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D Machin

Publications and source records attributed to D Machin.

At least 73 records · Page 4Linked to original sources
PubMed1997

Thirty years of Medical Research Council randomized trials in solid tumours.

This paper reviews the survival outcome from the randomized Phase III trials in solid tumours published on behalf of, or in collaboration with, the Cancer Therapy Committee (CTC) of the British Medical Research Council over a 30-year period to 31 December 1995. We review briefly the innovations in statistical methodology that have occurred over the period. We also note the ways in which standards of reporting the trials have improved, with more recent publications including, for example, estimates of the size of effect and confidence intervals. In all, 32 trials, involving over 5000 deaths in more than 8000 patients, have been published. Tumour types have included bladder, bone, brain, cervix, colon and rectum, head and neck, kidney, lung, ovary, prostate and skin. This paper presents a bibliography of these trials and gives details of the treatment comparisons made, the numbers of patients randomized and included in the analysis for each treatment arm, the observed numbers of deaths, and an estimate of the hazard ratio with associated 95% confidence intervals. The bibliography also indicates the main endpoint of each trial, whether recurrence-free survival or survival, and whether the trial was aimed at finding a difference or showing equivalence. The MRC trials have made an impact on both clinical practice and research activities. For example, the lung cancer programme has helped to establish the role of chemotherapy in small cell lung cancer and has developed better palliative treatment for non-small cell lung cancer. Trials of the radiosensitizer misonidazole have demonstrated that it has no role in the treatment of a number of cancers, trials of hyperbaric oxygen have defined the biological activity of this approach, and the appropriate dose of radiotherapy in patients with brain tumours has been found. The individual trials recruited between 44 and 824 patients (median 213). A better measure of the information in a trial is the number of deaths reported, which varied from 28 to 661 (median 145). A large proportion of the comparisons (8/29 or 28%) anticipating a survival difference, demonstrated such a difference at the 5% level of significance. Despite this, it is concluded that some of the trials should have been larger. In such cases, hindsight suggests either that an overoptimistic view of the anticipated survival benefit was taken at the design stage, or, for equivalence trials, the planned confidence interval was too wide for definitive statements to be made. As a consequence, the current CTC profolio of ongoing randomized trials open to patient accrual at 1 January 1996 have a projected median size of 600 and range from 120 to 2000 patients.

Clinical Trials, Phase III as Topic↗
PubMed1997

Quality of life assessment in clinical trials--guidelines and a checklist for protocol writers: the U.K. Medical Research Council experience. MRC Cancer Trials Office.

Many clinical trials groups now routinely consider including Quality of Life (QoL) assessment in trials. Indeed, several have policies stating that QoL should be considered as a potential endpoint in all new trials and that if it is not to be evaluated the applicants should justify not doing so. However, inclusion of QoL in clinical trials presents a number of difficult organisational issues, and serious problems in compliance have frequently been reported. Thus, in multicentre clinical trials many of the expected QoL questionnaires fail to be successfully completed and returned, although a few groups have claimed high success rates. However, it is well recognised that if questionnaires are missing, there may be bias in the interpretation of trial results, and the estimates of treatment differences and the overall level of QoL may be inaccurate and misleading. Hence it is important to seek methods of improving compliance, at the level of both the participating institution and the patient. We describe a number of methods for addressing these issues, which we suggest should be considered by all those writing clinical trial protocols involving QoL assessment. These are based upon over a decade of experience with assessing QoL in Medical Research Council (MRC) cancer clinical trials. In particular, we provide a checklist for points that should be covered in protocols. Examples are given from a range of current MRC Cancer Trials Office protocols, which it is proposed might act as templates when writing new protocols.

