Biomedical subjects

P M Wilkinson

Publications and source records attributed to P M Wilkinson.

At least 19 recordsLinked to original sources

PubMed1994

Weekly VAPEC-B chemotherapy for high grade non-Hodgkin's lymphoma: results of treatment in 184 patients.

UNLABELLED: BACKGROUND AND PATIENTS: A weekly schedule of chemotherapy (VAPEC-B) has been used to treat 184 consecutive patients with high grade non-Hodgkin's lymphoma (NHL). Median age for the group was 57 years (range 17-84) and 56% had stage IV disease. RESULTS: Following chemotherapy, 114 (62%) patients achieved CR or CR(u), 32 (17%) PR and 15 (8%) had not responded or progressed. Response to VAPEC-B was highly stage dependent with 70% or more of patients with stages I-III achieving CR or CR(u) but only 50% of those with stage IV. Twenty-four (15%) patients died during treatment with VAPEC-B and in 13 cases death was due to sepsis. This complication occurred mainly in patients with stage IV disease aged 60 years or older. After a median follow up period of 4.1 years, the actuarial 4 year survival for 184 patients is 45%, an overall result heavily influenced by the poor outcome for 103 patients with stage IV disease (4 year survival of 28%). Patients with earlier stage disease fared correspondingly better (44% for stage III, 68% for stage II and 80% for stage I). CONCLUSIONS: VAPEC-B gives similar results to other chemotherapy regimens currently used in the treatment of high grade NHL and has the advantage of brevity. Caution is advised in patients over the age of 60 especially in the presence of stage IV disease and dose reduction or haemopoietic growth factor support should be considered in these circumstances.

Adolescent↗

PubMed1992

Granulocyte colony-stimulating factor to prevent dose-limiting neutropenia in non-Hodgkin's lymphoma: a randomized controlled trial.

The effect of granulocyte colony-stimulating factor (G-CSF) on neutropenia, infection, and cytotoxic chemotherapy administration was studied in a randomized trial in patients receiving intensive weekly chemotherapy for non-Hodgkin's lymphoma (NHL). Eighty patients (aged 16 to 71 years) with high-grade NHL (Kiel) of any stage were randomized to receive VAPEC-B chemotherapy alone (39 patients) or with G-CSF administered as a daily subcutaneous dose of 230 micrograms/m2 (41 patients). Prophylactic ketoconazole and cotrimoxazole were administered to all patients throughout treatment. The protocol specified identical dose modification and antibiotic treatment criteria bor both groups. Neutropenia (absolute neutrophil count [ANC] less than 1.0 x 10(9)/L) occurred in 15 of 41 (37%) of the G-CSF-treated patients and in 33 of 39 (85%) of the controls, giving a relative risk for control patients of 2.31 (95% confidence interval [CI], [1.51, 3.54]; P = .00001). Fever (greater than or equal to 37.5 degrees C) with neutropenia (ANC less than 1.0 x 10(9)/L) occurred in 9 of 41 (22%) of the G-CSF group and in 17 of 39 (44%) of the controls (relative risk for control, 2.26; 95% CI [1.01, 5.06]; P = .04). There were fewer treatment delays, with shorter duration (P = .01) in patients receiving G-CSF. Chemotherapy doses were reduced in 4 of 41 (10%) of the G-CSF patients and 13 of 39 (33%) of the controls (P = .01). The dose intensity of cytotoxic chemotherapy was significantly increased in patients receiving G-CSF (median of 95% in G-CSF group compared with 83% in control patients). Three vascular deaths occurred in the G-CSF group. Delays in the control group most commonly resulted from neutropenia (19 patients, compared with 2 patients in the G-CSF-treated group, P = .000007). Severe mucositis was the major dose-limiting toxicity in G-CSF-treated patients, but did not occur more frequently than in controls (15 patients in each group). Overall, patients randomized to receive G-CSF achieved a greater dose intensity than control patients, but this did not result in significant differences in drug toxicity (other than neutropenia), intravenous antibiotic usage, or hospitalization between the two groups.

Adolescent↗

PubMed1992

Management of neutropenic colitis.

Neutropenic colitis is recognized as a rare complication of chemotherapy in haematological malignancies. By contrast, the complication is less well known in relationship to chemotherapy for solid malignancies. There are very few examples reported and this paper adds three further cases and reviews the literature. We emphasize that although some cases of neutropenic colitis may be managed medically, full thickness involvement of the bowel wall may lead to perforation and require surgery. The pathogenesis of this progression is discussed and it is concluded that clinical awareness is important in the diagnosis. The signs of peritonitis or septicaemia are indications for excisional surgery with the formation of a temporary ileostomy.

Adrenal Gland Neoplasms↗

PubMed1992

Recombinant human erythropoietin in patients with ovarian carcinoma and anaemia secondary to cisplatin and carboplatin chemotherapy: preliminary results.

