Biomedical subjects

S E Ashley

Publications and source records attributed to S E Ashley.

32 records · Page 2Linked to original sources

PubMed1993

A toxic interaction between mitomycin C and tamoxifen causing the haemolytic uraemic syndrome.

A comparison of patients receiving combination chemotherapy with mitomycin C, mitozantrone and methotrexate (3M) with and without tamoxifen for treatment of primary breast cancer indicates an increased risk of anaemia (P < 0.0001) and thrombocytopenia (P < 0.001), but not leucopenia for patients receiving tamoxifen with their chemotherapy compared to those receiving the chemotherapy alone. Furthermore, 9 out of 94 patients receiving tamoxifen with 3M developed progressive anaemia, thrombocytopenia and abnormal renal function as early features of microangiopathic haemolytic anaemia, progressing on to various degrees of the haemolytic uraemic syndrome (HUS). This is only rarely seen with patients receiving mitomycin C alone at higher doses than used in the 3M combination and in the presence of active metastatic disease. This syndrome can be fatal and 1 of our 9 patients died. These observations indicate that there may be an interaction between tamoxifen and mitomycin C, causing an increased incidence of anaemia, thrombocytopenia and an increased risk of HUS. The combination of these two drugs should be avoided or carefully monitored.

Adult↗

PubMed1992

Intracranial ependymoma: long-term results of a policy of surgery and radiotherapy.

Ninety-three patients with primary intracranial ependymoma were treated at the Royal Marsden Hospital, between 1952 and 1988, with postoperative radiotherapy. The survival probability at 5, 10, and 15 years was 51%, 42% and 31%, respectively, and the corresponding progression free survival (PFS) probability, 41%, 38%, and 30%. Tumor grade was the single most important prognostic factor for survival and PFS with gender of lesser prognostic significance. Treatment parameters were stratified for grade. In patients with low grade tumors survival and PFS were better following complete macroscopic excision compared to incomplete surgery. The extent of resection had no significant influence on survival or PFS in patients with high grade tumors. Extent of irradiation did not influence PFS, irrespective of tumor grade, while patients with high grade tumors had marginally better survival following extensive irradiation compared to more limited radiotherapy. The main problem in the treatment of ependymoma remains local progression which was the cause of death in all but two patients. New treatment strategies should focus on improvement of local control, especially in incompletely resected low grade tumors and all high grade tumors. The use of spinal irradiation is unlikely to significantly improve treatment results.

Adolescent↗

PubMed1992

Haemostatic changes and thromboembolic risk during tamoxifen therapy in normal women.

Tamoxifen has been implicated as a risk factor for venous thrombosis in advanced breast cancer although the evidence for increased arterial or venous thrombosis with tamoxifen in early breast cancer is less clear. The effect of tamoxifen on haemostasis, and thereby possible thromboembolic risk, was investigated in normal women enrolled in a placebo controlled trial of tamoxifen as a chemopreventative agent for breast cancer. There was an initial reduction in fibrinogen levels in all women on tamoxifen over the first year of follow-up and a marginal reduction in antithrombin III and Protein S in postmenopausal women at 6 months. There were no changes in cross linked fibrinogen degradation products or Protein C for pre or post-menopausal women. There was no increase in the incidence of thromboembolic events on tamoxifen. This study demonstrates that tamoxifen has only marginal effects on factors involved in haemostasis reported to affect the incidence of arterial or venous thromboembolic disease. The follow-up time is relatively short (maximum 36 months) and careful long term follow-up is necessary to detect clinically significant morbidity.

Antithrombins↗

PubMed1991

A randomised trial comparing combination chemotherapy using mitomycin C, mitozantrone and methotrexate (3M) with vincristine, anthracycline and cyclophosphamide (VAC) in advanced breast cancer.

This paper describes a randomised clinical trial in patients with advanced breast cancer, comparing the regimen 3M, mitomycin C 7-8 mg m-2 (day 1), mitozantrone 7-8 mg m-2 (day 1 and 21), methotrexate 35 mg m-2 (day 1 and 21) given on a 42 day cycle with a standard anthracycline containing regimen, VAC, vincristine 1.4 mg m-2 (day 1), anthracycline (adriamycin or epirubicin) 30 mg m-2 (day 1), cyclophosphamide 400 mg m-2 (day 1) given on a 21 day cycle. Of a total of 217 patients, 107 were randomised to 3M and 110 to VAC and a mean of 5.5 courses was given per patient. The overall response rate (complete and partial) was 53% (95% Confidence Limits (CL): 43-62%) for 3M and 49% (CL; 39-58%) for VAC. The response according to sites of metastases was the same for both treatment groups. Symptomatic toxicity including alopecia, neuropathy, vomiting (P less than 0.001) and nausea (P less than 0.01) were significantly less for 3M. Myelosuppression including leucopenia (P less than 0.001) and thrombocytopenia (P less than 0.001) was significantly greater with 3M at day 21, although there was no difference in nadir counts in patients at special risk of myelosuppression and there was no evidence of an increase in infective or bleeding complications. There was no significant difference in the duration of response to 3M (10 months, CL 6-15) and VAC (11 months, CL 7-12), nor in survival (3M, 8 months, CL 6-12; VAC, 10 months, CL 8-12). These results indicate that 3M is as effective as, but has significantly less symptomatic toxicity than, an anthracycline containing regimen for the treatment of advanced breast cancer.

