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Biomedical subjects

M K Parmar

Publications and source records attributed to M K Parmar.

At least 55 records · Page 3Linked to original sources
PubMed1995

Randomised consent designs in cancer clinical trials.

In 1977, Zelen proposed a new design for clinical trials with the aim of increasing recruitment by avoiding some of the problems associated with obtaining informed consent. These 'randomised consent' designs have proved controversial, and have not often been used. This paper explains the statistical aspects of single and double randomised consent designs and reviews some of the ethical issues. All identified published cancer treatment trials using a randomised consent design are considered in some detail. Reasons for and against the use of these designs are summarised.

Ethics, Medical↗
PubMed1995

Adjuvant chemotherapy for soft-tissue sarcoma: review and meta-analysis of the published results of randomised clinical trials.

Fifteen published randomised trials comparing adjuvant chemotherapy with no chemotherapy in soft-tissue sarcoma (STS) were identified (1546 patients). A qualitative review and a meta-analysis of this published literature were performed. With the qualitative review it was not possible to synthesise the apparently conflicting results of individual trials. The meta-analysis of the published data suggests an improvement in survival at 2 years (OR = 0.73, 95% CI = 0.53-0.99, P = 0.044) and at 5 years (OR = 0.59, 95% CI = 0.45-0.78, P = 0.0002) in favour of chemotherapy. However, the assumptions and approximations required to conduct this quantitative summary demand that the results are interpreted with caution. The only reliable means of assessing the current evidence on whether adjuvant chemotherapy has a role in the treatment of patients with STS, is to collect, check and reanalyse individual patients data (IPD) from each trial centrally, and formally combine the results in a stratified time-to-event analysis. Such an IPD analysis is currently being undertaken by an international collaborative group.

Adult↗
PubMed1995

The application of a prognostic factor analysis for Ta.T1 bladder cancer in routine urological practice.

OBJECTIVE: To assess the reproducibility of the prognostic factor findings of Parmar et al. [1], in a routine urological practice. PATIENTS AND METHODS: The superficial tumour recurrence-free rate has been analysed for 232 newly diagnosed consecutive patients with Ta.T1 transitional cell carcinoma of the bladder. All patients were without carcinoma in situ or muscle invasion at the time of diagnosis. RESULTS: Applying the prognostic factors recommended (number of tumours at diagnosis; tumour recurrence at first 3-month cystoscopy) patients with Ta.T1 bladder cancer may be divided into three distinct groups with significantly different chances of superficial bladder tumour recurrence. CONCLUSION: Two simple clinical criteria provide a reliable guide to the likelihood of tumour recurrence in patients with Ta.T1 bladder cancer. The modification of follow-up cystoscopy schedules on this basis requires prospective study.

Carcinoma, Transitional Cell↗
PubMed1994

A unified method for monitoring and analysing controlled trials.

Group sequential methods are becoming increasingly popular for monitoring and analysing large controlled trials, especially clinical trials. They not only allow trialists to monitor the data as it accumulates, but also reduce the expected sample size. Such methods are traditionally based on preserving the overall type I error by increasing the conservatism of the hypothesis tests performed at any single analysis. Using methods which are based on hypothesis testing in this way makes point estimation and the calculation of confidence intervals difficult and controversial. We describe a class of group sequential procedures based on a single parameter which reflects initial scepticism towards unexpectedly large effects. These procedures have good expected and maximum sample sizes, and lead to natural point and interval estimates of the treatment difference. Hypothesis tests, point estimates and interval estimates calculated using this procedure are consistent with each other, and tests and estimates made at the end of the trial are consistent with interim tests and estimates. This class of sequential tests can be considered in both a traditional group sequential manner or as a Bayesian solution to the problem.

Bayes Theorem↗
PubMed1994

Proposal for changes in cystoscopic follow up of patients with bladder cancer and adjuvant intravesical chemotherapy.

A famous surgeon observed that the most important instrument for the management of superficial bladder cancer was a typewriter because it facilitated the organisation of the regular follow up examinations that are so important in controlling this disease. Cystoscopic follow up must be lifelong, and the cost, in the broadest sense, to both patient and health service is considerable. A recent study has suggested that the conventional frequency of bladder examinations may not be necessary and that most patients could be spared many cystoscopies. Instillation of cytotoxic drugs in the bladder has been shown to reduce the recurrence of tumours destroyed endoscopically and the development of new tumours elsewhere in the bladder. Because intravesical instillations are inconvenient, expensive, and may be toxic they have been reserved for patients thought to be at greatest risk of recurrence. However, two clinical trials have shown that a single cytotoxic instillation may be beneficial for low risk patients. If this is verified in everyday practice, the routine use of intravesical chemotherapy for all patients at the time of initial treatment could reduce the need for cystoscopies even further. Such changes should improve the quality of life of the 7000 new patients with superficial bladder cancer each year in England and Wales and allow savings to be made in the NHS.

