Stopping rules, interim analyses and data monitoring committees.
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Advisory Committees↗
Biomedical subjects
D Machin
Publications and source records attributed to D Machin.
A randomised trial of three or six courses of etoposide cyclophosphamide methotrexate and vincristine or six courses of etoposide and ifosfamide in small cell lung cancer (SCLC). I: Survival and prognostic factors. Medical Research Council Lung Cancer Working Party.
A total of 458 eligible patients, from 21 centres, with histologically or cytologically confirmed SCLC were allocated at random to three chemotherapy regimens, each given at 3-week intervals. In two regimens, etoposide, cyclophosphamide, methotrexate and vincristine were given for a total of either three courses (ECMV3) or six courses (ECMV6). In the third regimen, etoposide and ifosfamide were given for six courses (EI6). Patients with limited disease (56% of the total) also received radiotherapy to the primary site after the third course of chemotherapy in all three groups. A partial response occurred in 45% of 144 ECMV3 patients, 48% of 141 ECMV6, and 53% of 141 EI6 patients assessed, and a complete response in a further 15%, 9%, and 13% respectively, giving total response rates of 60%, 57%, and 67%, respectively. There was no overall survival advantage to any of the three regimens. At 1 year, 24%, 29%, and 30% of patients were alive, and at 2 years 7%, 8%, and 9%, respectively. The median survival time was 7.4 months in the ECMV3 group, 8.6 months in the ECMV6 group and 8.8 months in the EI6 group. The individual factors: poor performance status, extensive disease, the presence of dysphagia and a raised white blood cell count on admission adversely affected prognosis. The results do not exclude the possibility of a minor survival advantage with the two 6-course regimens. The findings on quality of life are presented in the companion paper (MRC Lung Cancer Working Party, 1993b).
Adult↗
A randomised trial of three or six courses of etoposide cyclophosphamide methotrexate and vincristine or six courses of etoposide and ifosfamide in small cell lung cancer (SCLC). II: Quality of life. Medical Research Council Lung Cancer Working Party.
A total of 458 eligible patients, from 21 centres, with microscopically confirmed SCLC were allocated at random to three chemotherapy regimens, each given at 3-week intervals. In two regimens, etoposide, cyclophosphamide, methotrexate and vincristine were given for a total of either three courses (ECMV3) or six courses (ECMV6). In the third regimen, etoposide and ifosfamide were given for six courses (E16). Patients with limited disease also received radiotherapy to the primary site after the third course of chemotherapy in all three groups. As reported by clinicians, 59% of the ECMV3, 67% of the ECMV6 and 63% of the EI6 patients experienced moderate or severe adverse reactions to their chemotherapy. The major symptoms of disease, cough, haemoptysis, chest pain, anorexia, and dysphagia, were palliated in 63% or more of patients and the median duration of palliation was 63% or more of survival, the results being similar in the three groups. Among patients with poor overall condition, physical activity and breathlessness on admission, the proportions who improved were higher in the EI6 group but the differences were small. In all three groups, levels of anxiety fell substantially during treatment. Levels of depression were lower and showed little change. As assessed by patients using a daily diary card, the patterns of nausea, vomiting, activity and mood, associated with courses of chemotherapy were very similar in the three groups. In the EI6 group there was less dysphagia and better overall condition between courses, but these advantages need to be weighed against the inconvenience of the 24-h infusions required, compared with the 30-min infusions of the other two regimens. As reported in the companion paper (MRC Lung Cancer Working Party, 1993a) there was no statistically significant survival advantage to any of the three regimens, although the results do not exclude the possibility of a minor survival advantage with the two six-course regimens. In conclusion, there was no major clinical gain from continuing chemotherapy beyond three courses or from using the ifosfamide regimen.
Adult↗
A simulated sequential analysis based on data from two MRC trials.
The motivation for proposing sequential methods for cancer clinical trials is presented, and the methodology examined by re-analysing two completed phase III cancer trials of the Lung Cancer Working Party of the British Medical Research Council. The reanalysis proceeds as if the trials had been designed with a planned series of interim analyses governing stopping. Specifically, the triangular and double-triangular tests were applied. The sequential reanalysis gave a substantial reduction in the number of patient required, and deaths observed, for conclusions to be reached in comparison with the completed studies. In each case, the sequential analysis was stratified for baseline prognostic factors which were seen to be important at the first interim analysis.
Antineoplastic Combined Chemotherapy Protocols↗
Deprivation and general practitioner workload.