Adult↗

PubMed1991

Anthrapyrazole CI941: a highly active new agent in the treatment of advanced breast cancer.

Thirty-one patients with advanced breast cancer were treated with CI941, an anthrapyrazole structurally related to mitoxantrone. Patients had not previously been treated with anthracyclines or mitoxantrone, and 15 patients had not received any previous cytotoxic chemotherapy. CI941 was given at a dose of 50 mg/m2 by intravenous bolus injection every 21 days. Thirty patients were assessable for response, and all were assessable for toxicity. Two patients (7%) had complete responses (CRs), and 17 (56%) achieved partial responses (PRs; overall response rate, 63%; 95% confidence interval, 46% to 81%). The response rates in patients with and without prior chemotherapy were 63% and 64%, respectively. The median response duration was 37 weeks from start of treatment, with a maximum response duration of greater than 70 weeks. Median survival has not yet been reached. Leukopenia was the most frequently encountered toxicity, with a World Health Organization (WHO) grade greater than 3 occurring in 74% of courses. Thrombocytopenia and anemia were negligible. Only 10 patients (32%) had alopecia severe enough to wear a wig. There were no cardiac symptoms or events in any patient, but a slight median fall in left ventricular ejection fraction (LVEF) of 6% (from +7 to -12) during stress and 6% (from +14 to -14) at rest occurred. Other toxicities were mild, and the drug was generally well tolerated. CI941 is a very active and well-tolerated new agent in the treatment of advanced breast cancer, with neutropenia being the main toxicity.

Adult↗

PubMed1991

Postoperative radiotherapy in the management of spinal cord ependymoma.

Fifty-eight patients with histologically verified spinal cord ependymomas were treated at the Royal Marsden Hospital and Atkinson Morley's Hospital between 1950 and 1987. The median age in this series was 40 years (range 1 to 79 years) and the male:female ratio was 1.8:1. Ten patients had tumors in the cervical cord and 10 in the thoracic cord; 14 tumors involved the conus medullaris and 24 the cauda equina. Forty ependymomas were grade I and 13 were grades II to IV (in five patients there was insufficient material for grading). Eleven patients underwent biopsy only, 33 had partial or subtotal resection, and 14 had complete resection. Forty-three patients received postoperative radiotherapy. The median follow-up period was 70 months (range 3 to 408 months). Cause-specific survival rates were 74% and 68% at 5 and 10 years, respectively. On univariate analysis, age, histological grade, postoperative neurological function, and era of treatment were significant prognostic factors for survival. The histological grade was the only significant independent prognostic factor. The relative risk of death from ependymoma was 9.0 for patients with tumor grades II to IV compared to grade I (p less than 0.005, 95% confidence interval 2.7 to 30). The survival rates of patients following complete excision were significantly better compared to those after incomplete surgery (p less than 0.025). The majority of completely resected neoplasms were low-grade cauda equina tumors. Despite incomplete surgery, 5- and 10-year progression-free survival rates following radical radiotherapy were both 59%, and cause-specific survival rates were 69% at 5 years and 62% at 10 years. This suggests that radiotherapy may achieve long-term tumor control in over half of those patients with residual spinal ependymoma.

Adolescent↗

PubMed1990

Prevention of breast cancer with tamoxifen--an update on the Royal Marsden Hospital pilot programme.

An 'anti-oestrogen' such as tamoxifen may protect prophylactically against breast cancer. At the Royal Marsden Hospital, the blind randomised feasibility study of tamoxifen 20 mg per day versus placebo in 200 healthy women has been extended into a pilot trial. A total of 435 women with a family history of breast cancer have been accrued. Compliance, acute toxicity, clotting factors, lipids and bone mass were assessed. The pilot trial has confirmed the findings of the feasibility study. Compliance was high and the frequency of side-effects was similar in both groups, except for a significant increase in hot flushes in the tamoxifen-treated women (33 vs. 17%). Bone mass and clotting factors were not affected. Tamoxifen significantly reduced serum cholesterol, low-density lipoprotein cholesterol (LDLC) and apolipoprotein B levels in post-menopausal women. In premenopausal women, the effects on lipids and lipoproteins was smaller with a significant fall in total serum cholesterol and LDLC only. The trial has approval to accrue up to 1000 women.