Administration, Intravesical↗
PubMed1994

Pitfalls and biases in the reporting and interpretation of the results of clinical trials.

There are numerous biases (not all statistical) that can occur in the reporting and interpretation of the results of clinical trials. In this paper we review some of the major sources of such biases and propose some solutions for these problems. In particular, we review the biases that can occur in non-randomised studies; the effects of exclusion of patients after randomisation; reporting on the subset of patients receiving 'full' treatment only; comparing responders with non-responders; and emphasising secondary endpoints or subgroups. We also discuss the correct interpretation of a P-value and show the need for both estimates of the treatment effect and confidence intervals for reliable interpretation of the results. Finally, we consider the important but less well discussed problems of the interpretation of both classically 'negative' and 'positive' trials and the impact of the early stopping of the trial on the estimate of the treatment effect.

Bias↗
PubMed1994

Is double data entry necessary? The CHART trials. CHART Steering Committee. Continuous, Hyperfractionated, Accelerated Radiotherapy.

There is some controversy over the need for double data entry in clinical trials. In particular, does the number and types of errors identified with this approach justify the extra effort involved? We report the results of a study carried out to address this question. Our main outcome measure was the frequency and types of errors involved in the entry of data for the CHART (continuous, hyperfractionated, accelerated radiotherapy) trials. Data were reentered for a sample of 44 patients by a data manager other than the one making the initial entry. The second entry was then compared with the first entry. The error rate for the two entries combined was 14 per 10,000 data items (fields) (95% confidence interval 10, 19). The error rate for the initial entry alone was 15 per 10,000 fields (95% confidence interval 9.5, 22), and the vital/important error rate (defined as any error on a principal outcome measure or a major error on any other endpoint or variable) was 2.5 per 10,000 fields (95% confidence interval 0.68, 6.4). On this evidence double data entry is not performed for the CHART trials.

Carcinoma, Non-Small-Cell Lung↗
PubMed1994

Marker tumour response to Evans and Pasteur bacille Calmette-Guérin in multiple recurrent pTa/pT1 bladder tumours: report from the Medical Research Council Subgroup on Superficial Bladder Cancer (Urological Cancer Working Party).

OBJECTIVE: To compare the efficacy of Evans bacille Calmette-Guérin (BCG) and Pasteur BCG in eradicating marker bladder tumours and to compare the toxicity of the two strains. PATIENTS AND METHODS: Ninety-nine patients with multiple recurrent pTa or pT1 bladder tumours were allocated at random to six instillations at weekly intervals of either Evans BCG or Pasteur BCG. All tumours were resected except one marker tumour. At cystoscopy 3 months after randomization all tumours including the marker tumour, if still present, were resected. RESULTS: The incidence of adverse events was similar in the two groups but numbers were small and only large differences would have been detected. No statistically significant difference in efficacy regarding the response of the marker tumour or the appearance of other tumours at 3 months was noted in the two groups. There was no evidence of stage progression of the marker tumours. CONCLUSIONS: In multiple recurrent pTa or pT1 bladder tumours clearing the bladder of all except one marker tumour provides a safe and convenient way of measuring the response to intravesical therapy. No significant difference in efficacy or toxicity was detected between Evans BCG and Pasteur BCG.

Administration, Intravesical↗
PubMed1994

Superficial bladder cancer: the response of a marker tumour to a single intravesical instillation of epirubicin.

