Selecting participants for clinical trials.
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Clinical Trials as Topic↗
Biomedical subjects
V J Gebski
Publications and source records attributed to V J Gebski.
Scientific background and rationale for a randomised controlled trial.
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Australia↗
Randomised controlled trials: elements of a good study.
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Double-Blind Method↗
Improving interpretation of clinical studies by use of confidence levels, clinical significance curves, and risk-benefit contours.
The process of interpreting the results of clinical studies and translating them into clinical practice is being debated. Here we examine the role of p values and confidence intervals in clinical decision-making, and draw attention to confusion in their interpretation. To improve result reporting, we propose the use of confidence levels and plotting of clinical significance curves and risk-benefit contours. These curves and contours provide degrees of probability of both the potential benefit of treatment and the detriment due to toxicity. Additionally, they provide clinicians with a mechanism of translating the results of studies into treatment for individual patients, thus improving the clinical decision-making process. We illustrate the application of these curves and contours by reference to published studies. Confidence levels, clinical significance curves, and risk-benefit contours can be easily calculated with a hand calculator or standard statistical packages. We advocate their incorporation into the published results of clinical studies.
Clinical Trials as Topic↗
Comparison of two standard chemotherapy regimens for good-prognosis germ-cell tumours: a randomised trial. Australian and New Zealand Germ Cell Trial Group.
BACKGROUND: Most patients with metastatic germ-cell tumours are cured with chemotherapy. However, the optimum chemotherapy regimen is uncertain, and there is variation in international practice. We did a multicentre randomised trial to compare two standard chemotherapy regimens for men with good-prognosis germ-cell tumours. METHODS: Good prognosis was defined by modified Memorial Sloan-Kettering criteria. The first regimen (regimen A) was based on treatment recommendations from Indiana University and comprised three cycles of 20 mg/m2 cisplatin on days 1-5, 100 mg/m2 etoposide on days 1-5, and 30 kU bleomycin on days 1, 8, and 15, repeated every 21 days. The second regimen (regimen B) was based on the control regimen of a published randomised clinical trial and comprised four cycles of 100 mg/m2 cisplatin on day 1, 120 mg/m2 etoposide on days 1-3, and 30 kU bleomycin on day 1, repeated every 21 days. The primary outcome measure was overall survival. Analysis was by intention to treat. FINDINGS: 166 patients were randomised, 83 to each regimen. The trial was stopped when the second planned interim analysis met predefined stopping rules. The median follow-up was 33 months. Overall survival was substantially better with regimen A (three vs 13 deaths, hazard ratio 0.22 [95% CI 0.06-0.77], p=0.008). This difference was due to deaths from cancer (one vs nine), and not deaths from treatment (two vs two) and remained significant after adjustment for other prognostic factors (0.25 [0.07-0.88], p=0.03). INTERPRETATION: In men with good-prognosis germ-cell tumours, the regimen developed at Indiana University is superior to the alternative regimen studied in this trial. The lower total dose and dose-intensity of bleomycin and the lower dose-intensity of etoposide in regimen B could be responsible for the worse outcome.
Adolescent↗
Adjuvant radiotherapy following neck dissection and parotidectomy for metastatic malignant melanoma.
BACKGROUND: Regional recurrence remains a problem in the management of patients with metastatic malignant melanoma in the cervical lymph nodes and parotid. In this study, the influence of the number of positive nodes, extracapsular spread, and the use of adjuvant radiotherapy on regional control and survival were analyzed. METHODS: A non-randomized, prospectively documented series of 143 patients with histologically positive nodes in the neck or parotid was analyzed. There were 152 dissected necks or parotids: 45 of these received postoperative radiotherapy, 6 x 5.5 Gy fractions over 3 weeks; 107 were not irradiated. RESULTS: The regional recurrence rate was 6.5% in the irradiated group, compared with 18.7% in the non-irradiated group (p = .055). The irradiated group, however, had more extensive nodal involvement than the non-irradiated group: 65% had two or more positive nodes, and 48% had extracapsular spread, compared with 40% and 19%, respectively, in the non-irradiated group. Survival was significantly worse when there was extracapsular spread (p < .05) or multiple node involvement (p < .01). By multivariate analysis, the use of adjuvant radiotherapy was associated with a trend toward improved regional control (p = .065), but survival was not improved. CONCLUSIONS: Adjuvant radiotherapy was associated with improved control of metastatic malignant melanoma in the neck and parotid; however, statistical significance was not reached. A prospective trial should be supported to clarify this question.