Clinical Protocols↗
PubMed1997

Prophylactic cranial irradiation is indicated following complete response to induction therapy in small cell lung cancer: results of a multicentre randomised trial. United Kingdom Coordinating Committee for Cancer Research (UKCCCR) and the European Organization for Research and Treatment of Cancer (EORTC)

Prophylactic cranial irradiation (PCI) reduces the risk of cranial metastasis in small cell lung cancer (SCLC), but the magnitude and value of this reduction, the risks of radiation morbidity and whether PCI influences survival are unclear. We conducted a randomised trial in patients with limited-stage SCLC who had had a complete response to induction therapy. Initially, patients were randomised equally to (1) PCI 36 Gy in 18 daily fractions, (2) PCI 24 Gy in 12 fractions and (3) no PCI; subsequently, to increase the rate of accrual, randomisation was to clinicians' choice of PCI regimen versus no PCI (at a 3:2 ratio). The endpoints were appearance of brain metastases, survival, cognitive function, and quality of life (QoL). Three hundred and fourteen patients (194 PCI, 120 No PCI) were randomised. In the revised design, the most commonly used PCI regimens were 30 Gy in 10 fractions and 8 Gy in a single dose. With PCI, there was a large and highly significant reduction in brain metastases (HR = 0.44, 95% CI 0.29-0.67), a significant advantage in brain-metastasis-free survival (HR = 0.75, 95% CI 0.58-0.96) and a non-significant overall survival advantage (HR = 0.86, 95% CI 0.66-1.12). In both groups, there was impairment of cognitive function and QoL before PCI and additional impairment at 6 months and 1 year, but no consistent difference between the two groups and thus no evidence over 1 year of major impairment attributable to PCI. PCI can safely reduce the risk of brain metastases. Further research is needed to define optimal dose and fractionation and to clarify the effect on survival. Patients with SCLC achieving a complete response to induction therapy should be offered PCI.

Adult↗
PubMed1997

Randomized trials with quality of life endpoints: are doctors' ratings of patients' physical symptoms interchangeable with patients' self-ratings?

The assessment of physical symptoms is a key component of quality of life studies in palliative care, but is often hampered by missing data from patient-completed questionnaires. In two large multicentre randomized trials of palliative treatment conducted by the Medical Research Council Lung Cancer Working Party, Involving over 700 patients, patients completed Rotterdam Symptom Checklists and doctors reported on eleven of the same physical symptoms at each assessment, using the same 4-point severity scale. Ratings by doctors and patients were compared with respect to compliance, severity, and outcomes for the respective trials. Doctors provided more data than patients: 66% vs. 52% in the first 6 months in one trial, 58% vs. 61% in the other. Comparisons of over 33,000 symptom assessments showed 78% complete agreement between doctor and patient, 18% disagreement by one, 4% two, and 1% three grades (complete disagreement). There was no change in levels of agreement over time, but increasing disagreement with increasing symptom severity, and a consistent bias towards doctors underestimating severity. Nevertheless, the two methods of data collection resulted in similar between-treatment conclusions. Therefore, in randomized trials the doctors' assessments of key physical symptoms may be sufficient for the between-treatment comparison. However, the fact that doctors underestimate symptom severity 15% of the time has important implications for palliative interventions.

Attitude of Health Personnel↗
PubMed1997

Quality of life of Danish women: population-based norms of the EORTC QLQ-C30.

The aim of this was to derive population-based norms for women completing the EORTC QLQ-C30 version 1 which is designed for use with patients who have cancer. The study was conducted using two different questionnaires: one designed for use in female patients with breast cancer, the other for those with gynaecological cancers, but both including the EORTC QLQ-C30. The women were drawn from the Danish Central Population Register without knowledge of their health status and divided at random between the two questionnaires. All procedures for collecting data were identical. The response rate for those receiving the gynaecological cancer (GS) questionnaire was 49% and it was 71% for the breast cancer (BS) questionnaire. Detailed comparison between the two samples revealed several EORTC QLQ-C30 items showing a clear difference in distribution of scores between them. Because of this and the possible bias due to the relative low age-related response rate in GS, only the results from the BS are used for constructing norms. The norms cover all 30 single items on the EORTC QLQ-C30 and the nine derived scales, for women in four 10-year age groups commencing at 30 years and for those aged 70-75. Clear trends in, for example, declining ability to undertake strenuous activity are illustrated and quantified. Levels of certain symptoms, such as pain, are surprisingly high although it is recognized that the population sampled will contain a proportion of women with active disease including cancer. We recommend the use of these norms both as an aid to the clinical assessment of an individual patient, and to assist in the interpretation of clinical trial and longitudinal quality of life data. As a secondary result, we note that a population-based sample will have a lower response rate to a questionnaire with more questions, especially if many of these extra questions are on sexual issues.