Breast Neoplasms↗

PubMed1990

Combination of tamoxifen, aminoglutethimide, danazol and medroxyprogesterone acetate in advanced breast cancer.

Seventy-four post-menopausal women with metastatic breast cancer were treated with a combination hormonal regimen consisting of tamoxifen, aminoglutethimide danazol and medroxyprogesterone acetate (POND). 72% of the patients had received no previous treatment. The overall response rate (complete and partial remission) was 43.5% with a median response duration of 19 months and a median survival of 27 months. The most common sites of response were in regional nodes and local chest wall disease. The major side-effects were those expected from the individual agents: nausea, lethargy, rash and oedema.

Aged↗

PubMed1990

The treatment and long-term prognosis of children with intracranial tumors: a study of 610 cases, 1950-1981.

Six hundred and ten children aged under 16 years with intracranial tumors were referred for radiotherapy between 1950 and 1981: 579 were new cases and 31 had recurrent disease after primary treatment elsewhere. Radiotherapy was completed in 93% of all cases. The actuarial survival rate for all new cases was 53% at 5 years, 46% at 10 years, 40% at 20 years, and 39% at 30 years. The oldest children (10-15 years) had the best survival and the youngest (0-2 years) had the worst survival. Children treated with megavoltage x-ray equipment (1970 to 1981) had a significantly greater survival than those treated with orthovoltage X rays (1950-1969). Overall, a direct correlation was found between survival and maximum radiotherapy dose. Children having a total excision of the tumor prior to radiotherapy showed a greater survival than those treated by a subtotal or partial tumor removal. Children treated by radiotherapy alone had a survival comparable to those treated by sub-total excision and radiotherapy. There is a striking difference in survival expectation depending on initial functional category (I to III). The overall survival rates of 428 children completing treatment for glioma were 49% at 5 years, 43% at 10 years, and 40% at 15 years. The results according to certain specific tumor sites within the cerebral hemispheres are reported. Age is an important prognostic factor in low grade and also high grade astrocytomas, children having longer survivals than adults. Sub-total or partial excision of craniopharyngiomas combined with radical radiotherapy appears to give the best long-term results. Of 73 new cases, the 5-, 10-, and and 15-year survival rates were 92%, 84%, and 79%. Recurrent craniopharyngiomas treated by surgery alone can be salvaged by further conservative surgery and radical radiotherapy. Optic gliomas are slow growing low grade astrocytomas. Survival rates at 5, 10, and 15 years for 20 children with mostly chiasmal lesions were 89%, 89%, and 78%, respectively. In 73 children with brain stem tumors, 17% remained alive for up to 15 years. The risk of CNS seeding from intracranial ependymomas depends on site of origin and grade of malignancy, with 50% incidence occurring in cases with high grade lesions situated in the posterior fossa. Survivals at 5, 10, and 15 years in 51 children were 51%, 40%, and 31%. Adjuvant chemotherapy improves survival.(ABSTRACT TRUNCATED AT 400 WORDS)

Adolescent↗

PubMed1989

Phase I trial and pharmacokinetics of trimelamol (N2,N4,N6-trihydroxymethyl-N2,N4,N6-trimethylmelamine).

Trimelamol is an analogue of hexamethylmelamine and pentamethylmelamine which does not require metabolic activation and is sufficiently soluble to allow parenteral administration. A Phase I trial has been performed at the Royal Marsden Hospital in which two schedules of administration have been evaluated, a single i.v. infusion repeated every 3 weeks and 3 daily doses repeated every 3 weeks. Pharmacokinetic analysis was performed at all dose levels on both schedules and a linear correlation was demonstrated between dose and area under the curve. Myelosuppression was dose limiting for single dose administration with a maximum tolerated dose of 2400 mg/m2. Median leukocyte nadirs at 1800, 2100, and 2400 mg/m2 were 3.2, 2.6, and 1.5 x 10(9)/liter. Thrombocytopenia and anemia also occurred but were not dose limiting. Doses greater than 1500 mg/m2 caused WHO grade 3 nausea and vomiting but no acute sedation. Three day administration appeared to be less myelosuppressive, giving a maximum tolerated dose of 1000 mg/m2. Median leukocyte nadirs at 800, 900, and 1000 mg/m2 daily for 3 days were 3.0, 2.3, and 1.5 x 10(9)/liter. Nonhematological toxicities were also less marked on the fractionated schedule. Antitumor effects were observed including 1 complete and 9 partial responses. Demonstration of activity in ovarian cancer has led to further evaluation in this disease using the 3-day schedule at a dose of 800 mg/m2 daily for 3 days.