Female↗
Radical radiotherapy for early nonsmall cell lung cancer.
PURPOSE: To evaluate the results of a departmental treatment policy in a consecutive series of patients with nonsmall cell carcinoma of the lung. A second purpose was to estimate the survival of patients treated with radical intent. A third purpose was to estimate the impact of comorbidity on the selection of patients for treatment and on its outcome. METHODS AND MATERIALS: The records of 720 consecutive patients referred to a single Department of Radiation Oncology between 1979 and 1985 were reviewed. One hundred fifty patients with early stage (Stage I and II disease) were studied in detail and the results are presented for the outcome of 103 patients treated by radical radiotherapy. All patients were followed for a minimum period of five years or until death. RESULTS: Patients referred for radiation therapy were elderly and usually had squamous cell carcinoma of the lung. Comorbidity was significant as was weight loss which occurred in a third of patients. The overall survival of patients treated with radical intent was 13%. In a small subgroup of patients with T1 tumors without weight loss and aged under 70 survival reached 50% at 5 years with no treatment-related mortality and with insignificant treatment-related morbidity. CONCLUSION: Highly selected subsets of patients suitable for treatment with radiotherapy can be defined equally as well as highly selected subsets of patients can be selected for surgery. Treatment outcome can be surprisingly good in these subsets indicating that the treatment of nonsmall cell lung cancer, particularly in older patients without comorbidity should not automatically be by a surgical approach.
Adult↗
Dynamic balanced randomization for clinical trials.
Common methods of treatment allocation for multi-centre and/or stratified randomized clinical trials can result in substantial differences between the number of patients allocated to each treatment arm. This can occur in the overall trial for a permuted block design or within individual institutions/strata when using a minimization scheme. This may lead to a bias in the result. Also, these procedures can be predictable, with the possibility of an investigator-introduced selection bias. An easily implemented method of randomization is proposed which attempts to overcome these problems by balancing treatment allocations both within strata and across the trial as a whole. The method keeps a running tally on total treatment allocation numbers at all stratification levels. When a patient accrues a hierarchical decision rule is applied, and the allocation is deterministic if certain pre-defined limits are exceeded, and random otherwise. The method is an extension of the big stick design of Soares and Wu, and is related to both Zelen's key number randomization methods and the schemes of Nordle and Brantmark. Simulation studies are used to demonstrate that major imbalances possible with other schemes do not occur using this method, and that the potential for selection bias is much reduced.
Algorithms↗
Methadone dose and heroin use during maintenance treatment.
A retrospective study examined the association between methadone dose and in-treatment heroin use as measured by fixed-interval urine testing in a cohort of 62 patients admitted to an Australian maintenance program. Urinalysis and methadone dose data were collected on subjects for a maximum two years and were analysed using Zeger & Liang's (1986) method for modelling longitudinal data. While allowing for patient descriptors and the time period in which urine samples were collected, the relative odds of using heroin were reduced by 2% for every 1 mg increase in the maintenance dose of methadone. It is estimated that the odds of patients maintained on 40 mg of methadone using heroin were 2.2 times those of patients maintained on 80 mg.
Adult↗
Prediction of life-expectancy in hospice patients: identification of novel prognostic factors.
The prediction of life-expectancy in terminally ill patients is important both for medical and social reasons but is widely recognized as being inaccurate. In this study we prospectively collected data items which we proposed might influence survival on 148 consecutive patients at first admission to one of two hospices. Of the 19 parameters collected, four were associated with a significantly shortened survival. These were low performance status (PS), requirement for admission at first referral to the palliative care service, elevated serum bilirubin, and hypotension. Factors previously identified as predictive of shortened survival such as hyponatraemia, weight loss, confusion and tumour type were not confirmed as statistically significant independent variables. We plan to collect these data items on future patients in order to test the validity of these results.