OBJECTIVES: To examine general practitioner consultations by demographic and socioeconomic variables and to derive a method of measuring the impact of relative deprivation on general practitioner workload. DESIGN: The study was based on general practitioner consultations reported in the general household surveys of 1983-7, covering a sample of 129,987 individuals in Great Britain. Odds ratios for general practitioner consultations were obtained for selected variables among children (0-15 years), men (16-64), women (16-64), and elderly people (greater than or equal to 65). These were then used to derive deprivation indices specific to electoral wards for use in general practice. SETTING: Great Britain, with particular findings illustrated by English electoral wards and the conurbations of London, Manchester, Merseyside, and the West Midlands. RESULTS: Council tenure increased the likelihood of consultation significantly in all four groups. Odds ratios were raised in children, men, and women with no access to a car. Birth in the New Commonwealth or Pakistan yielded high odds ratios in men, women, and elderly people but not in children. Marginally increased consultation rates were evident in the manual socioeconomic groups in women, elderly people, and children with a single parent mother. The deprivation indices for general practice derived using these odds ratios varied substantially among English electoral wards with, for example, anticipated general practitioner consultations in the electoral ward of Hulme, Manchester, being 24% higher than the average ward in England as a result of local attributes, and consultations in the Cheam South ward of Sutton, London, 11% lower than average. CONCLUSION: This deprivation index for general practice overcomes several shortcomings expressed about the underprivileged area score, which has been adopted in the 1990 contract as a basis for allocating deprivation supplements to general practitioners. The proposed index can be applied nationwide.
Adolescent↗
Improving communications in clinical oncology: the EuroCODE project. The EuroCODE Steering Committee.
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Communication↗
Health risks associated with bathing in sea water.
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Adolescent↗
Coping with extra Poisson variability in the analysis of factors influencing vaginal ring expulsions.
The vaginal ring is one method of contraception currently under investigation and development by the Human Reproduction Programme of WHO. One factor that reduces its acceptability is that some women experience involuntary expulsions of the ring. WHO have collected prospective data on 1005 women from 19 centres worldwide to investigate various aspects of ring use including factors that might affect expulsions. For each subject the data include number of expulsions, age, parity, ponderal index, number of days of ring use and health care centre. To model the factors influencing expulsion, the number of expulsions was first considered as a Poisson variate with mean directly proportional to the log of the duration of ring use. Such a model gave a poor description of the data and it appeared that the number of expulsions was considerably over-dispersed for an assumed Poisson variate. This paper examines a variety of strategies for coping with the resulting lack of fit of the model. It turns out that a truncated Poisson model gives a better description of the expulsion data and that health care centre and parity influence the rates.
Contraceptive Devices, Female↗
A Medical Research Council phase II trial of alternating chemotherapy and radiotherapy in small-cell lung cancer. The Medical Research Council Lung Cancer Working Party.
In a non-randomised study in six centres in the UK, 24 patients with previously untreated small-cell lung cancer of limited extent were treated with a regimen of alternating chemotherapy and radiotherapy to assess response, toxicity, and the feasibility of applying such a regimen on a multicentre basis in the UK. The intention was to give six courses of chemotherapy on five consecutive days at 4-week intervals: etoposide 75 mg m-2 on days 1, 2, and 3; doxorubicin 40 mg m-2 on day 1; cisplatin 100 mg m-2 on day 2; and cyclophosphamide 300 mg m-2 on days 2, 3, 4 and 5. A dose of 20 Gy thoracic radiotherapy was to be given following the 2nd and the 3rd courses, and one of 15 Gy following the 4th course. After 12 patients had been admitted, the cisplatin dosage was reduced to 80 mg m-2 because of unacceptable toxicity. Two patients were withdrawn during treatment on review of their histology because their diagnosis was found to be incorrect. Only one patient of the 12 treated with cisplatin 100 mg m-2 was able to complete treatment, compared with five of the eligible ten given the lower dosage. Among the 22 patients with confirmed small-cell disease, a complete response was reported in 14 (64%) and a partial response in a further three (total response rate 77%). Myelosuppression was the commonest serious adverse effect. It occurred in 19 of the 24 patients and gave rise to septicaemia in five, four of whom were receiving the higher cisplatin dose. Sixteen patients required blood transfusion and ten platelet transfusion. Vomiting, oesophagitis, and peripheral neuropathy occurred in 12, four and four patients, respectively, and radiation pneumonitis developed in two. Treatment was considered a contributory cause of death in four. The working party concluded that the alternating regimen was feasible in only a small proportion of centres in the UK, and decided not to embark on a multicentre randomised trial comparing alternating with conventional scheduling.
Activities of Daily Living↗
The use of logit models to investigate social and biological factors in infant mortality. V: A multilogit analysis of stillbirths, neonatal and post-neonatal mortality.
Infant mortality data for England and Wales, cross classified by mother's age, parity and social class were published for 1949/50 and 1975. Previous analyses of these data have been based on graphical, tabular and logit models of stillbirths, neonatal and post-neonatal deaths separately. This paper summarizes the overall changes in infant mortality using a multilogit model. The model selected is illustrated by appropriate graphical presentations.
Adolescent↗
Inequalities in health: socioeconomic differences in self-reported morbidity.