OBJECTIVE: To determine the response of a marker tumour to a single instillation of intravesical epirubicin. PATIENTS AND METHODS: Eighty-one patients (54 men, 27 women) with a mean age of 69.3 years (range 36-92) with superficial bladder cancer were randomized to receive a single instillation of intravesical epirubicin. At the initial cystoscopy all but one papillary marker tumour was resected. Subsequently the patients were randomized to receive either intravesical epirubicin at a concentration of 1 mg/ml (n = 40) or 2 mg/ml (n = 41) in 50 ml of saline for 1 h. The response of the marker tumour was determined at 3 months (first check cystoscopy). The toxicity associated with both treatments was also recorded. RESULTS: A complete response (no visible or microscopic bladder carcinoma) was observed in 46% (95% confidence interval (CI) 35-57%) of patients. No patient experienced systemic side-effects. Chemical cystitis and bladder irritability were the most frequent local side-effects, occurring in 15% (95% CI 8-24%) of the patients. CONCLUSIONS: A single instillation of intravesical epirubicin has a demonstrable effect in superficial bladder cancer. The results compare favourably with more onerous regimes. Side-effects were minimal at 1 mg/ml and acceptable at 2 mg/ml.

Administration, Intravesical↗
PubMed1993

Meta-analysis of the literature or of individual patient data: is there a difference?

The use of meta-analyses or overviews to combine formally the results of related randomised clinical trials is becoming increasingly common. However the distinction between analyses based on information extracted from the published literature and those based on collecting and reanalysing updated individual patient data is not clear. We have investigated the difference between meta-analysis of the literature (MAL) and meta-analysis of individual patient data (MAP) by comparing the two approaches using randomised trials of cisplatin-based therapy in ovarian cancer. The MAL was based on 788 patients and the MAP on 1329 and estimated median follow-ups were 3.5 and 6.5 years, respectively. The MAL gave a result of greater statistical significance (p = 0.027 vs p = 0.30) and an estimate of absolute treatment effect three times as large as the MAP (7.5% vs 2.5%). Publication bias, patient exclusion, length of follow-up, and method of analysis all contributed to this observed difference. The results of a meta-analysis of the literature alone may be misleading. Whenever possible, a meta-analysis of updated individual patient data should be done because this provides the least biased and most reliable means of addressing questions that have not been satisfactorily resolved by individual clinical trials.

Antineoplastic Agents↗
PubMed1993

Adjuvant therapy in prostatic cancer.

BACKGROUND: Prostatic cancer is an unusual malignancy because, commonly, it is slowly progressive and occurs at an age where the patient's life expectancy is short as a result of considerable competing mortality rates from other diseases. In addition, the place of radical surgery, i.e., radical prostatectomy is still not defined completely or established uniformly. METHODS: This article attempts to offer comparisons of the initial forms of primary therapy and to determine the way in which adjuvant therapy may be tested and its results assessed. RESULTS AND CONCLUSION: Additional information should come from large-scale randomized clinical trials involving several hundred patients in each treatment arm.

Combined Modality Therapy↗
PubMed1993

The design of observer agreement studies with binary assessments.

We discuss the design of observer agreement studies with binary assessments, with particular emphasis on the need for adequate sample size and the use of replicate observations. First, we present a method and tables for determining the sample size required for ensuring a desired precision for the estimate of the probability of disagreement between two observers. Second, for studies including replicate observations, we present a statistical model that allows estimation of the magnitude of within- and between-observer variation. We then derive sample sizes guaranteeing a specified precision for these estimates, present tables of these sample sizes and give examples of their use.

Confidence Intervals↗
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

Applying Bayesian ideas in drug development and clinical trials.

The Bayesian paradigm emphasizes that studies are not performed in isolation, and that external evidence can be used formally in the design, monitoring and reporting of clinical trials. A variety of tools for assessing the current evidence for treatment efficacy are presented, making use of graphical display to provide insight into ethical and efficiency issues in starting and stopping trials--these are illustrated with a trial in osteosarcoma that is currently taking place. Finally we recommend that an additional 'interpretation' section is placed in clinical reports to provide a bridge between 'results' and 'discussion'--it is this section that would contain the Bayesian perspective.

Bayes Theorem↗
PubMed1993

The results of a quantitative overview of chemotherapy in advanced ovarian cancer: what can we learn?

The results of a quantitative overview (meta-analysis) of randomised clinical trials, considering the roles of combination chemotherapy and platinum in advanced ovarian cancer are briefly reviewed. This overview collected individual patient data from 45 randomised trials, comprising information from over 8,000 women, but even with this large dataset, no firm conclusions could be reached. However, the results suggest that in terms of survival: i) immediate platinum-based therapy is better than a non-platinum regimen; ii) platinum in combination is better than single-agent platinum when used at the same dose, and iii) carboplatin and cisplatin are equally effective. These results led to the launch of two international randomised clinical trials in ovarian cancer, each of which plans to accrue 2,000 patients.

Antineoplastic Combined Chemotherapy Protocols↗