Adult↗
The cost of treating small cell lung cancer.
OBJECTIVE: To determine the cost of treating small cell lung cancer (SCLC) and to assess quality-adjusted survival in these patients. DESIGN: Retrospective analysis. SETTING: Westmead Hospital, a tertiary referral institution. PATIENTS: Consecutive sample of 31 patients with histologically proved SCLC, treated between January 1987 and December 1987. MAIN OUTCOME MEASURES: The cost of investigation, hospitalisation, chemotherapy, radiotherapy and follow-up of patients overall and for those with limited and extensive disease respectively. Quality-adjusted survival was based on a Q-TWiST analysis. RESULTS: The median overall cost per patient was $14,413 (range, $1188-$39,598) for all patients and for limited disease and extensive disease was $18,234 (range, $1914-$39,598) and $13,177 (range, $1188-$32,798) respectively. The two major costs were hospitalisation (42%) and chemotherapy (18%). Radiotherapy accounted for 11% of all costs. The Q-TWiST analysis suggests that for patients with limited disease, quality-adjusted survival is similar to absolute survival. CONCLUSIONS: The treatment of SCLC at our institution was expensive but the cost may be reduced by reduction in the duration of hospitalisation, the use of less expensive combination drug regimens, or the use of "true" outpatient chemotherapy. Despite intensive therapy, patients with limited disease maintained a reasonable quality of life.
Aged↗
Breast conservation: long-term Australian data.
Long-term data on the management of early breast cancer in Australia by conservative surgery and radiation therapy is limited. To examine this issue we reviewed our experience of 131 patients with Stage I or II breast cancer treated between November 1979 and December 1985. Ninety patients had a T1 tumor and 41 a T2 tumor. The extent of surgery varied from a local excision (LE), a wide local excision, to a quadrantectomy or partial mastectomy. Sixty-two per cent of patients also had an axillary dissection. One hundred and nineteen patients were treated using 6Mev photons to the whole breast (Median dose; 50 Gy) +/- regional nodes followed by a single plane Iridium-192 boost to the primary tumor site (median dose; 30 Gy). Ten patients did not receive a boost and two elderly patients were treated with an implant only. The median follow-up of surviving patients was 83 months (range, 51-133 months). Six other patients were lost to follow-up at a median of 48 months (range, 4-62). The pattern of first relapse is: breast alone, 7.0%; breast + distant, 0.75%; breast + nodes, 0.75%; regional nodes only, 0.75%; and distant disease, 18%. The extent of surgery did not influence the probability of a recurrence in the primary tumor region. The time to a breast recurrence ranged from 12 to 127 months (median, 61 months). The 5-year actuarial rate of a breast recurrence was 4.5%. The 5-year freedom from distant relapse was 80%. The complications of treatment were acceptable. These included rib fracture (5%), symptomatic pneumonitis (4%), fat necrosis or fibrosis requiring surgery (4.5%), severe arm edema (4.5%). The treatment of the axilla by both surgery plus radiation therapy was associated with a moderate or severe arm edema rate of 29% compared to 8% for surgery alone and 6% for radiation therapy alone. Our long-term data indicate that conservative surgery plus radiation therapy is associated with low rates of breast cancer recurrence which are independent of the extent of surgical resection. Complications were acceptably low provided that the axilla was treated by surgery or radiation therapy but not by both modalities.
Adult↗
Ponderal index: a better definition of the 'at risk' group with intrauterine growth problems than birth-weight for gestational age in term infants.
A study was undertaken at Nepean Hospital, Penrith to compare the outcome of pregnancies with growth retarded infants; 2,508 consecutive births were analyzed between August 1, 1989 and April 30, 1990. A comparison of outcome was made between infants whose birth-weight for gestational age was below the tenth percentile and infants who had a low ponderal index from 37 weeks' gestation. The Caesarean section delivery and fetal distress rates were significantly higher for infants with a low ponderal index than for infants with a low birth-weight. Ponderal index appears to be a better measure of infants with intrauterine growth problems than birth-weight percentiles.
