0.830). Multivariate Cox regression analysis showed that the extent of residual disease and performance status were the most important prognostic factors for PFS. Fifty-two per cent of patients received dose escalations based on nadir blood counts, and 89% of all dose adjustments were made according to protocol. Failure to achieve a significant degree of leucopenia was associated with worse progression free survival (P less than 0.001). A total of 29.4% of patients fall into this category. The median survival was similar in both arms, i.e. 75 weeks. It is unlikely that there is any major clinical advantage to adding chlorambucil to single agent carboplatin for the management of advanced ovarian cancer, but whether used in combination or a single agent, the dose of carboplatin should be sufficient to cause at least grade I leucopenia. This may best be achieved by determining the initial dose based on renal function, and then adjusting subsequent doses according to nadir blood counts.

Adult↗
PubMed1991

Epirubicin at two dose levels with prednisolone as treatment for advanced breast cancer: the results of a randomized trial.

Two hundred eleven patients with advanced breast cancer were randomized to receive either epirubicin (E) 50 mg/m2 and prednisolone (LEP) or E 100 mg/m2 and prednisolone (HEP). The intended treatment consisted of 16 courses of LEP or eight courses of HEP given at 3-weekly intervals. Reasons for stopping treatment early included progressive disease, stable disease without symptomatic improvement, or severe toxicity deemed intolerable by either the patient or physician. Toxicity was recorded at 3-weekly and response at 9-weekly intervals using the World Health Organization (WHO) criteria of response and toxicity. Two hundred nine patients were eligible for analysis, 98% of whom have been followed for more than a year. One hundred four patients received LEP and 105 HEP. Significantly worse myelosuppression, alopecia, nausea and vomiting, and mucositis were seen in the high-dose arm (P less than or equal to .001). More patients in the LEP arm stopped treatment before the fourth course than in the HEP arm, and the commonest reason for stopping was progressive disease. A similar median number of courses was given in each arm. There was a significantly higher response in the HEP arm (HEP - complete response [CR] + partial response [PR] = 41%, LEP - CR + PR = 23%). Despite this, no statistically significant differences was seen in overall survival or progression-free interval. The median survival for HEP and LEP was 44 and 46 weeks, respectively.

Adult↗
PubMed1990

Phase I and pharmacokinetic study of intraperitoneal thioTEPA in patients with ovarian cancer.

A total of 15 patients with residual ovarian cancer confined to the peritoneal cavity after first-line systemic chemotherapy were treated with triethylene-thiophosphoramide (thioTEPA) in a phase I study. A total of 50 courses of thioTEPA were given intraperitoneally in doses ranging from 30 to 80 mg/m2. The dose limiting toxicity was myelosuppression, which occurred at 80 mg/m2 and was frequently prolonged. Short-lived nausea and vomiting was easily controlled, and there was no local toxicity. Three patients remain free of disease progression at 6, 6 and 12 months. ThioTEPA concentrations were measured by gas chromatography. Peritoneal fluid concentrations declined rapidly in a first-order fashion, with a half-life of 0.96 +/- 0.1 h. A mean of 93% of the drug was absorbed during the 4-h dwell time. Peak plasma levels were achieved 30-60 min after drug instillation and were substantially lower than corresponding peritoneal levels. A pharmacokinetic advantage for intraperitoneal delivery was detected for peak drug concentration (24.9 +/- 8.5) and AUC (9.2 +/- 4.8). Based on this study, the recommended dose for intraperitoneal thioTEPA is 60 mg/m2 every 3-4 weeks. However, the rapid absorption of this drug from the peritoneum, secondary to thioTEPA's small molecular weight and lipophilic nature, suggests that it has only a limited role in intraperitoneal therapy.

Adult↗
PubMed1990

A pilot study of quinidine and epirubicin in the treatment of advanced breast cancer.

Thirty-one patients were entered into a pilot study combining oral quinidine with epirubicin 100 mg m-2 as first line chemotherapy in advanced breast cancer. Three patients were treated with quinidine 1 g b.d., and developed symptoms of toxicity. Of eight subsequent patients treated with quinidine 500 mg b.d., two experienced tiredness and nausea and one severe oral toxicity with epirubicin. The remaining 20 patients received quinidine 250 mg b.d.; one developed cinchonism and one malaise, the remainder showing no excess toxicity compared with epirubicin alone. The median nadir WBC was similar with or without quinidine (2.3 vs 1.6 x 10(9) l-1) as was median nadir platelet count (175 vs 157 x 10(9) l-1). There was no evidence of significant cardiac toxicity. The median plasma quinidine level achieved was 5.6 mumol l-1 (range 2.1-22.1), which is within the range of concentrations which is effective in vitro at reversing experimental anthracycline resistance. A randomised controlled study is proposed to assess the impact of this potential modulation on the efficacy of epirubicin in advanced breast cancer.

Adult↗
PubMed1989

Phase I clinical and pharmacokinetic study of LY 195448.