Socioeconomic differences in self-reported chronic and acute illness were investigated in men and women using data from the General Household Surveys (1981-4). Logit models were used to investigate the influence of age, socioeconomic group, tenure, access to cars, area of residence and marital status on these measures of morbidity. For both measures local authority tenants, whether male or female, reported the most morbidity as did those with no access to cars. Both males and females reported increasing levels of illness the lower their socioeconomic group but similar patterns were not observed with acute illness. The significance of these present day inequalities is discussed.
Adolescent↗
Improving house physicians' assessments of self-poisoning.
A questionnaire was developed to help the assessment of patients who take overdoses. Twenty-four house physicians in Southampton university hospitals were randomly divided into a group who used the questionnaire and another group who asked whatever questions they felt appropriate. One hundred and fifty patients who had taken overdoses were included in the study. After the house physician's assessment, a research assistant interviewed all of the patients and the two assessments for each patient were then compared. There was greater agreement between the research assistant and the house physicians who used the questionnaire than those who interviewed patients in an unstructured way with respect to assessments of severity of depression, purpose of the act, suicidal intent, diagnosis, and future management.
Adult↗
Heart valve measurement at autopsy can distinguish cardiac from non-cardiac causes of death.
The circumferences of the four intact cardiac valves were measured during 397 coroner's autopsies using an obturator cone to assess the value of this measurement in the postmortem diagnosis of cardiac disease. Valve sizes of cases with cardiac and noncardiac causes of death were compared using logistic regression to assess the effects of confounding variables including sex, age, height, build and the presence of chronic obstructive airways disease. Mitral valve enlargement was found to be significantly associated with cardiac death, as were build, age, and sex. Measurement of the mitral valve at autopsy can help distinguish cardiac from noncardiac causes of death.
Age Factors↗
Calculating confidence intervals for survival time analyses.
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Follow-Up Studies↗
The autopsy: a useful tool or an old relic?
In a combined retrospective and prospective study, clinical and autopsy data were collected to assess the changes in autopsy rate in recent years, the attitudes of clinicians and pathologists to the autopsy, and the accuracy of ante-mortem diagnosis when compared with autopsy findings. Between 1962 and 1986, the total autopsy rate for hospital patients remained relatively constant, with an increase in Coroner's and a decrease in the hospital autopsy rate. Analysis of 5064 deaths over a 6-year period showed a significantly greater number of males than females coming to autopsy and a decrease in autopsy rate with age for both sexes. Attitudes to the autopsy were assessed using a questionnaire. The majority of clinicians considered the autopsy to be an important investigation despite new diagnostic techniques and confirmed its value in teaching and research. Seventy-seven per cent agreed that autopsy findings occasionally led to modification of the treatment of subsequent patients with the same condition. Pathologists disagreed that the autopsy is outdated in its present form and considered that not enough hospital autopsies are being requested. They also upheld its use and value in education. The cause of death as given by clinicians for a group of 60 patients was inaccurate in 12 cases.
Adult↗
Improving the quality of data in randomized clinical trials: the COMPACT computer package. COMPACT Steering Committee.
One crucial component for a successful clinical trial is that the data gathered have a high level of reliability and completeness. This paper reviews some problems of data management and describes the computer package COMPACT which has been developed to deal with such problems. The package allows range and consistency checks and can monitor complex follow-up schedules. A unique feature of the package is a PROBLEMS file which has use both for identification of queries about the data and of patients with particular characteristics of interest. The ability to monitor drug dosages and to signal deviations from the protocol is of particular value. COMPACT has the syntax necessary to create a 'flat' file for transfer to statistical packages for analysis, and the variable description files for SAS, SPSS and MINITAB. The package is written in standard FORTRAN which enables transfer to different types of mini and micro computer systems.
Clinical Trials as Topic↗
A micro-computer software for the analysis of menstrual diaries: the menstrual diary system.
A microcomputer software was developed to analyse menstrual diaries following the reference period method as described in the article "The analysis of vaginal bleeding patterns induced by fertility regulating methods" published in this journal (Contraception, 34:253-260, 1986). The programme allows the analysis of groups of diaries selected according to subjects' characteristics recorded at commencement of the diary. It also offers flexibility in selecting options of analysis within the reference period method. The output can be presented graphically as Box-whisker plots. A tutorial is included in the package.
Contraception↗
Assessing changes in vaginal bleeding patterns in contracepting women.
In clinical trials comparing alternative contraceptive methods, women often discontinue for disturbances in menstrual bleeding patterns. Vaginal bleeding diaries have been used to monitor these patterns, and this paper suggests two new methods of analysis of these data. One analysis measures trends over time in the occurrence of specific patterns and, a second analysis, the relation between a woman's current experience and the probability of continuing method use. Contrasts between these approaches and the reference period method of analysis are made. A randomised clinical trial of the relative efficacy of 100 and 150 mg doses of depot-medroxyprogesterone acetate (DMPA) is used for illustration.
Amenorrhea↗