Adult↗
PubMed1997

Sample sizes for randomized trials measuring quality of life in cancer patients.

This paper describes the methods appropriate for calculating sample sizes for clinical trials assessing quality of life (QOL). An example from a randomized trial of patients with small cell lung cancer completing the Hospital Anxiety and Depression Scale (HADS) is used for illustration. Sample size estimates calculated assuming that the data are either of the Normal form or binary are compared to estimates derived using an ordered categorical approach. In our example, since the data are very skewed, the Normal and binary approaches are shown to be unsatisfactory: binary methods may lead to substantial over estimates of sample size and Normal methods take no account of the asymmetric nature of the distribution. When summarizing normative data for QOL scores the frequency distributions should always be given so that one can assess if non-parametric methods should be used for sample size calculations and analysis. Further work is needed to discover what changes in QOL scores represent clinical importance for health technology interventions.

Adult↗
PubMed1997

Geographical variation in the standardized years of potential life lost ratio (SYPLR) in women dying from malignancies of the breast in England and Wales.

Geographical variation in the standardized years of potential life lost ratio (SYPLR) in women aged 20-74 dying from breast cancer has been mapped by local authority district in England and Wales and compared with the variation as described by the standardized mortality ratio (SMR). The geographical distribution of areas of low and high SMRs is similar to that observed some 15 years earlier, showing an increase from north to south. In contrast, the pattern of SYPLRs shows a less obvious trend. Years of life lost because of breast cancer mortality were particularly high in eight of the 401 county districts (SYPLR 1.22-1.48) and particularly low in nine (0.60-0.86). Mapping SYPLRs for breast cancer gives a different pattern from mapping SMRs, and one which is possibly more appropriate for targeting resources in circumstances in which death at younger age will have major social consequences. Care is required in interpreting maps indicating high and low rates in the presence of multiple comparisons. However, the range of values observed is suggestive of the need to investigate districts with contrasting values of SYPLR with respect to the inter-relationships between sociodemographic characteristics, duration of symptoms, clinical presentation and treatment efficacy.

Adult↗
PubMed1996

Radiotherapy with or without hyperthermia in the treatment of superficial localized breast cancer: results from five randomized controlled trials. International Collaborative Hyperthermia Group.

PURPOSE: Claims for the value of hyperthermia as an adjunct to radiotherapy in the treatment of cancer have mostly been based on small Phase I or II trials. To test the benefit of this form of treatment, randomized Phase III trials were needed. METHODS AND MATERIALS: Five randomized trials addressing this question were started between 1988 and 1991. In these trials, patients were eligible if they had advanced primary or recurrent breast cancer, and local radiotherapy was indicated in preference to surgery. In addition, heating of the lesions and treatment with a prescribed (re)irradiation schedule had to be feasible and informed consent was obtained. The primary endpoint of all trials was local complete response. Slow recruitment led to a decision to collaborate and combine the trial results in one analysis, and report them simultaneously in one publication. Interim analyses were carried out and the trials were closed to recruitment when a previously agreed statistically significant difference in complete response rate was observed in the two larger trials. RESULTS: We report on pretreatment characteristics, the treatments received, the local response observed, duration of response, time to local failure, distant progression and survival, and treatment toxicity of the 306 patients randomized. The overall CR rate for RT alone was 41% and for the combined treatment arm was 59%, giving, after stratification by trial, an odds ratio of 2.3. Not all trials demonstrated an advantage for the combined treatment, although the 95% confidence intervals of the different trials all contain the pooled odds ratio. The greatest effect was observed in patients with recurrent lesions in previously irradiated areas, where further irradiation was limited to low doses. CONCLUSION: The combined result of the five trials has demonstrated the efficacy of hyperthermia as an adjunct to radiotherapy for treatment of recurrent breast cancer. The implication of these encouraging results is that hyperthermia appears to have an important role in the clinical management of this disease, and there should be no doubt that further studies of the use of hyperthermia are warranted.