Preliminary results from the first 21 patients of a group of 30 with International Federation of Gynaecology and Obstetrics (FIGO) stage II-IV epithelial ovarian carcinoma and anaemia are reported. Patients entered this open-label, comparative-group, out-patient study and were randomized to receive conventional support alone (control patients) or recombinant human erythropoietin (r-HuEPO) in addition to conventional support for 6 months. The aim of the study was to determine the effects of r-HuEPO on the anaemia induced by platinum-based chemotherapy. Patients randomized to r-HuEPO therapy received 300 U/kg subcutaneously 3 times weekly in addition to conventional chemotherapy. All patients underwent regular haematological monitoring. One patient developed a deep venous thrombosis after 17 doses of r-HuEPO; it was thought that this event may have been related to therapy and the patient was withdrawn from the study. Three other withdrawals occurred after 11, 15 and 40 doses of r-HuEPO because of progressive anaemia, metoclopramide-induced skin rash and change of chemotherapy, respectively. In the 21 patients analysed to date, there was a notable reduction in blood transfusion requirements during the 6 months of chemotherapy and an improvement in mean serial haemoglobin concentrations in patients on r-HuEPO compared with the control group. In conclusion, r-HuEPO has the potential for reducing haematological toxicity in patients with ovarian carcinoma receiving platinum-based chemotherapy. Also, r-HuEPO may allow modest dosage increments in chemotherapy or the addition of abdominopelvic radiotherapy.

Adult↗

PubMed1992

The Second Medical Research Council study of prognostic factors in nonseminomatous germ cell tumors. Medical Research Council Testicular Tumour Working Party.

PURPOSE: To assess prognostic factors in a large population of patients with metastatic nonseminomatous germ cell tumors (NSGCT) arising in gonadal or extragonadal sites. PATIENTS AND METHODS: Data from 795 patients treated with chemotherapy between 1982 and 1986 in 13 centers were analyzed. Particular emphasis was placed on exact tumor measurements (eg, size of nodal masses, number of lung metastases), and the diagnostic pathology was also reviewed. Cox regression analysis was performed on these data. The patients were treated with a variety of cisplatin-containing chemotherapy regimens, 86% of which included etoposide. RESULTS: With median follow-up of 45 months, overall 3-year survival is 85%. The independently adverse features proved to be (1) the presence of liver, bone, or brain metastases; (2) raised marker levels (alpha-fetoprotein [AFP] level greater than 1,000 kU/L or beta subunit of human chorionic gonadotropin [HCG] greater than 10,000 IU/L [corrected]); (3) the presence of a mediastinal mass greater than 5 cm in diameter; (4) the presence of 20 or more lung metastases; (5) increasing age; and (6) absence of undifferentiated teratoma (embryonal carcinoma) or fibrous tissue from the primary tumor. CONCLUSIONS: The first four factors were used to define a simple prognostic classification. A good-prognosis group having none of these features comprised 67% of our patient population and had a 3-year survival of 93%. The remaining 33% of patients having at least one of these features had a 3-year survival rate of 68%. These patient groups are currently the subjects of international randomized clinical trials.

Adult↗

PubMed1991

The stability of ifosfamide in aqueous solution and its suitability for continuous 7-day infusion by ambulatory pump.

Dose fractionation is known to reduce the toxicity of ifosfamide and also results in an increased production of alkylating metabolites. Administration by slow infusion using the convenience of ambulatory pumps is therefore of interest. We used HPLC to investigate the stability of ifosfamide in aqueous solution (either alone, solution A, or mixed with mesna, solution B) under various conditions over a 9-day period. At both ambient temperature in daylight and 27 degrees C in a dark environment, there was no evidence of ifosfamide decay in either solution. However, at 37 degrees C in a dark environment, a fall was detected in both solutions, which at 9 days amounted to a loss of 7% of the amount of ifosfamide present at time zero. At 70 degrees C, levels of ifosfamide in both solutions fell within 72 h to markedly lower levels than controls, thus confirming that the methods used were indicative of stability. We conclude that ifosfamide, either alone or mixed with mesna, is stable for 9 days at temperatures up to 27 degrees C; even at 37 degrees C, the measured loss is small. The continuous infusion of ifosfamide over 7 days by ambulatory pump is now a practical proposition.

Ambulatory Care↗

PubMed1991

An analysis of prognostic factors in stage III and IV Hodgkin's disease treated at a single centre with MVPP.

Two hundred and twenty seven patients with stage IIIA-IVB Hodgkin's disease have been treated at a single centre with MVPP chemotherapy followed by radiotherapy to sites of previously bulk disease. The median follow up is 58 months. 119 patients (52%) had stage IV disease. Overall complete remission (CR) rate was 72%. Discriminant analysis of factors predictive for complete remission showed that low albumin was the only independent factor that predicted a significantly lower chance of CR. Overall five year survival was 73%. A Cox multivariate analysis demonstrated that age greater than 40 years, stage IV disease, presence of bulk disease, low serum IgG and male sex to be variables which independently predicted poorer prognosis in terms of overall survival. Stage IV and lymphocyte depleted or unclassified histologies were independently predictive for poorer progression-free survival. Patient weight greater than 70 kg and stage IV disease were adverse prognostic factors for relapse free survival. Results are compared to other published multivariate analyses of prognostic factors in advanced Hodgkin's disease.

