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Biomedical subjects

C R Pinkerton

Publications and source records attributed to C R Pinkerton.

At least 91 records · Page 5Linked to original sources
PubMed1995

Randomised comparison of ondansetron and metoclopramide plus dexamethasone for chemotherapy induced emesis.

The serotonin (5HT3) antagonist ondansetron was compared in a randomised study with metoclopramide and dexamethasone for the prevention of chemotherapy induced emesis. Thirty children aged 1-15 years with acute lymphoblastic leukaemia received 'intensification modules' according to the MRC United Kingdom acute lymphoblastic leukaemia regimen UKALL XI. This contains the moderately emetogenic drugs daunorubicin, etoposide, and cytarabine. Fifteen children received an intravenous loading dose of ondansetron followed by intravenous or oral doses 12 hourly for five days. Fifteen children received intravenous metoclopramide every six hours for three days with a loading dose of dexamethasone, repeated every eight hours for three days intravenously or orally. Efficacy was assessed by a diary card documenting the incidence of nausea, retching, or vomiting. In the 24 hour period after starting chemotherapy, ondansetron was more effective, with a complete or major response rate of 93%, compared with 33% using metoclopramide/dexamethasone.

Administration, Oral↗
PubMed1995

Intensive chemotherapy with stem cell support-experience in pediatric solid tumours.

A recent Consensus Conference in Lyon reviewed the role of high-dose therapy with stem cell rescue in a variety of malignancies including childhood tumours. The conclusion was that with the exception of metastatic neuroblastoma there is still no proven role for this treatment strategy. It is more than 10 years since this approach was used in neuroblastoma and it has subsequently been applied to most of the common childhood solid tumours. Although a single randomised study has suggested that the progression-free survival is significantly prolonged with high-dose melphalan, the superiority of this over continued intensive conventional therapy is unclear. It seems likely that a selected subgroup of children with stage IV disease may benefit from megatherapy and the results of current randomised trials are awaited. In rhabdomyosarcoma, the duration of treatment may be shortened by dose escalation, but the impact on the outcome in very high-risk patients remains unproven. In Ewing's sarcoma, there has been difficulty defining high-risk patients, but recent studies suggest that megatherapy may have a role in patients with bone or bone marrow disease who have little chance of long-term survival with conventional chemotherapy approaches. In brain tumours, the results have been disappointing for gliomas, but there is currently enthusiasm about a possible role in the chemosensitive primitive neuroectodermal tumours. In this group of diseases which are inherently chemosensitive, the poor results from chemotherapy in the past have resulted from a failure to achieve appropriate drug levels at the tumour site and this may be potentially overcome by dose escalation. In Wilms' tumour, although the overall cure rate is very high, there appears to be a useful role for megatherapy in certain high-risk relapsed patients who have little chance of cure with conventional salvage therapy. There is an urgent need for international collaboration to design randomised studies which will as rapidly as possible address the issue of the role of these expensive and high morbidity procedures in childhood cancer.

Adolescent↗
PubMed1995

Autologous bone marrow transplantation for acute myeloid leukemia in first remission: identification of modifiable prognostic factors.

Seventy-four consecutive patients (median age 31 years) with acute myeloid leukemia (AML) undergoing unpurged autologous bone marrow transplantation (ABMT) in first remission after melphalan and total-body irradiation were studied to assess the impact of 14 modifiable and non-modifiable prognostic factors on relapse and disease-free survival. Thirty patients were alive in continuous CR at a median of 37.5 months (range 3-94), 14 died of transplant-related toxicity at a median of 5.5 months (range 0.5-18), and 30 relapsed at a median of 7.5 months (range 2-23). The actuarial 5-year probabilities of relapse and disease-free survival were 53.4 and 34.2%, respectively. On multivariate analysis, administration of two or more courses of consolidation chemotherapy prior to the harvest and transplant was found to be the most significant factor associated with decreased relapse (relative risk 2.62, P = 0.0012) and improved disease-free survival (relative risk 3.03, P = 0.0009). A nucleated cell dose of > 2 x 10(8)/kg improved disease-free survival (relative risk 2.17, P = 0.045) by decreasing transplant-related mortality (P = 0.047). We conclude that adequate consolidation of remission before ABMT is the most important factor associated with continuing remission after ABMT. Short-term therapy of AML with two courses of consolidation therapy followed by ABMT requires comparison with repeated courses of intensive chemotherapy for efficacy and cost-effectiveness.

Adolescent↗
PubMed1994

Peripheral blood stem cells used to augment autologous bone marrow transplantation.