LY 195448 is a phenethanolamine that has shown anti-tumour activity in a range of murine tumour models, although its mechanism of action is unknown. Pre-clinical studies have indicated the absence of "standard" side effects such as myelosuppression and gastrointestinal toxicity. The present phase I trial was carried out in nine patients at doses ranging up to 133 mg/m2. The major toxicities up to that dose were mild, reversible hypotension, tachycardia and tremor. No haematological or biochemical toxicity was observed. Murine pharmacokinetics were assessed at a dose level that was effective in experimental tumours and compared with human pharmacokinetic parameters derived from this study. The results indicated the clinical possibility of reaching peak drug levels associated with experimental activity. However, no responses were seen at the doses used. This study was terminated prior to its completion due to an unexplained loss of activity against murine tumours since September 1987. No significant loss of the in vitro anti-mitotic activity originally reported by Boder et al. [3] was observed. Possible reasons for the apparent loss of in vivo activity have been intensively investigated, but no cause has been determined. Therefore, clinical trials with LY 195448 have been discontinued.

Adult↗
PubMed1989

Hypersensitivity reaction to epirubicin.

A patient with metastatic breast cancer treated with epirubicin (Pharmorubicin) developed a severe urticarial reaction which progressed to ulceration following possible sensitisation to the drug by preceding extravasation.

Bone Neoplasms↗
PubMed1989

Metastatic vipoma arising from colonic primary tumour.

We describe a case of a tumour of the sigmoid colon with hepatic metastases in a patient with previously documented ulcerative colitis. A diagnosis of metastatic vipoma was made on the basis of high plasma levels of vasoactive intestinal polypeptide (VIP). Profuse diarrhoea and profound metabolic upset were corrected by the use of a somatostatin analogue SMS 201-995, whilst conventional cytotoxic therapy produced a significant tumour response with return of the plasma VIP level to normal.

Adenoma, Islet Cell↗
PubMed1988

Pharmacokinetics and anti-emetic efficacy of BRL43694, a new selective 5HT-3 antagonist.

Twenty patients receiving a variety of emetogenic cytotoxics (including cisplatin in 5) were given a single i.v. infusion of 40 micrograms kg-1 of BRL43694 (as the hydrochloride salt) in successive groups of 3-4 patients between 0-6 hours after chemotherapy. Eleven patients were completely protected from vomiting; 9 had mild to moderate nausea and vomiting, but none severe enough to require alternative anti-emetic 'rescue'. In 4 of the patients in whom BRL43694 was delayed until 4-6 h after chemotherapy, vomiting had already begun; in each case immediate termination of vomiting occurred when BRL43694 was infused. No adverse effects attributable to the anti-emetic were observed. Mean pharmacokinetic parameters in 14 patients in whom plasma assay data are available were: Maximum observed concentration = 30.7 ng ml-1; terminal phase half-life = 8.96 h; total body clearance = 0.376 (1 h-1) kg-1; apparent volume of distribution = 2.85 l kg-1. This study shows BRL43694 to be an effective and well tolerated anti-emetic. Further studies aimed at defining an optimal dose and schedule for use against the most emetogenic cytotoxics are in progress.

Adolescent↗
PubMed1988

Transcatheter embolisation to control severe bleeding in fungating breast cancer.

Severe and recurrent haemorrhage from ulcerating breast or skin lesions was controlled in seven of nine women with breast cancer. Arterial catheterisation and embolisation with a variety of materials (gelfoam, polyvinyl alcohol, steel coils, 50% dextrose) was used. Local anaesthesia only was needed, allowing very ill patients to be treated. This approach is the treatment of choice for severe haemorrhage in breast cancer.

Adenocarcinoma, Papillary↗
PubMed1987

Phase I and pharmacokinetic study of flavone acetic acid.

Flavone acetic acid is the second in a series of compounds based on the flavonoid aglycone ring structure to be clinically evaluated in malignant disease. Preclinical studies have indicated that a minimum plasma level of 150 micrograms/ml is required before therapeutic efficacy (in a wide range of experimental tumors) is seen in mice; both in vitro and in vivo studies also suggest that the duration of drug exposure is crucial in determining activity. Thus a Phase I trial has been performed in a total of 54 patients using 3 schedules, i.e., a 1-, 3-, and 6-h infusion. In each case, treatment was given once weekly for a minimum of 3 weeks. The maximum tolerated doses were 6.4, 6.4, and 10.0 g/m2, respectively. Dose limiting toxicity was denoted by an intense feeling of warmth and flushing with a 1-h infusion, hypotension with a 3-h infusion, and hypotension and diarrhea with a 6-h infusion. No objective responses were seen in this Phase I trial. The recommended doses for Phase II trials of flavone acetic acid in Europe are 4.8 g/m2 over 1 h or 8.6 g/m2 over 6 h. At these doses the peak plasma concentrations obtained are 650 and 388 micrograms/ml, respectively. Total drug exposure (assessed by an area under the curve greater than 100 micrograms/ml) was approximately 50% greater for the 6-h schedule. This Phase I trial indicates that peak plasma concentrations associated with experimental activity are achievable in humans, although optimal drug exposure times have not yet been defined.

Adult↗