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Biomedical subjects

D Machin

Publications and source records attributed to D Machin.

At least 109 records · Page 6Linked to original sources
PubMed1994

Treatment-related deaths in small cell lung cancer trials: can patients at risk be identified? Medical Research Council Lung Cancer Working Party.

OBJECTIVES: This paper investigates the problem of treatment-related deaths in small cell lung cancer (SCLC). DESIGN: To observe and define increased hazard levels, and to identify factors relating to these excess deaths. SETTING: The United Kingdom. SUBJECTS: A total of 2196 patients entered into the series of six randomised clinical trials in SCLC conducted by the Medical Research Council (MRC) Lung Cancer Working Party (LCWP). RESULTS: In this large series of patients an increased risk of death in the second week after commencing the first cycle of chemotherapy was observed, suggesting that of the 10% of patients who died within 3 weeks of starting chemotherapy, half may have been treatment-related. Much less additional risk was associated with subsequent cycles of chemotherapy, and no additional risk with either initial surgery or radiotherapy. Radford et al. [Eur J Cancer 1993; 29A: 81-86] suggested that the risk factors for death from sepsis were a Karnofsky Performance (KP) score of < or = 50 (translated as a WHO performance grade (PS) > or = 3), age > 50 years and three or more drugs in the chemotherapy regimen utilised. Starting with this model we found that our data suggest it can be refined by omitting age and including a white blood cell count > or = 10,000/mm3 (this variable was not tested by Radford), and changing the other categories to WHO PS > or = 2 (KP < or = 70), and four or more drugs. Within our data this revised model identified a high risk group of patients with an excess death rate of more than 15% in the second week after starting chemotherapy. Radford et als' suggestion that high risk patients be given half doses of drugs at the first cycle should be tested in a randomised clinical trial.

Aged↗
PubMed1994

Statistical methods for clinical trials.

The object of this paper is to describe the essential features for the design and conduct of clinical trials. We include aspects of patient eligibility, random allocation to treatment including the principle of uncertainty, assessment of endpoints including those observed at different time points for each patient and trial size. Indications of appropriate methods of analysis are given, and the intention to treat principle is discussed. Some pointers to difficulties associated with data collection and management are included.

Clinical Trials as Topic↗
PubMed1994

Does clinical experience with a treatment regimen affect survival of lung cancer patients? An analysis based on consecutive randomized trials of the Medical Research Council in small cell and non-small cell tumours. Medical Research Council Lung Cancer Working Party.

This paper investigates the influence on patient survival of an individual clinician's experience with a particular treatment regimen and the collective experience of the centre through which the patient is recruited to a particular clinical trial. Data were available from two series of randomized trials, one series in small cell and the other in non-small cell lung cancer, which were conducted by the Medical Research Council Lung Cancer Working Party. Successive small cell trials used the same chemotherapy regimen and successive non-small cell trials the same radiotherapy regimen. We found no evidence that either the degree of experience of individual clinicians with the regimen or the participation in terms of number of patients recruited to centres influenced patient survival. There is a strong suggestion, in non-small cell lung cancer that, as clinicians' experience with the regimen extended, they became increasingly likely to admit patients in poor condition to the trials. We stress how important it is to take account of patient prognostic characteristics in such an analysis, as we found that unadjusted comparisons suggested negative influences of increasing experience with the regimen. The implications for routine audit are self evident, in particular that it is not a substitute for the randomized controlled trial.

Aged↗
PubMed1994

Prophylactic supraclavicular fossa radiotherapy in early breast cancer: is it worthwhile?

A total of 291 consecutive patients with early breast cancer who did not receive any supraclavicular prophylactic irradiation of the ipsilateral fossa have been followed for a minimum of 5 years. Isolated relapse in that site occurred in 4.5% of patients and was controlled by radical radiotherapy with a post-relapse 5-year survival of 33%. Relapse with co-existing distant metastases occurred in a further 7% and no patient survived to 3 years. Supraclavicular fossa irradiation contributes to morbidity, does not improve survival and should be abandoned in favour of delayed treatment for proven recurrence.

Adult↗
PubMed1994

Can long-term survival be improved in patients with small-cell lung cancer (SCLC) and good performance status? Medical Research Council Lung Cancer Working Party.

Results from a long-term follow-up suggest that in patients with limited small-cell lung cancer (SCLC) and normal performance status intensive alternating chemotherapy and radiotherapy improve long-term survival rates. In a non-randomised study, 22 patients with SCLC of limited extent and good performance status were prescribed six cycles of etoposide, doxorubicin, cisplatin and cyclophosphamide at 4 week intervals with doses of thoracic radiotherapy following the second, third and fourth cycles. Although only six patients received all their prescribed treatment, nine (41%) were alive at 1 year, seven (32%) at 2 years, six (27%) at 3 years, and four are still alive at, respectively, 42, 47, 50, and 61 months, all four being in the subgroup of eight patients with WHO performance status grade 0 at the start of treatment. In a comparison with similar patients receiving conventionally scheduled chemotherapy and radiotherapy in a concurrent trial, no difference in survival was seen in the patients with performance status grade 1 or 2, but a large difference in favour of the alternating schedule in those with grade 0 status was seen. We encourage other investigators to report the results achieved with intensive treatment in patients with WHO grade 0 performance status at the start of treatment.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed1993

Monitoring clinical trials: experience of, and proposals under consideration by, the Cancer Therapy Committee of the British Medical Research Council.

The accumulating data from all randomized trials conducted by the Cancer Therapy Committee (CTC) of the British Medical Research Council are monitored on a regular basis. However, for important practical reasons the form of this data monitoring may vary from trial to trial. Thus a trial addressing what is considered a major question in the treatment of cancer patients, (a 'pivotal' or 'high profile' trial), has a formal data monitoring committee (DMC). This is usually made up of two clinicians and one statistician who are completely independent of the trial organization and do not enter patients into the trial. Other trials, which constitute the majority, are monitored by a less formal trial progress group made up of the clinical co-ordinator and trial statistician, sometimes supplemented by a trial participant. Experience with this dual system has led to a new proposal: if the trial progress group wish to modify or stop a trial then they are required to set up and consult an ad hoc DMC for independent advice. This proposal has many advantages, including maximizing the use of resources available, while achieving the degree of objectivity in decision-making required for the many different types of cancer trials conducted by the CTC.

Clinical Trials as Topic↗
PubMed1993

Pathology review in cancer research.

Pathology observer agreement studies are clearly important in the development of new pathology assessments and in the quality control of those assessments in common use. Setting up such studies, and reporting and interpreting their results requires careful thought and statistical expertise. Investigators are advised to seek collaboration with a statistician before embarking on these studies. Pathology reference panel reviews in multicentre studies are useful for checking eligibility when there is a high level of disagreement on the eligibility criterion between local pathologists and the reference panel members, but good agreement between members of the panel. However, such situations are uncommon.

Animals↗
PubMed1993

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↗
PubMed1993

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↗
PubMed1993

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↗
PubMed1992

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↗
PubMed1991

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↗