Peripheral blood stem cells (PBSC) were used to augment autologous bone marrow transplantation (ABMT), aiming to hasten engraftment after high dose treatment in a group of heavily pretreated patients. PBSC were obtained by leukapheresis during the rebound after standard chemotherapy. In 11 patients aged 7-17 years, high dose chemotherapy consisted of busulphan 16 mg/kg orally with melphalan 160 mg/m2 intravenously for seven patients, and melphalan 200 mg/m2 intravenously alone for four. The median number of granulocyte-macrophage colony forming units in the reinfused PBSC was 3.42 x 10(4)/kg (3.03-18.01) and bone marrow 12.4 x 10(4)/kg (4.16-28.6). Neutrophil recovery to > or = 0.5 x 10(9)/l and platelet transfusion independence occurred at a median of 14 days (11-18) and 22 days (9-84) respectively. In five patients the early engraftment was transient with neutrophils again dropping below 0.5 x 10(9)/l then slowly recovering. There was one toxic death due to sepsis. PBSC harvesting in these children was undertaken without interrupting routine chemotherapy and without the use of bone marrow growth factors. In some patients PBSC failed to influence engraftment and the use of combined chemotherapy and growth factor priming for PBSC collection may give improved results.

Acute Disease↗
PubMed1993

When is the optimum time to harvest peripheral blood stem cells in children following standard dose chemotherapy?

The optimal time for peripheral stem cell harvest may be predicted by recovery of blood count following priming doses of chemotherapy. Bone marrow growth factors have also been used to enhance yield. Both these manoeuvres may necessitate alterations to standard treatment programmes. In order to determine whether adequate peripheral stem cell yields could be obtained without altering chemotherapy regimens, 18 children with either leukaemia or solid tumours were studied. Circulating bone marrow progenitor cells were estimated by CFU-GM cultures in soft agar. There were 8 males and 10 females, median age 5.6 years (range 2-13 years). Six out of 13 studies in leukaemia patients were done when the bone marrow contained significant leukaemic blasts, and in 2 of 9 studies in patients with solid tumours, there was active infiltration of the bone marrow. In 15 of 23 studies, a rise in CFU-GM levels to greater than 1,000 x 10(3)/l were observed following postchemotherapy aplasia. Maximum CFU-GM levels were maintained for only 1-2 days and could be predicted by the achievement of a total white cell count in the region of 2 x 10(9)/l and platelet count around 100 x 10(9)/l. Neutrophil recovery did not predict the rise in CFU-GM levels. A rapid rise in monocyte levels also preceded maximum CFU-GM levels. Predictably, the CFU-GM counts were lower in patients who were heavily pretreated, but in several children, the counts were sufficient to predict an adequate harvest to be used in conjunction with bone marrow autotransplantation. It is concluded that in children with active bone marrow recovery, chemotherapy priming or the use of bone marrow growth factors may not be necessary to achieve useful stem cell harvests.

Adolescent↗
PubMed1993

24-hour plasma etoposide profile after oral and intravenous administration in children.

Pharmacokinetic profiles of oral and intravenous etoposide have been compared in 9 children receiving the drug either as a single agent or in combination chemotherapy. The plasma etoposide levels were estimated using a competitive coated antigen ELISA technique. The median bioavailability was 48% and beyond 30 min after either oral or intravenous injection there was little difference in the plasma profile. The duration of plasma concentrations above 1, 5 and 10 micrograms/ml following either route were compared. It is concluded that unless the height of initial peak concentration is of therapeutic value the oral route should be comparable in children provided that twice the intravenous dose is administered. The short elimination half-life results in low plasma levels beyond 12 h and suggests that a twice daily regimen may be preferable.

Administration, Oral↗
PubMed1993

21-day schedule oral etoposide in children--a feasibility study.

To determine the feasibility and toxicity of prolonged oral etoposide in children, 22 patients with relapsed or refractory disease were commenced on etoposide 50-100 mgs/m2 per day for 21 days. A second course was administered after full blood count recovery, followed by disease reassessment. In total, 72 courses were evaluable for toxicity, with 10% of completed courses complicated by febrile neutropenia. 15 patients were evaluable for response, with 1 partial response, 10 stable disease and 4 progressive disease. This schedule was well tolerated with acceptable toxicity when doses of less than 80 mg/m2/day were administered and warrants further evaluation.

Administration, Oral↗
PubMed1993

Carboplatin pharmacokinetics in children: the development of a pediatric dosing formula. The United Kingdom Children's Cancer Study Group.