Adult↗

PubMed1989

Chemoprevention of breast cancer.

The hypothesis that oestrogen is an important promoter of human breast cancer raises the possibility that endocrine intervention could prevent the disease. Various methods of reducing oestrogenic activity have been proposed including dietary control, progestin therapy, and ovarian ablation. Tamoxifen is a synthetic anti-oestrogen of low toxicity with proven anti-proliferative activity in endocrine sensitive breast cancer which makes it an attractive alternative for a trial of endocrine prevention. We have undertaken a double-blind placebo-controlled pilot study to assess the feasibility of mounting a large multicentre study of tamoxifen in the prevention of breast cancer in high risk women. Two hundred women were randomised to tamoxifen or placebo during an 18 month accrual period. Acute toxicity was mild and serial studies of blood lipids, clotting factors, and bone mineral density suggested that no long-term deleterious effects are likely to be seen. It is estimated that 10,000 women would be required with a 10-15 year follow up in order to detect a 25% prevention effect.

Adult↗

PubMed1989

A pilot trial to evaluate the acute toxicity and feasibility of tamoxifen for prevention of breast cancer.

Epidemiological and experimental evidence indicates that oestrogens are involved in the carcinogenic promotion of human breast cancer. We have undertaken a pilot trial of tamoxifen, an anti-oestrogen, compared to placebo given to 200 women at a high risk of developing breast cancer. The results of this trial show that acute toxicity is low and that accrual and compliance are satisfactory. Furthermore, biochemical monitoring of lipids and clotting factors indicate that tamoxifen may reduce the risk of cardiovascular deaths. At this stage no untoward long-term risks have been identified, and it is therefore proposed that a large multicentre trial should be started.

Adult↗

PubMed1988

Carboplatin (JM8), etoposide (VP16) and thoracic irradiation for small cell lung cancer (S.C.L.C.): an evaluation of lung toxicity.

Carboplatin (JM8) and etoposide (VP16) have demonstrated activity against a range of solid tumours. A retrospective study has looked for evidence of enhanced radiation pneumonitis when these drugs are employed in conjunction with irradiation. Twenty-nine patients with limited disease small cell lung cancer (S.C.L.C.) received JM8 (300 mg/m2) and VP16 (300 mg/m2) at intervals of 3-4 weeks for 4 cycles followed by thoracic irradiation. Twenty-one were evaluated and compared with 21 matched non-S.C.L.C. patients treated by radiotherapy alone. Patients were stratified into three groups according to the radiation dose schedule normalised using Wara's modification of Ellis' formula (n = 0.38, t = 0.06) [28]. Group 1 received less than 1014 rets, Group 2 1015-1250 rets and Group 3 greater than 1250 rets. Radiological pneumonitis was observed in 57% (12/21) of patients receiving combined modality treatment compared to 71% (15/21) of patients receiving radiation alone with evidence of a radiation dose-response relationship for the appearance of pneumonitis in both groups of patients (p greater than 0.1). In conclusion, no enhancement of radiation pneumonitis by carboplatin (JM8) or etoposide (VP16) has been observed.

Adult↗

PubMed1987

Prognostic factors in small cell lung cancer: a simple prognostic index is better than conventional staging.

Conventional staging in small cell lung cancer (SCLC) is only of limited prognostic value and is often based on elaborate investigations. We have carried out univariate and multivariate analysis of possible prognostic factors at presentation in 333 consecutive patients with SCLC. Fifteen parameters were found to have individual prognostic significance, of which the most powerful were serum albumin, bone marrow aspirate, disease extent and performance status (all P less than 0.00005). Factors which were not of prognostic significance included age, sex, SVC obstruction, and pleural involvement. Multivariate analysis excluded many factors including bone marrow aspirate as not being independently variable, and a simple combination of clinical performance status, serum albumin and alanine transaminase could be used to define 3 groups (good; medium; poor) of better prognostic significance (survival at 1 year 50% vs. 27% vs. 3%) than conventional limited/extensive disease staging (1 year survival 48% vs. 18%). Other simple combinations of biochemical parameters including plasma sodium and alkaline phosphatase achieved almost as good prognostic groupings. We suggest that consideration should be given to replacing the conventional limited/extensive disease staging system with a simpler system along the lines we have described.

Adult↗