Breast Neoplasms↗
PubMed1996

Guidelines for reporting results of quality of life assessments in clinical trials.

Clinical trials involving quality of life measurement published in the literature suffer from important weaknesses due to the lack of information on numerous topics. The psychometric properties of the instruments are often lacking as well as data on the number of patients treated and analyzed. The handling of missing data is rarely documented. In order to facilitate the reporting of trials and the evaluation of published results, this article proposes a set of general guidelines for the reporting of clinical trials which include a quality of life assessment. A checklist designed to assist authors is appended.

Clinical Trials as Topic↗
PubMed1996

Long-term survival in small cell lung cancer: the case for a standard definition. Medical Research Council Lung Cancer Working Party.

OBJECTIVES: This paper investigates whether a particular time point can be recommended as the standard definition for long-term survival (LTS) in small cell lung cancer (SCLC). DESIGN: A review of the literature specifically referring to long-term survival in SCLC in the title. Individual and updated survival data from 2196 patients entered into six Medical Research Council (MRC) SCLC randomised trials to investigate changes in the hazard, or risk of death, over time. Examination of subgroups to identify different hazard patterns. SETTING: World-wide literature and patients recruited to SCLC trials conducted by the MRC Lung Cancer Working Party (LCWP). SUBJECTS: Papers accessed through computerised literature and hand searches and 2196 patients from six randomised clinical trials in SCLC conducted by the MRC LCWP. RESULTS: In all, 111 publications were identified by the literature searches. Although the majority defined LTS as 2 years, the definitions ranged from 18 months to greater than 5 years. There thus appears to be no agreed standard definition. The daily hazard was plotted for the large series of patients entered into the MRC LCWP SCLC trials to observe any patterns of change. There was an approximately constant daily hazard of 0.0035 during the first 2 years from randomisation, and following a transitional period, there was a further approximately constant, but smaller, daily hazard of 0.00035 from 3 years onwards. When subgroups of patients were examined this transition to a lower risk was observed in patients with limited disease, but patients with extensive disease remained at a high constant hazard throughout. It is suggested that 3 years should be adopted as the standard definition of LTS in SCLC, and that studies should always report limited and extensive stage patients separately.

Aged↗
PubMed1996

Randomized trial of palliative two-fraction versus more intensive 13-fraction radiotherapy for patients with inoperable non-small cell lung cancer and good performance status. Medical Research Council Lung Cancer Working Party.

In patients with non-metastatic but inoperable non-small cell lung cancer that is locally too extensive for radical radiotherapy (RT), but who have good performance status, it is important to determine whether thoracic RT should be the minimum that is required to palliate thoracic symptoms or whether treatment should be more intensive, with the aim of prolonging survival. A total of 509 such patients from 11 centres in the UK between November 1989 and October 1992 were admitted to a trial comparing palliative versus more intensive RT with respect to survival and quality of life. They were allocated at random to receive thoracic RT with either 17 Gy in two fractions (F2) 1 week apart (255 patients) or 39 Gy in 13 fractions (F13) 5 days per week (254 patients). Survival was better in the F13 group, the median survival periods being 7 months in the F2 group compared with 9 months in the F13 group, and the survival rates 31% and 36% at one year and 9% and 12% at 2 years, respectively (hazard ratio = 0.82; 95% CI0.69-0.99). There was a suggestion of a trend towards greater benefit in fitter patients. Metastases appeared earlier in the F2 group. As recorded by patients using the Rotterdam Symptom Checklist, the commonest symptoms on admission were cough, shortness of breath, tiredness, lack of energy, worrying and chest pain. These were more rapidly palliated by the F2 regimen. Psychological distress was generally lower in the F13 group. Three patients (two F13, one F2) exhibited evidence of myelopathy. As recorded by patients using a diary card, 76% of the F2 compared with 81% of the F13 patients had dysphagia associated with their RT. This was transient, lasting for a median of 6.5 days in the F2 group compared with 14 days in the F13 group. In conclusion, the F2 regimen had a more rapid palliative effect. In the F13 group, although treatment-related dysphagia was worse, survival was longer.