Binomial Distribution↗
An evaluation of planned early postnatal transfer home with nursing support.
A community-based programme of planned early postnatal transfer home with the continuity of hospital nursing care was instituted in a defined geographic area of the western suburbs of Sydney in 1983. Mothers were offered the option of discharge in 24-48 hours after delivery, with home visits by a hospital midwife, subject to certain medical and social criteria. An evaluation of the programme in terms of morbidity, psychosocial impact on the family and costs was undertaken. For evaluation, a quasi-experimental study of parallel groups was designed in preference to randomized selection as it was believed that the personal choice would be fundamental to the success of the scheme. A contemporary control group was achieved with volunteer mothers who opted for the traditional five- to seven-day hospital stay. Studies of maternal response and the partner's response and adjustment were undertaken, including the administration of questionnaires that were designed to detect the presence of mild postnatal depression. No increased morbidity occurred in the early discharge group. The early discharge group performed more favourably on the questionnaire that was designed to measure their postpartum adjustment. Continued postnatal domiciliary surveillance reduces the risk that early neonatal pathological changes, especially jaundice, may be overlooked.
Adaptation, Psychological↗
Platelets and uric acid in the prediction of preeclampsia.
Fifty-four pregnancies that were subsequently complicated by preeclampsia had platelet parameters and uric acid levels measured during pregnancy. The expected fall in platelet count and rise in platelet volume parameters and uric acid levels beyond those that occur in normal pregnancy were seen only in the week before delivery.
Blood Platelets↗
The need for palliative care services in a general hospital.
A population census in a major Sydney teaching hospital showed that, at any one time, between 5% and 10% of inpatients were in the terminal stages of their disease and, thus, were in need of palliative care. These needs challenge conventional patterns of practice in large hospitals and illustrate the magnitude of the problems arising from the generally observed trend towards hospitalization of the dying.
Hospitals, General↗
Practical approaches to minimize problems with missing quality of life data.
Missing information on quality of life (QOL) is a significant problem in many cancer trials particularly for patients with advanced disease, where clinical deterioration may be a reason for not responding to quality of life assessments. Examples from four clinical trials are presented where non-respondents to quality of life assessments have poorer health than respondents. In this context, auxiliary outcome variables, such as health status, may be useful proxies in assessing the impact of missing QOL data on estimated treatment effects. This approach is illustrated in a trial of palliative treatment in advanced cancer. A method for imputation of missing QOL data based on auxiliary outcome variables is also illustrated. However, the most effective method of minimizing the problem of missing data is in designing the trial with preventative strategies in place. Since some missing data due to deteriorating health may still occur, the design should include the collection of auxiliary QOL information. Preventative strategies are illustrated with an ongoing trial in advanced breast cancer.
Breast Neoplasms↗
A longitudinal analysis of predictors of quitting smoking among participants in a self-help intervention trial.
Predictors of 7-day abstinence from smoking were identified among participants in a randomized self-help smoking-cessation intervention trial conducted from 1985 to 1988 in Seattle, WA. Subjects were adult smokers belonging to a health maintenance organization who responded to an offer of free quitting assistance. Self-reported smoking status was assessed at 8, 16, and 24 months following enrollment. Predictors of abstinence were identified by longitudinal data analysis using Generalized Estimating Equations (GEEs), a modeling approach which handles repeated-measures data and accommodates time-dependent as well as time-independent covariates. Seventeen items emerged as significant (p < .05) predictors, with odds ratios ranging from 1.3 to 2.1. While much of the previous work in smoking-cessation research has focused on demographic and smoking history variables, results of this study indicate that emphasis should also be placed on psychosocial/motivational factors and quitting activities as important predictors of abstinence. Longitudinal data analysis represents a powerful technique for handling correlated (repeated measures) data, which may prove very useful for future studies of smoking cessation as well as other dynamic processes.
Adult↗