PURPOSE: The aim of this study was to define the pharmacokinetics of carboplatin in children and use the data to develop a pediatric dose formula. It was anticipated that renal function would be a major determinant of carboplatin disposition and the relationship between carboplatin clearance and glomerular filtration rate (GFR) was examined in detail. PATIENTS AND METHODS: Plasma carboplatin pharmacokinetics were measured as ultrafiltrable platinum in 22 patients (5 to 63 kg) following 200 to 1,000 mg/m2 of carboplatin. GFR was measured by the plasma clearance of chromium 51-edathamil (51Cr-EDTA). RESULTS: Carboplatin pharmacokinetics in children were best described in most patients (16 of 22) by a two-compartment model. The dose-normalized area under the plasma carboplatin concentration versus time curve (AUC) ranged from 3.1 to 9.6 mg/mL.min/400 mg/m2 and there was only a weak linear relationship between carboplatin dose and AUC (R2 = .31). There was a significant relationship between absolute carboplatin and 51Cr-EDTA clearances (R2 = .56), but the relationship was weaker (R2 = .28) when both clearances were normalized for body surface area. Carboplatin plasma clearance was predicted by the equation: clearance = GFR (mL/min) + 0.36 x body weight (BW; kg), and a modified form of the adult carboplatin dose formula is proposed: dose (mg) = target AUC x (GFR [mL/min] + [0.36 x BW(kg)]). Two further equations were developed that use the 51Cr-EDTA half-life (t1/2) to calculate the GFR and these may reduce errors resulting from inaccurate measurement of the volume of distribution for 51Cr-EDTA. In patients treated with single-agent carboplatin or carboplatin plus vincristine, there was a significant sigmoidal relationship between AUC and thrombocytopenia (R2 = .56). CONCLUSION: GFR-based carboplatin dosing in children should be feasible and will be evaluated prospectively.

Adolescent↗
PubMed1992

High-dose methylprednisolone sodium succinate as a single agent in relapsed childhood acute lymphoblastic leukaemia.

Twenty children received methylprednisolone (1 g/m2), daily for 5 to 8 days, as initial single agent therapy for relapsed acute lymphoblastic leukaemia. Bone marrow blasts were reduced to less than 5% in 2 and 5-10% in 3 of 12 patients with bone marrow relapses. In 3/9 with central nervous system relapses the cerebrospinal fluid (CSF) blasts completely cleared and were reduced in 4 others. In two patients with testicular relapses there was shrinkage of tumour and one patient with a navicular bone relapse became pain free. Toxicity was minimal. These results indicate high-dose methylprednisolone is an effective agent, particularly in the treatment of established central nervous system (CNS) disease and could contribute to early CNS directed therapy in acute lymphoblastic leukaemia.

Administration, Oral↗
PubMed1992

Seizures and cortical dysfunction following high-dose cisplatin administration in children.

Four of eight children with advanced neuroblastoma treated with a rapid delivery high dose intensity cisplatin based regimen developed acute neurological toxicity. Three had seizures and one developed transient blindness. In the absence of other causes it seems probable that high dose cisplatin (200 mg/m2) as a continuous infusion over five days followed 10 days later by 80 mg/m2 infused over 48 hours was responsible. Other risk factors included an associated deterioration in renal function and neutropenia related fever.

Adrenal Gland Neoplasms↗
PubMed1992

Metastatic rhabdomyosarcoma and histologically similar tumors in childhood: a retrospective European multi-center analysis.

This is a retrospective analysis of children with metastatic soft tissue sarcoma (STS) registered in the major European STS studies: the SIOP MMT 75, the German CWS 1981 and 1986 studies, the Italian STS study, and the United Kingdom Children's Cancer Study Group centres in Britain. One hundred forty-six patients out of 164 were evaluable in this analysis. The median age was 7 years (1-18) and the male/female ratio was 1.3:1. The median follow-up was 80 months (7-171). The most common site of the primary tumor was the extremity (28%), which correlated well with the high preponderance (39%) of the alveolar type of RMS (aRMS). There was no dominant combination of metastatic sites and the most common single organ with metastasis was the lung (41%). Since the therapy depended on the country and period in which the patient was treated, we did not analyse the outcome and therapy together. Complete remission was achieved in 50% of the cases. Those with aRMS had a good chance of achieving CR (61%) but the majority of these patients relapsed (78%). The median time needed to relapse was 243 days (53 days to 47 months) for all patients. Analysis of the site of the primary tumor showed that the CR rate was best in the GU non-BP site (62%) and worst in PM cases (35%). The overall survival and DFS rate were 18% and 15%, respectively. The GU non-BP patients had a DFS rate of 50%, while the rate for all other sites varied between 12% and 18%. A total of 24 patients remained in CCR. The majority of them had embryonal type of RMS and metastases in only one anatomic site. Our analysis indicates that the best chance of prolonged survival was in metastatic GU non-BP cases, patients with embryonal type RMS, and those with metastases in only one organ. To try to improve the treatment of metastatic STS, a prospective European cooperative study was started in 1989.