Aged↗
PubMed1996

Radiation myelopathy: estimates of risk in 1048 patients in three randomized trials of palliative radiotherapy for non-small cell lung cancer. The Medical Research Council Lung Cancer Working Party.

Radiation myelopathy (RM) is an uncommon but serious late effect of thoracic radiotherapy (RT), which oncologists try to avoid by careful planning and dose selection. Five patients with RM are described from among 1048 with inoperable non-small cell lung cancer treated with palliative RT in three randomized trials conducted by the Medical Research Council Lung Cancer Working Party. Seven RT regimens were used in these trials: 10 Gy in a single fraction on one day (10/1/1) (114 patients), 17/2/8 (524 patients), 27/6/11 (47 patients), 30/6/11 (36 patients), 30/10/12 (88 patients), 36/12/16 (86 patients) and 39/13/17 (153 patients). Of the five instances of RM, three occurred in the 524 patients treated with 17 Gy in two fractions, and two in the 153 treated with 39 Gy in 13 fractions. The estimated cumulative risks of RM by 2 years were 2.2% for the 17 Gy group, 2.5% for the 39 Gy group, and 0% for the remainder, but the annual risks had wide 95% confidence intervals, indicating that the distribution of episodes among the seven regimens could have been random. Nevertheless, calculation of cord doses in terms of the total doses that would have an equivalent biological effect if given in 2 Gy fractions (LQED2 values) from our data for different values of the ratio of the linear quadratic parameters of the cell survival curve (alpha/beta), suggest that the best estimate of alpha/beta is less than 3 Gy, and possibly close to 2 Gy. This emphasizes the sensitivity of human spinal cord to changes in fraction size. We recommend that, when the computed LQED2 for a schedule of treatment that includes the thoracic spinal cord (assuming alpha/beta = 2 for cord) exceeds 48 Gy, oncologists should consider reducing the dose to the cord.

Aged↗
PubMed1996

The role of post-operative radiotherapy in non-small-cell lung cancer: a multicentre randomised trial in patients with pathologically staged T1-2, N1-2, M0 disease. Medical Research Council Lung Cancer Working Party.

The role of post-operative radiotherapy for patients with non-small-cell lung cancer (NSCLC) is unclear despite five previous randomised trials. One deficiency with these trials was that they did not include adequate TNM staging, and so the present randomised trial was designed to compare surgery alone (S) with surgery plus post-operative radiotherapy (SR) in patients with pathologically staged T1-2, N1-2. M0 NSCLC. Between July 1986 and October 1993, 308 patients (154 S, 154 SR) were entered from 16 centres in the UK. The median age of the patients was 62 years, 74% were male, > 85% had normal or near normal levels of general condition, activity and breathlessness, 68% had squamous carcinoma, 52% had had a pneumonectomy, 63% had N1 disease and 37% N2 disease. SR patients received 40 Gy in 15 fractions starting 4-6 weeks post-operatively. Overall there was no advantage to either group in terms of survival, although definite local recurrence and bony metastases appeared less frequently and later in the SR group. In a subgroup analysis, in the N1 group no differences between the treatment groups were seen, but in the N2 group SR patients appeared to gain a one month survival advantage, delayed time to local recurrence and time to appearance of the bone metastases. There is, therefore, no clear indication for post-operative radiotherapy in N1 disease, but the question remains unresolved in N2 disease.

Aged↗
PubMed1996

Assessment of quality of life in clinical trials of the British Medical Research Council.

This article describes aspects of the way the Cancer Therapy Committee of the British Medical Research Council incorporates quality-of-life (QOL) assessments in randomized clinical trials in patients with cancer. The steps taken in incorporating QOL assessments in individual trial protocols are described. The aspects described concern problems associated with choice of instruments, time of assessment, sample size, and analysis. A protocol for patients with small-cell lung cancer that compares oral etoposide with intravenous multidrug chemotherapy is used for illustration.

Clinical Trials, Phase III as Topic↗