Adult↗

PubMed1990

Comparative pharmacokinetics of escalating doses of doxorubicin in patients with metastatic breast cancer.

Recombinant human granulocyte colony-stimulating factor (G-CSF) has been shown to reduce neutropenia following cytotoxic therapy, thereby enabling dose escalation to improve the response rate. It is important to know whether drug kinetics change as doses are increased. Doxorubicin was selected because of its broad spectrum of activity and its known efficacy in metastatic breast cancer. Doses of 75, 100, 125 and 150 mg/m2 were given to 11 patients with metastatic breast cancer by infusion over 30 min. Serum concentrations of parent drug and metabolites were determined during the first 48 h following the infusion by high-performance liquid chromatography (HPLC). The serum concentration vs time curve decayed as a triple exponential function in four patients and as a double exponential function in seven. A four-compartment model, one central and three peripheral, would predict concentrations to within 1 SE of the observed values. Doxorubicinol was the principal metabolite, and doxorubicinone and 7-deoxydoxorubicinone were clearly identified. There was a linear increase in the AUC infinity with dose. In addition, a small and transient increase in circulating levels of doxorubicinol and other important metabolites was observed 6 h following the administration of doxorubicin, which suggests the existence of an enterohepatic, or other, re-circulation mechanism. We conclude that in the dose range selected the kinetics of doxorubicin are linear and that the increase in toxicities seen with the higher doses of doxorubicin, following the second and third fortnightly administration, may be due to intracellular drug accumulation in tissues.

Adult↗

PubMed1990

The stability of ifosfamide in aqueous solution and its suitability for continuous 7-day infusion by ambulatory pump.

Ambulatory Care↗

PubMed1990

The effect of age on the pharmacokinetics of ifosfamide.

The effect of age on the pharmacokinetics of ifosfamide was studied in 20 patients with advanced non small cell lung cancer. A positive correlation was found between the elimination half-life of ifosfamide and age (r = 0.48, 0.05 less than P less than 0.01). This was due to an increase in volume of distribution with age (r = 0.66, 0.001 less than P less than 0.01). Total plasma clearance, renal clearance and non renal clearance did not change with age. Age did not affect the autoinduction of ifosfamide metabolism. Further studies are needed to demonstrate any adverse effects of ifosfamide in the elderly.

Adult↗

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↗

PubMed1988

The treatment of advanced seminoma with chemotherapy and radiotherapy.

Between 1979 and 1984 thirty-seven patients were treated with combination chemotherapy for metastatic seminoma; 27 of these had relapsed following initial radiotherapy for stage I and IIA disease and 10 patients with stage IIB-IV disease received chemotherapy de novo followed by radiotherapy to sites of bulk disease. Treatment consisted of either a cis-platinum containing combination (25 patients), or cyclophosphamide and etoposide (12 patients). The overall survival of all patients at 5 years was 49%, 34 patients were assessable for response; a CR was obtained in 8 (24%) and a GPR in 19 (56%), the 5 year survival of this group being 66% at 5 years. No difference in survival was seen in relation to age, previous irradiation, serum HCG or LDH; bulk disease however, was an adverse prognostic factor. Survival was similar for both chemotherapy schedules but neutropenia and life-threatening sepsis was less with the cyclophosphamide etoposide combination.

Adult↗

PubMed1987

Clinical pharmacology of oral and intravenous 4-demethoxydaunorubicin.

The clinical pharmacology of 4-demethoxydaunorubicin (4-DMDNR) was studied in 28 patients with advanced breast cancer, using a sensitive reverse-phase HPLC technique. All patients had normal renal and hepatic function. The serum levels of 4-DMDNR after a single i.v. bolus injection followed a triple exponential decay curve (T 1/2 alpha = 9.6 min, T 1/2 beta = 3.2 h and T 1/2 gamma = 34.7 h) and conformed to a three-compartment model. Comparison of the area under the curve (AUC) and urinary excretion for the oral and i.v. routes suggests an oral bioavailability of approximately 24%. In patients treated with a schedule of weekly oral administration for periods of up to 12 months there was no significant alteration in either AUC or elimination half-life for the parent drug or its principal metabolite 13-OH4DMDNR. Moreover, there was no evidence of accumulation of the metabolite although measurable amounts were present 7 days after administration of 4-DMDNR.

Administration, Oral↗

PubMed1987

A randomised clinical trial to contrast radiotherapy with radiotherapy and methotrexate given synchronously in head and neck cancer.

Three hundred and thirteen patients with squamous cell cancer of the head and neck were entered in a randomised clinical trial to determine whether the addition of methotrexate during the course of irradiation improved the rate of primary control and subsequent survival. The overall primary control (P = 0.016) and survival (P = 0.075) for the patients receiving methotrexate was better than the patients treated by radiotherapy alone. The improvement in primary control (P = 0.0019) and survival (P = 0.0089) in patients with oropharyngeal cancers who had methotrexate in addition to radiotherapy is statistically significant. The treatment was well tolerated and there has been no increase of late morbidity.

Carcinoma, Squamous Cell↗

PubMed1986

Treating ovarian cancer.

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Antineoplastic Combined Chemotherapy Protocols↗

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↗