Adolescent↗
PubMed1992

High-dose rapid schedule chemotherapy for disseminated neuroblastoma.

In a high-dose schedule for disseminated neuroblastoma, eight courses of chemotherapy were administered every 10 days, regardless of myelosuppression, to eradicate tumour cells rapidly and reduce emergence of drug-resistant clones. Relatively non-myelotoxic vincristine and cisplatin were alternated with high-dose cisplatin-etoposide and cyclophosphamide-etoposide. Of 12 evaluable patients, there were 1 complete (CR), 3 very good partial (VGPR), 5 partial (PR) and 3 mixed responses (MR) 100 days after starting treatment. 6 out of 9 achieved a bone marrow CR at 40 days. 9 of 11 primary tumours were completely resected, after which 4 patients had CR, 3 VGPR (bone scan alone being abnormal), 4 PR and 1 mixed response (MR). Myelotoxicity was the major adverse effect. The only death was due to fungal infection. Clinically important renal dysfunction occurred in 3 patients. 4 had convulsions and 4 temporary hypertension. This schedule produced a rapid response and its toxicity, though serious, was manageable. Further evaluation is warranted.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed1992

Pilot study of a rapid etoposide-cisplatin regimen in paediatric soft tissue sarcomas.

10 patients with refractory or relapsed soft tissue sarcoma were treated with weekly etoposide (150 mg/m2 on days 1, 2 and 3) and cisplatin (60 mg/m2 on day 2). Toxicity was mainly myelosuppression which resulted in deviation from planned weekly chemotherapy scheduling. With this rapid dose-delivery schedule the tolerated median dose intensities were 161 mg/m2 per week for etoposide and 49 mg/m2 per week for cisplatin. In 9 evaluable patients there were 7 responses, 2 complete and 5 partial, giving a response rate of 78% (confidence interval 51-100%). The combination of etoposide and cisplatin in this schedule produced a higher response rate than reported with previous schedules and is worthy of further evaluation.

Adolescent↗
PubMed1992

'VEEP' in children with Hodgkin's disease--a regimen to decrease late sequelae.

In an attempt to decrease the risk of second malignancies and future infertility in children with Hodgkin's disease (HD) while retaining acceptable remission rates, an anthracycline based regimen containing no alkylating agent has been devised. VEEP contains vincristine, epirubicin, etoposide and prednisolone given at 3 weekly intervals. Forty-four patients, aged 2-15 years, have been treated: ten relapsed patients and 34 previously untreated with chemotherapy (including three relapsed stage I treated initially with radiotherapy). The median follow up for all patients is 25 months (range 6-52 months). The response rate in previously treated patients was 80% (95% CI 44-97%) and five remain alive in remission. The response rate in untreated patients was 88% (95% CI 72-97%) with 62% CR + CR(u) (uncertain/unconfirmed) (95% CI 44-77%). Of four patients who had a final response of CR(u) three have relapsed at 9, 16 and 38 months. Two of the children in CR have relapsed at 6 and 16 months. The relapse free rate at 3 years is 67% (95% CI 17-82%). In this pilot study the event free survival appears somewhat poorer than conventional combinations and further follow up is required to confirm the salvagability of relapsed patients.

Adolescent↗
PubMed1992

Treatment of advanced stage T cell lymphoblastic lymphoma: results of the United Kingdom Children's Cancer Study Group (UKCCSG) protocol 8503.

Ninety-five unselected patients with stage III and IV T cell lymphoblastic lymphoma were treated according to the United Kingdom Children's Cancer Study Group protocol 8503. This was a continuous, intensive leukaemia type regimen including cranial irradiation (18 Gy in 10 fractions) and continuing chemotherapy for 2 years identical to the concurrent Medical Research Council ALL protocol. Four-year event-free survival was 65% (95% CI 50-80%) with no significant difference between stage III and stage IV cases. 4.2% of patients died of infection or non-tumour related events. Following relapse salvage was unlikely without high dose chemotherapy and bone marrow rescue. These results show an improvement over previous U.K. studies but we need to continue to search for subsets of patients with resistant disease for whom even more intensive therapy possibly combined with bone marrow rescue is required.

Adolescent↗